Novel triplicate compounds and their applications

Abstract

The present invention relates to a novel trifunctional compound comprising at least one target substance T and at least one payload P, wherein, in addition to a covalent warhead that may be present in the target substance T itself, the trifunctional compound further comprises a covalent warhead C capable of forming a reversible or irreversible covalent linkage with at least one protein or tissue (e.g., FAP protein or other biomolecules in vivo). The present invention further relates to drug compositions and reagent kits comprising the trifunctional compound, as well as applications for using the trifunctional compound in the diagnosis or treatment of diseases.

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical field, and more specifically to a trifunctional compound comprising a covalent warhead, a drug composition thereof, and its use in the diagnosis or treatment of diseases. [Background technology]

[0002] Radiotherapy, surgery, and chemotherapy have traditionally been the three main therapies used by humankind to combat cancer. Radiopharmaceuticals (abbreviated as "radiotherapy") can be considered an internal irradiation form of radiotherapy and, compared to conventional radiotherapy, have the advantage of so-called powerful "cross-firing," making them one of the few treatment options for patients with advanced cancer that has metastasized throughout the body. In terms of its mechanism of action, radiotherapy promotes the death of cancer cells by cleaving DNA strands with high-energy ionizing radiation produced by the decay of medical isotopes. This requires extremely high tumor selectivity / targeting and a certain degree of tumor uptake and retention, and it is necessary to target and deliver a sufficient dose only to the tumor while limiting damage to surrounding normal tissue.

[0003] Radionuclide ligand conjugates (RLCs) are one of the main drug forms of radiopharmaceuticals, generally a binary conjugate of a chelating agent, a linker, and a target ligand. The ligand portion can be a small molecule, polypeptide, nucleic acid aptamer, antibody, etc. The linker mainly functions as a spacer, preventing a decrease in target molecule affinity due to binding with the chelating agent and regulating pharmacokinetic properties. The chelating agent portion can be coordinated with different diagnostic / therapeutic radionuclides by changing the same molecule or the chelating agent, depending on different diagnostic and therapeutic needs, offering the advantage of "integrating diagnosis and treatment." Therefore, while targetability and safety are generally average, molecules with high tumor uptake are still expected to be applied to molecular imaging diagnostics. Diagnostic radionuclides are classified into two types, and positron-electron radionuclides that can be tracked by positron emission tomography (PET-CT) (e.g., 18 F, 68 Ga, 64 Cu,86 Y, 89 Zr, etc.), and nuclides having γ-ray emission that can be traced by single photon emission computed tomography (SPECT-CT) (e.g., 99m Tc, 133 Xe, 123 I, 91m Kr, etc.). Therapeutic nuclides include β-emitting nuclides (β-emitter, e.g., 90 Y, 124 I, 151 Tb, 177 Lu, etc.) and α-emitting nuclides (α-emitter, e.g., 211 At, 212 Pb, 213 Bi, 223 Ra, 225 Ac, etc.). Also, those in which part of the chelating agent is replaced with an optical dye (dye) that absorbs and emits light of different wavelengths become optical probes and are also used for optical imaging at the level of cells and living organisms, etc.

[0004] In recent years, diagnostic / therapeutic RLCs based on prostate-specific membrane antigen (PSMA) and somatostatin receptor (SSTR) have obtained FDA / EU approval and are promoting the entry of more RLC drugs into clinical research. Since PSMA and SSTR are expressed only in prostate cancer and neuroendocrine tumors respectively and do not have broad efficacy against tumors, researchers around the world are pursuing the development of more RLC drugs.

[0005] Fibroblast activation protein (FAP-α) is a type II membrane-bound glycoprotein and also a member of the serine protease family, and is overexpressed in cancer-associated fibroblasts (CAFs) and activated fibroblasts at wound healing / inflammatory sites. As a broad cancer target, it is expressed in more than 90% of epithelial tumor microenvironments such as pancreatic, colon, breast, and ENT (ear, nose, and throat) cancers. In 2019, Kratochwil et al. reported in a clinical trial that quinoline-containing 68The Ga-FAPI-04 small molecule nuclear medicine drug has been demonstrated to be able to detect up to 28 types of cancer (J. Nucl. Med. 2019, 60, 801). Due to its extremely low expression in normal tissues, FAP-α is not only a promising biomarker for tumor diagnosis and prognosis, but also a promising target for radiopharmaceutical therapy. Since Lindner et al. first applied FAPI-04 clinically in 2018 (J. Nucl. Med. 2018, 59, 1415), PET imaging and radiotherapy based on FAP-α inhibitors (FAPI) have been studied for their application to various cancers and non-cancerous diseases.

[0006] Covalent inhibitors are a type of inhibitor that exerts its biological function by irreversibly binding to target protein residues via covalent bonds, and morphologically, most are small molecule kinase inhibitors (Eur. J. Med. Chem. 2017, 138, 96). Generally, covalent inhibition is a two-step process (Figure 1): first, the inhibitor reversibly binds to the target enzyme, bringing the warhead in the small molecule close to the enzyme's active residue; then, a binding reaction occurs between the inhibitor warhead and the residue, forming a covalent bond. Common nucleophilic amino acid residues that can undergo covalent reactions include cysteine, serine, tyrosine, lysine, arginine, and glutamic acid. Common covalent warheads are generally electrophiles and are classified into two types depending on whether the covalent bond they form is reversible or irreversible. One type typically forms irreversible covalent bonds, such as propyleneamide, epoxy, chloroacetyl, and sulfonyl fluoropolymers, while the other type typically forms reversible covalent bonds, such as cyanopolymers and ketone carbonyl polymers. Covalent warheads that can be used in vivo and ultimately become pharmaceuticals require a balance between activity and stability. Promising covalent warheads are "latent electrophiles," which are activated only when bound to specific proteins, accelerating covalent bond formation and thus minimizing off-target toxicity associated with warhead activity. In 2014, Sharpless et al. developed a novel "potential electrophilic" fluorosulfate (Angew. Chem. Int. Ed. 2014, 53, 9430) based on hexavalent sulfur click chemistry (SuFEx). Compared to the most common propyleneamide-based covalent warheads that react only with cysteine ​​residues, it not only offers superior in vivo stability but also has the potential to become a novel drug covalent warhead because, after binding to the target protein, it can covalently link to a wider range of adjacent lysine, histidine, tyrosine, and serine residues.Similarly promising examples include phosphorus (pentavalent)-fluorine covalent warheads, such as (hetero)aryl phosphoramidofluoridates. [Overview of the project]

[0007] This invention, building upon prior art and conducting innovative research, unexpectedly achieves the following effects by introducing a covalent warhead containing a (hetero)aromatic group-substituted halogenated sulfate ester or (hetero)aromatic group-substituted phosphoamide fluoride into a drug containing a target substance and payload: it modulates the pharmacokinetics of the drug, significantly improving drug uptake and retention in target organs, such as tumors, while simultaneously ensuring relatively low levels of uptake and retention in non-target organs, such as sustainably reducing uptake in the liver, kidneys, and / or blood pools. Therefore, compared to conventional drug modification strategies, drugs engineered by the strategy of this invention have a high target-to-background ratio, can optimize the performance (sensitivity and / or specificity) of probe drugs in diagnosis, and can expand the safe therapeutic window and improve bioavailability in treatment, thus enabling enhanced therapeutic efficacy while ensuring safety.

[0008] One aspect of the present disclosure provides a trifunctional compound, a pharmaceutically acceptable salt thereof, a stereoisomer or solvate thereof, the trifunctional compound comprising at least one target substance T, at least one payload P, and in addition to a covalent warhead which may be present in the target substance T itself, the trifunctional compound comprising at least one covalent warhead C capable of forming a reversible or irreversible covalent linkage with a protein or tissue targeted by the target substance T (e.g., an FAP protein or other biomolecule in vivo), wherein the covalent warhead C is preferably a covalent warhead C comprising a (hetero)aromatic substituted halogenated sulfate ester or a (hetero)aromatic substituted phosphoamide fluoride.

[0009] The present invention, by using a trifunctional compound containing the three functional groups described above, can improve the uptake and / or retention of target organs (e.g., tumors), thereby enhancing the sensitivity of diagnostic probes and the efficacy of therapeutic agents. At the same time, because the binding capacity to plasma albumin is not significantly increased, uptake and retention in vital organs such as the blood vessels, liver, and kidneys can still be maintained at low levels, thus ensuring the specificity and controllable toxicity of the diagnostic probes. Ultimately, a compound with high diagnostic performance or a broad therapeutic window is provided.

[0010] Preferably, the present invention enables the use of a trifunctional compound containing a covalent warhead C, thereby significantly improving the uptake and retention of the compound in a target (e.g., tumor tissue) (improving the efficacy of the drug) while maintaining a certain level of targetability (ensuring drug safety).

[0011] More preferably, by adjusting or controlling the length and conformation of the linking base chain, the trifunctional compounds of the present invention can achieve a better target-to-background ratio.

[0012] More preferably, the present invention provides high detection sensitivity for targets such as tumor tissue when the payload P is a diagnostic group, and better achieves drug efficacy when the payload P is a therapeutic group.

[0013] In another embodiment, the present invention provides a superior pharmacokinetic effect by introducing a covalent warhead to other modification sites, for example, by introducing an additional covalent warhead to the payload P.

[0014] In one embodiment, the present invention relates to a trifunctional compound, a pharmaceutically acceptable salt thereof, a stereoisomer or solvate thereof, wherein the trifunctional compound comprises at least one target substance T and at least one payload P, characterized in that, in addition to a covalent warhead that may be present in the target substance T itself, the trifunctional compound comprises at least one of the following covalent warheads C.

[0015] The payload P is any optical functional group, radiolabeling functional group, radiolabelable functional group, or functional group of a small molecule cytotoxic drug that can be used for optical imaging, positron emission tomography, single-photon emission computed tomography, chemotherapy, or radiotherapy. The target substance T comprises a targeting group capable of targeting proteins or tissues (e.g., FAP proteins or other biomolecules in living organisms), and the targeting group is a small molecule. The covalent warhead C can form a reversible or irreversible covalent bond with the protein or tissue targeted by the target substance T. Here, the covalent warhead C is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] ,

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[0016] In a preferred embodiment of the present invention, the covalent warhead C in the trifunctional compound is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] Selected from the group consisting of, Here, :Het is an arbitrarily substituted C4-C 12 Heterocyclic groups, or optionally substituted C5-C groups 12 If a heteroaryl compound contains an N atom, the N atom may exist in a free form or in the form of an onium salt. Hal is F, Each p is an independent integer between 0 and 6. R 1This is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0017] In a preferred embodiment of the present invention, C in the trifunctional compound is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] Selected from the group consisting of, Here: Het is a C4, C5, or C6 heterocyclic group, or a C5 or C6 heteroaryl group, wherein the heterocyclic group or heteroaryl group contains one or two heteroatoms selected from N, O, or S, and if the heteroaryl contains an N atom, the N atom may exist in a free form or in the form of an onium salt, preferably in a free form, and more preferably Het is azetidinyl, pyridyl, pyrrolyl, or N-oxypyridinyl. Hal is F, Each p is an independent integer between 0 and 4. In a preferred embodiment of the present invention, the trifunctional compound comprises 1 to 3 payloads P, for example 1 or 2, and 1 to 3 target substances T, for example 1 or 2, in addition to covalent warheads that may be present in the target substance T itself, the trifunctional compound comprises 1 to 3 covalent warheads C, for example 1 or 2, and each linking group portion independently comprises 0 to 6 linking group units, the linking group units may be divalent linking groups (e.g., single bonds) or trivalent linking groups.

[0018] In a preferred embodiment of the present invention, the trifunctional compound has the structure of general formula (I), general formula (II), or general formula (III), [ka] General formula (I) [ka] General formula (II) [ka] General formula (III) Here: Payloads P and P' are, independently, the same or different groups containing radionuclides, or chelating groups, optical dye groups, or small molecule cytotoxic drug groups capable of chelating radionuclides. Target substances T and T' are targeting groups that can independently target the same or different proteins or tissues (e.g., FAP proteins or other biomolecules in the body), and the targeting groups are small molecules. In general formulas (I), (II), and (III), in addition to the covalent warheads that may be present in the target material T itself, there are further one, two, or three identical or different covalent warheads C, each of which is independently linked to P, T, L1, T', or P' represented by the general formula via the same or different linking base portion L4. Each of L1, L2 and L3 is a linking group moiety and each independently contains from 0 to 6 linking group units.

[0019] In a preferred embodiment of the present invention, the trifunctional compound has a structure of general formula (Ia), general formula (Ib), general formula (Ic), general formula (IIa) or general formula (IIIa),

Chemical formula

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Chemical formula

Chemical formula

Chemical formula

[0020] In a preferred embodiment of the present invention, the targeting group in the trifunctional compound targets fibroblast-activating protein-a (FAP-a). In a preferred embodiment of the present invention, the targeting group in the trifunctional compound has general formula (IV), preferably general formula (IVa), more preferably general formula (IVc), general formula (IVd), general formula (IVe), or general formula (IVf), [ka] General formula (IV) Here, in general formula (IV), A is O, S, NR A Selected from, R A It is selected from H, C1-C6 alkyl, Multiple R f There is a base, and each R f Each group is independently selected from H, F, Cl, -CN, -B(OH)2, C1-C6 alkyl, and α-chloroketone groups, and any two R groups on adjacent carbons. f The groups can link together to form a cycloalkyl group, preferably a C3-C7 cycloalkyl group. B1 and B2 are independently selected from O or S. R f1 and R f2 These are independently selected from H, D, or C1-C4 alkyl groups. Ar is a C6-C group containing one N atom. 10 It is a heteroaryl, [ka] General formula (IVa) Here, in general formula (IVa), A is O, S, NR A Selected from, R A It is selected from H, C1-C6 alkyl, On the shown tetrahydropyrrolo ring, there are multiple Rs f groups present, and each R f group is independently selected from H, F, Cl, -CN, C1-C6 alkyl, and α-chloro ketone group, and any two R f groups on adjacent carbons can be linked to each other to form cycloalkyl, preferably C3-C7 cycloalkyl,

Chemical formula

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[0021] In a preferred embodiment of the present invention, the targeting group in the trifunctional compound has general formula (V),

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[0022] In a preferred embodiment of the present invention, the payload P in the trifunctional compound comprises at least one group selected from the following group of groups, Group 1: A group having at least one radionuclide, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] Selected from, Here, R 2 , R 3 , R 4 and R 5These are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. X is 18 F, 123 I, 124 I, 125 I, 131 I and 211 Selected from At or its non-radioactive isotopes, q and r are independent integers between 0 and 4. The nitrogen atom on the triazole ring at the linking site shown here is not present on the payload P, but may be located on the linking unit. Group 2: Chelate groups capable of chelating radionuclides, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] Selected from, Group 3: Optical dye groups, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] Selected from, Group 4: Small molecule cytotoxic drug groups, [ka] , [ka] and [ka] Selected from.

[0023] In a preferred embodiment of the present invention, in the three-functional compound, When L1 is a trivalent linking group, that is, when the covalent warhead C is linked, or when L4 is independently [ka] , [ka] , [ka] and [ka] If selected from, L1~L 17 The divalent linking units contained within are independently single bond, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] Selected from, The methylene in the divalent linking group unit described herein is one or more -COR L2 Base or -COOR L2 It can be substituted with a base, where each R L2 These are independently H, C1-C6 alkyl, and C6-C 10 Ariel, C6-C 10 Selected from aryl-substituted C1-C6 alkyl groups, L 18 These are single bonds, -CH2-, -NHCH2-, or [ka] And, Church [ka] , [ka] , [ka] , [ka] and

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[0024] In a preferred embodiment of the present invention, the trifunctional compound has a structure of general formula (Ia), and L4 is,

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[0025] In a preferred embodiment of the present invention, the trifunctional compound has the structure of general formula (Ia) or general formula (Ib), [ka] General formula (Ia) [ka] General formula (Ib) Here: The L4 shown is a trivalent linking group portion. Each of the indicated L5, L6, L7, and L8 is independently a divalent linking group portion, and each independently contains 0 to 6, preferably 0 to 3, linking group units. The indicated C is a covalent warhead, jj [ka] , [Chemical formula] and [Chemical formula] and [Chemical formula] and [Chemical formula] and [Chemical formula] and [Chemical formula] and [Chemical formula] and [Chemical formula] and [Chemical formula] and [Chemical formula] selected from the group consisting of, Het is an optionally substituted C4-C 12 heterocyclic group, or an optionally substituted C5-C 12 heteroaryl, and when the heteroaryl contains an N atom, the N atom may exist in a free form or in the form of an onium salt, Hal is F or Cl, Y is selected from the group consisting of O, S and NR 1 and each p is independently an integer from 0 to 6, Each R 1These are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. Each R is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, optionally substituted mercapto, optionally substituted seleno, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino. The indicated T is a targeting group that targets fibroblast-activating protein-α (FAP-α), The P shown is a chelating group capable of chelating radionuclides.

[0026] In a preferred embodiment of the present invention, the trifunctional compound has the structure of general formula (Ia) or general formula (Ib), Here: The aforementioned L4 is a trivalent linking group. [ka] , [ka] , [ka] , [ka] , and [ka] Selected from, Each of the aforementioned L5, L6, L7, and L8 is independently a divalent linking group portion, each independently containing 0 to 3, preferably 0 or 1, linking group units, and each of the linking group units independently single bond, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] and [ka] Selected from, The methylene in the divalent linking group unit described herein is one or more -COR L2 Base or -COORL2 It can be substituted with a base, where each R L2 These are independently H, C1-C6 alkyl, and C6-C 10 Ariel, C6-C 10 Selected from aryl-substituted C1-C6 alkyl groups, L 18 These are single bonds, -CH2-, -NHCH2-, or [ka] And, Church [ka] , [ka] , [ka] , [ka] , [ka] and [ka] Selected from, u, u1, u2, u3, u4, u5, u6, u7, u8, u9, u10, u11, u12, v and o are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1, 2, 3, 4 or 5. Each R 6 and R 7 These are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. * indicates a part connected to T, ** is the part connected to C, The conditions are that in L5, L6, L7, and L8, the heteroatoms are not directly linked via covalent bonds, and the heteroatoms are selected from N, O, and S. C is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] Selected from the group consisting of, Here: Het is a C4, C5, or C6 heterocyclic group, or a C5 or C6 heteroaryl group, wherein the heterocyclic group or heteroaryl group contains one or two heteroatoms selected from N, O, or S, and if the heteroaryl group contains an N atom, the N atom may exist in a free form or in the form of an onium salt, preferably in a free form, preferably Het is a C4, C5, or C6 heterocyclic group, or a C5 or C6 heteroaryl group, wherein the heterocyclic group or heteroaryl group contains one N, O, or S, preferably an N heteroatom, and more preferably Het is azetidinyl, pyridyl, pyrrolyl, or N-oxypyridinyl. Hal is F, Each p is an independent integer between 0 and 4. The indicated T is a targeting group that targets fibroblast-activating protein-α (FAP-α), The P shown is a chelating group capable of chelating radionuclides. [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] Selected from.

[0027] In a preferred embodiment of the present invention, the trifunctional compound has the structure of general formula (Ia), Here: C is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] Selected from the group consisting of, Here: Het is a C4, C5, or C6 heterocyclic group, or a C5 or C6 heteroaryl group, wherein the heterocyclic group or heteroaryl group contains one or two heteroatoms selected from N, O, or S, and if the heteroaryl group contains an N atom, the N atom may exist in a free form or in the form of an onium salt, preferably in a free form, preferably Het is a C4, C5, or C6 heterocyclic group, or a C5 or C6 heteroaryl group, wherein the heterocyclic group or heteroaryl group contains one N, O, or S, preferably an N heteroatom, and more preferably Het is azetidinyl, pyridyl, pyrrolyl, or N-oxypyridinyl. Hal is F, Each p is an independent integer between 0 and 4. The P shown is a chelating group capable of chelating radionuclides. [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] Selected from, L4 is [ka] , [ka] , [ka] , or [ka] Having a structure, L5 and L6 are independent of each other. single bond, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] and [ka] And, Here, u, u1, u2, u3, u4, u5, u6, u7, u8, u9, u10, u11, u12, v and o are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1, 2, 3, 4 or 5. Each R 6 and R 7 These are independently selected from the group consisting of hydrogen and optionally substituted C1-C4 atoms. * indicates a part connected to T, ** is the part connected to C, The conditions are that, in L5 and L6, the heteroatoms are not directly linked via covalent bonds, and the heteroatoms are selected from N, O, and S. T is general formula (IV), preferably having general formula (IVa), more preferably having general formula (IVc), general formula (IVd), general formula (IVe), or general formula (IVf). [ka] General formula (IV) Here, in general formula (IV), A is O, S, NR A Selected from, R A It is selected from H, C1-C6 alkyl, Multiple R f There is a base, and each R f Each group is independently selected from H, F, Cl, -CN, -B(OH)2, and C1-C6 alkyl, and any two R groups on adjacent carbons. f The groups can link together to form a cycloalkyl group, preferably a C3-C7 cycloalkyl group. B1 and B2 are independently selected from O or S. R f1 and R f2 These are independently selected from H, D, or C1-C4 alkyl groups. Ar is a C6-C group containing one N atom. 10 It is a heteroaryl, [ka] General formula (IVa), Here, in general formula (IVa), A is O, S, NR A Selected from, R A It is selected from H, C1-C6 alkyl, Multiple R f There is a base, and each R f Each group is independently selected from H, F, Cl, -CN, and C1-C6 alkyl, and any two R groups on adjacent carbons. f The groups can link together to form a cycloalkyl group, preferably a C3-C7 cycloalkyl group. [ka] General formula (IVb), [ka] General formula (IVc), [ka] General formula (IVd), [ka] General formula (IVe), Here, in general formulas (IVb), (IVc), (IVd), or (IVe), A is O, S, NR A Selected from, R A The compound is selected from H, methyl, ethyl, n-propyl, and isopropyl.

[0028] In a preferred embodiment of the present invention, the trifunctional compound has the structure of general formula (Ib), Here: In general formula (Ib), C is, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] Selected from the group consisting of, Here: Het is a C4, C5, or C6 heterocyclic group, or a C5 or C6 heteroaryl group, wherein the heterocyclic group or heteroaryl group contains one or two heteroatoms selected from N, O, or S, and if the heteroaryl group contains an N atom, the N atom may exist in a free form or in the form of an onium salt, preferably in a free form, preferably Het is a C4, C5, or C6 heterocyclic group, or a C5 or C6 heteroaryl group, wherein the heterocyclic group or heteroaryl group contains one N, O, or S, preferably an N heteroatom, and more preferably Het is azetidinyl, pyridyl, pyrrolyl, or N-oxypyridinyl. Hal is F, Each p is an independent integer between 0 and 4. The P shown is a chelating group capable of chelating radionuclides. [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] Selected from, L7 and L8 are independent of each other. single bond, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] and [ka] And, Here, u, u1, u2, u3, u4, u5, u6, u7, u8, u9, u10, u11, u12, v and o are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1, 2, 3, 4 or 5. Each R 6 and R 7 These are independently selected from hydrogen and optionally substituted C1-C4, The conditions are that, at L7 and L8, the heteroatoms are not directly linked via covalent bonds, and the heteroatoms are selected from N, O, and S. T has the general formula (V), [ka] General formula (V), The peptide sequence is drawn from left to right, in the direction from the N-terminus to the C-terminus. Xaa1 is an amino acid residue of general formula (VI), [ka] General formula (VI) Here: R 1a is -NH-R 1a’ And R 1a’ is a protecting group or an amino acid, preferably the protecting group is R 1a’’ -C(O)- or R 1a’’ -S(O2)- and R 1a’’ This is a C1-C6 alkyl group, where optionally one -CH2- group is substituted with -S- or -O-. R 1b is H or methyl, g is either 0 or 1. The carbonyl group of Xaa1 is covalently bonded to the nitrogen of Xaa2. The sulfur atom of Xaa1 is covalently bonded to Yc as a thioether. Xaa2 and Xaa3 are independently selected from amino acid residues of general formula (VII) or general formula (VIII). [ka] General formula (VII), [ka] General formula (VIII), Here, h is 0, 1, or 2. i is either 1 or 2. j is 1, 2, or 3. The amino acid of the general formula (VII) may be substituted at ring positions 3 and 4 with one or two substituents selected from methyl, OH, NH2, and F. Xaa4 is an amino acid residue of general formula (IX), [ka] General formula (IX), Here, R 4a It is selected from H, OH, COOH, and CONH2. q is 1, 2, or 3, where optionally, 1 or 2 hydrogens in the 1, 2, or 3 CH2 groups are independently substituted with methyl or ethyl. R 4b is H or methyl, Xaa5 is an amino acid residue of general formula (X), [ka] General formula (X), Here: R 5a It is either OH or NH2, m is 1, 2, or 3. R 5b is H or methyl, Xaa6 is an amino acid selected from aromatic La-amino acids, preferably a residue of an amino acid of general formula (XI). [ka] General formula (XI), Here, R 6a and R 6b Each of these is independently selected from H, methyl, ethyl, propyl, and isopropyl, and is preferably H. R 6c The ∫ represents 0 to 3 substituents, and each substituent is independently F, Cl, Br, NO2, NH2, CN, CHF3, OH, OR 6d and selected from C1-C4 alkyl groups, R 6d It is selected from methyl, ethyl, propyl and isopropyl, l is 0 or 1, preferably 0. The CR shown here 6a R 6b (CH2) l PhR 6c This part can constitute a part of C in general formula (Ib), Xaa7 is an aminothiol or amino acid residue of general formula (XII), [ka] General formula (XII), Here, R 7a These are H, -COOH, -CONH2, or CH2OH. n is either 1 or 2. Yc has the structure of general formula (XIII), [ka] General formula (XIII), When two thioether bonds are formed, the sulfur atom of Xaa1 and the sulfur atom of Xaa7 are linked, thereby forming a cyclic structure of general formula (XIV). [ka] General formula (XIV), Here, in general formula (XIII), the substitution pattern of the aromatic group is ortho, para, or meta. g is either 0 or 1. n is either 1 or 2. Y 1 is CH or N, Y 2 CR L1 And, R L1 This is a linking unit that is linked to the other parts in general formula (Ib).

[0029] In a preferred embodiment of the present invention, the trifunctional compound has the structure of general formula (Ib), Here: L7 and L8 are independent of each other. single bond, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] and [ka] And, Here, u, u1, u2, u3, u4, u5, u6, u7, u8, u9, u10, u11, u12, v and o are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1, 2, 3, 4 or 5. Each R 6 and R 7 These are selected independently from each other, from hydrogen and optionally substituted C1-C4. The conditions are that, at L7 and L8, the heteroatoms are not directly linked via covalent bonds, and the heteroatoms are selected from N, O, and S. C is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] Selected from the group consisting of, Here: Het is a C4, C5, or C6 heterocyclic group, or a C5 or C6 heteroaryl group, wherein the heterocyclic group or heteroaryl group contains one or two heteroatoms selected from N, O, or S, and if the heteroaryl group contains an N atom, the N atom may exist in a free form or in the form of an onium salt, preferably in a free form, preferably Het is a C4, C5, or C6 heterocyclic group, or a C5 or C6 heteroaryl group, wherein the heterocyclic group or heteroaryl group contains one N, O, or S, preferably an N heteroatom, and more preferably Het is azetidinyl, pyridyl, pyrrolyl, or N-oxypyridinyl. Hal is F, Each p is an independent integer between 0 and 4. The P shown is a chelating group capable of chelating radionuclides. [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] Selected from, T has the general formula (V), [ka] General formula (V), The peptide sequence is drawn from left to right, in the direction from the N-terminus to the C-terminus. Xaa1 is an amino acid residue of general formula (VI), [ka] General formula (VI) Here: R 1a is -NH-R 1a’ And R 1a’ is a protecting group or an amino acid, preferably the protecting group is R 1a’’ -C(O)- or R 1a’’ It is -S(O2)- and R 1a’’ This is a C1-C6 alkyl group, where optionally one -CH2- group is substituted with -S- or -O-. R 1b is H or methyl, g is either 0 or 1. The carbonyl group of Xaa1 is covalently bonded to the nitrogen of Xaa2. The sulfur atom of Xaa1 is covalently bonded to Yc as a thioether. Xaa2 and Xaa3 are independently selected from amino acid residues of general formula (VII) or general formula (VIII). [ka] General formula (VII), [ka] General formula (VIII), Here, h is 0, 1, or 2. i is either 1 or 2. j is 1, 2, or 3. The amino acid of the general formula (VII) may be substituted at ring positions 3 and 4 with one or two substituents selected from methyl, OH, NH2, and F. Xaa4 is an amino acid residue of general formula (IX), [ka] General formula (IX), Here, R 4a It is selected from H, OH, COOH, and CONH2. q is 1, 2, or 3, where optionally, 1 or 2 hydrogens in the 1, 2, or 3 CH2 groups are independently substituted with methyl or ethyl atoms. R 4b is H or methyl, Xaa5 is an amino acid residue of general formula (X), [ka] General formula (X), Here: R 5a It is either OH or NH2, m is 1, 2, or 3. R 5b is H or methyl, Xaa6 is an amino acid residue of general formula (XI), [ka] General formula (XI), Here, R 6a and R 6b Each of these is independently selected from H, methyl, ethyl, propyl, and isopropyl, and is preferably H. R 6c represents 0 to 1 substituent, and each substituent is independently selected from F, Cl, NO2, NH2, CN, CHF3, OH, and C1-C4 alkyl. R 6d It is selected from methyl, ethyl, propyl and isopropyl, l is 0 or 1, preferably 0. The CR shown here 6a R 6b (CH2) l PhR 6c This part can constitute a part of C in general formula (Ib), Xaa7 is an aminothiol or amino acid residue of general formula (XII), [ka] General formula (XII), Here, R 7a is H or -COOH, n is either 1 or 2. Yc has the structure of general formula (XIII), [ka] General formula (XIII), When two thioether bonds are formed, the sulfur atom of Xaa1 and the sulfur atom of Xaa7 are linked, thereby forming a cyclic structure of general formula (XIV). [ka] General formula (XIV), Here, in general formula (XIII), the substitution pattern of the aromatic group is ortho, para, or meta. g is either 0 or 1. n is either 1 or 2. Y 1 is CH or N, Y 2 CR L1 And, R L1 is a linking unit that is linked to the other parts in general formula (Ib), The aforementioned T is preferably, [ka] It has the formula (Va).

[0030] In a preferred embodiment of the present invention, the three functional compounds are [ka] , [ka] ,

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[0031] Yet another aspect of the present invention relates to the trifunctional compound, a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof, wherein the payload P is a chelating group capable of chelating a radionuclide, and the chelating group chelates the radionuclide. In a preferred embodiment of this design, the radioactive nuclide contained in or chelated by the trifunctional compound is a positron nuclide, a beta-ray emitter, an alpha-ray emitter, an Auger electron-emitting isotope, an X-ray-emitting isotope, a fluorescence-emitting isotope, or a stable metal / nonmetal element coordinated with a radioactive nuclide, preferably 11 C, 13 N, 15 O, 18 F and its coordinating elements, 47 Sc, 51 Cr, 67 Ga, 68 Ga, 86 Y, 90 Y, 64 Cu, 67 Cu, 72 As, 72 Se, 89 Zr, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 142 Pr, 151 EU, 153 EU, 169 EU, 159 Gd, 161 Tb, 177 Lu, 198 Au, 199 Ag, 201 Tl, 211 At, 203 Pb, 212 Pb, 212 Bi, 213 Bi, 225 Ac, 99m Tc, 111 In, 149 PM, 153 Sm,165 Dy, 169 Er, 186 Re, 188 Re, 197 Hg, 227 Th, 67 Ga, 68 Ga, 86 Y, 90 Y, 55 Co, 139 La, 140 La, 149 Tb, 152 Tb, 155 Tb, 166 Ho, 175 Yb, 226 Th, 223 Ra and 230 It is U. Yet another aspect of the present invention relates to a drug composition comprising the above-mentioned trifunctional compound, a pharmaceutically acceptable salt, stereoisomer or solvate thereof, and a pharmaceutically acceptable carrier. A further aspect of the present invention relates to a reagent kit comprising or comprising the above-mentioned trifunctional compound, a pharmaceutically acceptable salt thereof, a stereoisomer or solvate thereof, or the above-mentioned drug composition, and instructions for diagnosing a disease. A further aspect of the present invention relates to a method for diagnosing or treating a disease, preferably a disease related to FAP, the method comprising administering to a subject a therapeutically effective amount of the trifunctional compound, a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof, wherein the disease is preferably a central nervous system disorder, a metabolic disorder (preferably a cardiovascular metabolic disorder), or cancer. In a preferred embodiment of the present invention, a method for diagnosing or treating the disease, preferably a disease related to FAP, wherein the cancer is selected from prostate cancer, breast cancer, pancreatic cancer, liver cancer, lung cancer, stomach cancer, kidney cancer, ovarian cancer, bladder cancer, esophageal cancer, head and neck cancer, thymic cancer, cervical cancer, endometrial cancer, neuroendocrine tumor, thyroid cancer, colorectal cancer, glioma, and bone metastatic cancer. [Brief explanation of the drawing]

[0032] [Figure 1] A diagram illustrating the mechanism of action of typical covalent inhibitors. [Figure 2]This is a radioactive purity spectrum diagram of 68Ga-FAPI-CB-30. The left diagram shows the quality control after labeling, the middle diagram shows the stability monitoring after incubation with serum for 1 hour, and the right diagram shows the stability monitoring after incubation with serum for 2 hours. [Figure 3] The left, middle, and right figures are radioactive HPLC spectral diagrams of 68Ga-FAPI-CB-31, 68Ga-FAPI-CB-50, and Al18F-FAPI-CB-36, respectively. [Figure 4] This figure shows the efficiency of covalent linkage between 177Lu-FAPI-CB-30 obtained after co-incubation with protein, gel electrophoresis, autoradiography, and Coomassie blue staining, and FAP target proteins. The left figure shows a control incubated at pH 7.4 for 1 hour, and the right figure shows a sample treated with a strong acid after incubation for 1 hour. [Figure 5] This figure shows the ratio of covalent linkage between 177Lu-FAPI-CB-30 molecules obtained after co-incubation with protein, gel electrophoresis, autoradiography, and Coomassie blue staining, and FAP human recombinant protein. The left figure is the autoradiography diagram, and the right figure shows the grayscale values ​​of the bands quantified using an image quantification tool such as ImageJ, corresponding to the molecular ratio of covalent linkage. [Figure 6] This figure shows the ratio of covalent linkage between 177Lu-FAPI-CB molecules obtained after co-incubation with proteins, gel electrophoresis, autoradiography, and Coomassie blue staining, and recombinant FAP human-derived proteins. The courses in the figure, from left to right, are 177Lu-labeled FAPI-CB-22, FAPI-CB-28, FAPI-CB-31, FAPI-CB-44, FAPI-CB-45, FAPI-CB-47, and FAPI-CB-50, respectively. [Figure 7]This figure shows comparative PET / CT images taken 90 minutes after injecting 68Ga-FAPI-CB-30, 68Ga-FAPI-CB-02, and 68Ga-FAPI-04 into the same HT-1080-FAP mouse model. The left figure shows the structure of FAPI-CB-02, the middle figure shows PET-CT images of 68Ga-FAPI-CB-30 and 68Ga-FAPI-CB-02, where SUV is the standard uptake value, and the right figure shows PET-CT images of 68Ga-FAPI-CB-30 and 68Ga-FAPI-04. [Figure 8] This figure shows a comparison of tumor SUV values ​​for 68Ga-FAPI-CB-31 and 68Ga-FAPI-04 in HT-1080-FAP tumor-bearing mouse models. [Figure 9] This figure shows comparative PET / CT images of Al18F-FAPI-CB-36 and 68Ga-FAPI-04 in HT-1080-FAP tumor-bearing mouse models. [Figure 10] This figure shows comparative PET / CT images of 68Ga-FAPI-CB-50 and 68Ga-FAPI-04 in HT-1080-FAP tumor-bearing mouse models. [Figure 11] This figure shows comparative PET / CT images of 68Ga-FAP-2286 and 68Ga-FAPI-CB-45 in HT-1080-FAP tumor-bearing mouse models. [Figure 12] This figure shows comparative PET / CT images of 68Ga-FAPI-CB-53 and 68Ga-FAPI-04 in HT-1080-FAP tumor-bearing mouse models. [Figure 13] This figure shows comparative PET / CT images at different time points in an HT-1080-FAP tumor-bearing mouse model of 68Ga-FAPI-CB-59. [Figure 14] This figure shows comparative PET / CT images of Al18F-FAPI-CB-77 and Al18F-FAPI-74 in HT-1080-FAP tumor-bearing mouse models. [Figure 15]This figure shows comparative PET / CT images of 68Ga-FAPI-CB-86 and 68Ga-FAPI-04 in HT-1080-FAP tumor-bearing mouse models. [Figure 16] This figure shows comparative PET / CT images of 68Ga-FAPI-CB-93 and 68Ga-FAPI-04 in HT-1080-FAP tumor-bearing mouse models. [Figure 17] This figure shows comparative PET / CT images of 68Ga-FAPI-CB-94 and 68Ga-FAPI-04 in HT-1080-FAP tumor-bearing mouse models. [Figure 18] This figure shows comparative PET / CT images of Al18F-FAPI-CB-95 and Al18F-FAPI-74 in HT-1080-FAP tumor-bearing mouse models. [Figure 19] This figure shows a comparison of tumor SUV values ​​60 minutes after injection of 68Ga-FAPI-CB-30 and 68Ga-FAPI-04 into an HT-1080-FAP mouse model. [Figure 20] This figure shows that the compounds FAPI-CB-28 and FAPI-CB-30 of the present invention significantly improved the ratio of tumor to blood pool standard uptake values ​​in the HT-1080-FAP tumor mouse model compared to the control (FAPI-04). [Figure 21] This figure shows that the FAPI-CB-31 molecule did not show a significant difference in blood pool uptake at 1 hour compared to FAPI-04, but showed higher tumor uptake. [Figure 22] This figure shows that the FAPI-CB-47 molecule rapidly reduces blood pool uptake at 0.5 hours and 2 hours, while tumor uptake is sustained to increase, with statistically significant improvement in tumor uptake compared to FAPI-04. [Figure 23] This figure shows 68Ga-FAPI-CB-50 PET / CT images of cancer patients. [Figure 24] This figure shows 177Lu-FAPI-CB-30 SPECT / CT images of cancer patients. [Figure 25]This figure shows SPECT / CT images of a tumor model mouse, 177Lu-FAPI-CB-86. [Figure 26] This figure shows the therapeutic effect of 177Lu-FAPI-CB-30 on tumor model mice. [Figure 27] This figure shows comparative PET / CT images of 68Ga-FAPI-CB-30 and 68Ga-FAPI-04 in a renal fibrosis model mouse. [Modes for carrying out the invention]

[0033] The present invention provides a trifunctional compound obtained by introducing a covalent warhead into a drug. This trifunctional compound exhibits significantly improved uptake and retention in targets such as tumors, and significantly reduced toxicity due to low uptake in non-target organs. Furthermore, the trifunctional compound of the present invention possesses excellent pharmacokinetic properties.

[0034] Before further describing the present invention, the following chapters compile some terms used in the specification, examples, and additional claims. The definitions set forth herein should be read and understood by those skilled in the art in relation to the rest of the invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in the field of the invention. definition Unless otherwise specified, when disclosing or seeking protection for any range of any kind, it is intended that each possible numerical value that can reasonably be included by such range (including any subranges that fall within that range) be disclosed or sought protection separately. For example, if the base number is 1 to 6, this refers to the integers within that range, where 1 to 6 includes 1, 2, 3, 4, 5, and 6, and should be understood to also include the subranges 1 to 5, 1 to 4, and 1 to 3. The specifications of this disclosure should be interpreted as being consistent with the laws and principles of chemical bonding. In some cases, hydrogen atoms may be removed to accommodate substituents in place. Similar terms used in this disclosure, such as “include,” “contain,” or “incorporate,” mean that the element preceding the term includes the elements listed after the term and their equivalents, and do not exclude any elements not listed. As used herein, “contain” or “include (incorporate)” may be open, semi-closed, or closed. In other words, these terms also include “essentially consisting of ....,” or “consisting of ....” In this application, the term "pharmaceutically acceptable" means that the compound or composition is chemically and / or toxicologically compatible with the other components of the formulation and / or with the human or mammal to whom the disease or condition is to be prevented or treated. In this application, the terms “subject” or “patient” include humans and mammals. In some embodiments, “patient” means an individual who has been diagnosed with, suspected of having, or has or is at risk of developing, a disease, wherein the disease is one of the diseases described herein, preferably a disease related to FAP. In the context of this application, unless otherwise specifically stated, the term “treatment” may also include “prevention.” The term "alkyl" refers to a saturated linear or branched carbon chain. Preferably, the chain contains 1 to 10 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms. The alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, pentyl, or octyl. The alkyl is optionally substituted. The term "heteroalkyl" refers to a saturated linear or branched carbon chain. Preferably, the chain contains 1 to 9 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, or octyl, which are interrupted one or more times by the same or different heteroatoms, for example, once, twice, three times, four times, or five times. Preferably, the heteroatom is selected from O, S, and N, for example -O-CH3, -S-CH3, -CH2-O-CH3, -CH2-O-C2H5, -CH2-S-CH3, -CH2-S-C2H5, -C2H4-O-CH3, -C2H4-O-C2H5, -C2H4-S-CH3, -C2H4-S-C2H5, etc. The heteroalkyl is optionally substituted. Unless otherwise specified, the terms “cycloalkyl” and “heterocycloalkyl,” either alone or in combination with other terms, refer to the cyclic forms of “alkyl” and “heteroalkyl,” respectively, where preferably 3, 4, 5, 6, 7, 8, 9, or 10 atoms form the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The terms “cycloalkyl” and “heterocycloalkyl” are intended to further include their bicyclic, tricyclic, and polycyclic forms. The term "heterocycloalkyl" preferably refers to a four-membered saturated ring in which at least one ring member is a nitrogen atom, a five-membered saturated ring in which at least one ring member is a nitrogen, oxygen, or sulfur atom and optionally contains one additional oxygen or one additional nitrogen atom, a six-membered saturated ring in which at least one ring member is a nitrogen, oxygen, or sulfur atom and optionally contains one additional oxygen, one additional nitrogen, or two additional nitrogen atoms, or a nine-membered or ten-membered saturated biring in which at least one ring member is a nitrogen, oxygen, or sulfur atom and optionally contains one, two, or three additional nitrogen atoms. "Cycloalkyl" and "heterocycloalkyl" are optionally substituted, where optionally substituted means that the ring carbon atoms on the ring are substituted with carbonyl (C=O) atoms. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, and adamantyl.Examples of heterocycloalkyls include azetidinyl, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,4-diazabicyclo[2.2.2]octan-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl. As used herein, the terms “heterocyclic group” or “heterocyclic” refer to a non-aromatic 5-, 6-, or 7-membered ring or polycyclic group, including, but not limited to, heterocyclic or tricyclic groups comprising condensed, spirocyclic, or bridging three-, four-, five-, six-, or seven-membered rings, wherein at least one carbon atom in any one of the rings is substituted with a heteroatom. Each heteroatom is independently selected from an oxygen, sulfur (including sulfoxides and sulfones), and / or nitrogen (which may be oxidized or quaternarily ammoniumlated) atom. The term “heterocyclic group” or “heterocyclic” is intended to include groups in which the -CH2- in the ring is replaced with -C(=O)-, for example, cyclic urea groups (such as 2-imidazolidone), cyclic amide groups (e.g., β-lactam, γ-lactam, δ-lactam and ε-lactam), and piperazine-2-one, where (i) each 5-membered ring has 0 to 1 double bond, and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen-sulfur heteroatom may be optionally oxidized, (iii) the nitrogen heteroatom may be selectively quaternarily ammoniumd, and (iv) any of the above heterocyclic rings may be condensed to an aryl or heteroaryl ring, such as a benzene ring. Representative heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuranyl. The term "aryl" preferably refers to an aromatic monocyclic system containing six carbon atoms, an aromatic bicyclic system containing ten carbon atoms, or an aromatic tricyclic system containing fourteen carbon atoms. Examples include phenyl, naphthyl, or anthryl. The aryl group may be optionally substituted. The term "heteroaryl" preferably refers to a compound in which at least one carbon atom is substituted with 1, 2, 3, or 4 (in the case of a five-membered ring) or 1, 2, 3, 4, or 5 (in the case of a six-membered ring) identical or different heteroatoms, wherein the heteroatoms are preferably five-membered or six-membered aromatic monorings selected from O, N, and S; or a compound in which 1, 2, 3, 4, 5, or 6 of 8, 9, 10, 11, or 12 carbon atoms are substituted with identical or different heteroatoms, wherein the heteroatoms are preferably aromatic bicyclic systems selected from O, N, and S; or a compound in which 1, 2, 3, 4, 5, or 6 of 13, 14, 15, or 16 carbon atoms are substituted with identical or different heteroatoms, wherein the heteroatoms are preferably aromatic tricyclic systems selected from O, N, and S. The nitrogen atom present in heteroaryls can exist in the form of an onium group. For example, trivalent aromatic nitrogen can be linked to an alkyl or oxygen atom to form an onium group. That is, "heteroaryl" in the context of this application includes both heteroaryls in free form (where the nitrogen atom is not in a salt) and heteroaryls that exist in the form of an onium salt. Examples include pyridyl, N-oxypyridinyl, N-alkylpyridinyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, and 1,3 Examples include 5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2-benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, indolidinyl, 2,1-benzoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, quinolyl, isoquinolyl, quinoxalil, quinazolinyl, quinolyl, 1,2,3-benzotriazinyl, or 1,2,4-benzotriazinyl. As used herein, the term “linking group” refers to any chemically appropriate linking group. Preferably, linking groups are not cleaved under physiological conditions or are cleaved very slowly. When multiple substituents or multiple linking groups are described by their usual chemical formulas written from left to right, such multiple substituents or multiple linking groups also include multiple chemically identical substituents resulting from structures written from right to left, for example: -CH2O- is equivalent to -OCH2-, -C(=O)O- is equivalent to -OC(=O)-, -OC(=O)NR- is equivalent to -NRC(=O)O-, and so on. When the term “independently selected” is used, the plurality of substituents it refers to (e.g., multiple R groups, e.g., groups R1, R2, etc., or variables, e.g., “m” and “n”) may be the same or different. The term "protecting group" refers to multiple chemical moieties that block some or all of the reactive moieties of a compound, preventing those moieties from participating in multiple chemical reactions until the protecting group is removed, such as those listed and described in, for example, TW Greene, PGMWuts (Multiple Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons (1999)). When employing different protecting groups, it is advantageous that each (different) protecting group can be removed in a different way. For multiple protecting groups decomposed under completely different reaction conditions, these protecting groups can be removed selectively. For example, multiple protecting groups can be removed by acid, base, and hydrolysis. For example, multiple groups of triphenylmethyl, dimethoxytriphenylmethyl, acetal, and tert-butyldimethylsilyl can be used to protect the reactive moieties of carboxyl and hydroxyl in the presence of multiple amino acids protected by multiple Cbz groups, which are acid-sensitive and can be removed by hydrolysis, and multiple Fmoc groups, which are base-sensitive. The carboxylic acid and hydroxyl-reactive moieties can be blocked by multiple base-sensitive groups, including but not limited to methyl, ethyl, and acetyl, in the presence of amines blocked by multiple acid-sensitive groups such as tert-butyl carbamate, or by carbamate esters that are stable in both acids and bases but can be removed by hydrolysis. "Arbitrarily substituted" means that one, two, three, or three or more hydrogen atoms in the group can be substituted independently of each substituent. The substituent is C 1~6 The following can be selected: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halogen, cyano, amino, nitro, -OH, and -COOH. As used herein, “radionic nuclide” refers to a radioactive isotope of an element that emits alpha particles, beta particles, and / or gamma rays. The radioactive nuclide is, 18 F, 51 Cr, 67 Ga, 68 Ga, 89 Zr, 111 In, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 86 Y, 88 Y, 90 Y, 149 PM, 161 Tb, 165 Dy, 169 Er, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 197 Hg, 211 At, 151 EU, 153 EU, 169 EU, 201 Tl, 203 Pb, 212 Pb, 64 Cu, 67Cu, 188 Re, 186 Re, 198 Au, 225 Ac, 227Th and 199 This includes, but is not limited to, Ag. As used in the context of this invention, the term "radioactive drug" refers to a biologically active compound modified with a radioisotope or radionuclide. The terms "chelating agent" or "chelate" in the context of this invention refer to molecules that are interchangeably used and have two or more lone pairs of electrons that can donate to a metal ion, and are often organic molecules, and often Lewis bases. Metal ions typically coordinate with chelating agents via two or more pairs of electrons. The terms "bidentate chelating agent," "tricate chelating agent," and "tetradentate chelating agent" refer to chelating agents that have two, three, and four pairs of electrons, respectively, that are readily donated simultaneously to the metal ion coordinated by the chelating agent. Typically, the electron pairs of a chelating agent form a coordinate bond with a single metal ion. However, in certain cases, a chelating agent can form a coordinate bond with one or more metal ions, and various bonding modes are possible. The term "chelate group" refers to a group formed after removing one or more hydrogen atoms from a "chelating agent" or "chelate." The term "optical dye" refers to a compound that emits visible or infrared light after being excited by electromagnetic radiation of a short, appropriate wavelength. Those skilled in the art should understand that each optical dye has a predetermined excitation wavelength. The term "nuclear drug molecule" or "nuclear drug" refers to a molecule or compound that contains or is chelated with a radionuclide. The term "targeting fibroblast-activating protein-α" refers to a molecular fragment derived from a fibroblast-activating protein inhibitor, such as a molecular fragment formed from a compound disclosed in WO2019154886A1. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic addition salt of the compounds disclosed herein. See, for example, S.M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. Suitable pharmaceutically acceptable salts of the compounds of the Disclosure may be acid addition salts of the compounds of the Disclosure having sufficient basicity, for example, having nitrogen atoms in the chain or ring, such as acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid, or 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, 3-hydroxyl-2-naphthoic acid, nicotinic acid, pamoic acid, pectin esters, persulfate, 3- It is an acid addition salt formed with phenylpropionic acid, bitter acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfate, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, cambasulfonic 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, glycerin phosphate, aspartic acid, sulfosalicylic acid, or thiocyanic acid. Furthermore, other suitable pharmaceutically acceptable salts of the compounds of the present invention having sufficient acidity are salts formed with alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts, or organic bases that provide physiologically acceptable cations, for example, salts formed with N-methylglucosamine, dimethylglucosamine, ethylglucosamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropylene glycol, and 1-amino-2,3,4-butanetriol. Furthermore, basic nitrogen-containing groups can be quaternarily ammoniumlated with reagents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate), long-chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), and arylalkyl halides (e.g., benzyl and phenethyl bromides). Those skilled in the art will recognize that acid addition salts of compounds requiring protection can be prepared by reacting the compound with a suitable inorganic or organic acid in any of several known methods. Alternatively, alkali metal salts and alkaline earth metal salts of the acidic compounds of this disclosure can be prepared by reacting them with a suitable base in various known methods. The present invention comprises all possible salts of the compounds disclosed herein, which may be single salts or any mixture of said salts in any ratio. The term "solvate" refers to a substance formed by combining the compound of the present invention with a solvent molecule and physically bonding and / or solvating it, for example, a disolvate, monosolvate, or hemisolvate, where the ratio of solvent molecule to compound of the present invention is about 2:1, about 1:1, or about 1:2, respectively. This physical bonding is related to ionization and covalent bonding (including hydrogen bonding) to varying degrees. In some cases (for example, when one or more solvent molecules bond to the crystal lattice of a crystalline solid), it is possible to separate the solvate. Thus, solvates include solvates that are separable from the solution phase. The compounds of the present invention can exist in solvated forms with pharmaceutically acceptable solvents (e.g., water, methanol, and ethanol), and this application is intended to encompass both solvated and non-solvated forms of the compounds of the present invention. One solvate is a hydrate. The compounds of this disclosure may contain one or more chiral centers, depending on the position and properties of various desired substituents. The chiral carbon atom may be present in a (R) or (S) configuration, and if there is one chiral center, a racemic mixture is obtained, and if there are multiple chiral centers, a diastereomer mixture is obtained. In some cases, chirality may also be present because rotation around a particular bond is inhibited, for example, when the central bond links two substituted aromatic rings of a particular compound. Preferred compounds are those capable of producing more desirable biological activity. Separated, purified, or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds disclosed herein, are all within the scope of the present invention. Purification and separation of these substances can be achieved by standard techniques known in the art. As used in this application, the term "drug composition" refers to a substance and / or combination of substances used to identify, prevent, or treat a tissue condition or disease. A drug composition is prepared in a form suitable for administration to a patient for the purpose of diagnosing, preventing, and / or treating a disease. A drug composition also refers to a combination of an activator and an inactive or active carrier, which is suitable for therapeutic use. "Pharmacologically acceptable" means approved by a federal or state regulatory authority, or listed in the United States Pharmacopeia or other authorized pharmacopoeias for animals, particularly for humans. As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or carrier administered with a therapeutic agent. This drug carrier may be a sterile liquid, such as an aqueous solution of salt in water or oil, including, for example, peanut oil, soybean oil, mineral oil, or sesame oil of petroleum, animal, plant, or synthetic origin. Salt solutions are preferred carriers when the drug composition is administered intravenously. Salt solutions, aqueous glucose solutions, and glycerin solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable drug excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene, ethylene glycol, water, and ethanol. If necessary, the composition may further contain small amounts of wetting agents or emulsifiers or pH buffers. Examples of suitable drug carriers are described in E.W. Martin’s “Remington’s Pharmaceutical Sciences”. The term "halogen" refers to fluorine, chlorine, bromine, and iodine. The term "optional" refers to a situation that may or may not occur. The term "not directly linked via a covalent bond" means that at least one carbon atom is interposed between the two, and that carbon atom may exist in the form of C, CH, CH2, or C=O. As used herein, FAP-related diseases refer to diseases in which cells expressing FAP (preferably in an upregulation manner) (including, but not limited to, fibroblasts), and tissues containing or expressing FAP, or preferably in an upregulation manner, cells expressing FAP (e.g., fibroblasts), are the cause of the disease and / or symptoms of the disease, or part of the underlying pathology of the disease. Preferably, the FAP-expressing cells are cancer-associated fibroblasts (CAFs). In embodiments of the disease, preferably used in combination with the treatment, management, and / or therapy of the disease, the cells, tissues, and pathology, respectively, affect the disease and / or symptoms of the disease, resulting in the cure, treatment, or improvement of the disease. In embodiments of the disease, preferably used in combination with the diagnosis and / or implementation of the diagnosis, the FAP-expressing cells and / or tissues can be distinguished or identified from healthy or non-FAP-expressing cells and / or healthy or non-FAP-expressing tissues by labeling them. More preferably, this distinction or identification forms the basis for the diagnosis and implementation of the diagnosis. In this embodiment, the label refers to a detectable label and a direct or indirect interaction between a cell expressing FAP and / or a tissue expressing FAP, or a tissue containing cells expressing FAP, more preferably, the interaction is related to or based on the interaction between the label or a compound having the label and FAP. As used herein, a tumor is an abnormal new growth of cells. Cells within a tumor grow faster than normal cells and will continue to grow if left untreated. Tumors may be benign or malignant. As used herein, a tumor is a mass-like lesion that may be benign or malignant. As used herein, cancer refers to a malignant tumor. The amino acid sequences of peptides provided herein are described in the form of typical peptide sequences. For example, the three-letter codes for common amino acids, or the codes for atypical amino acids, or the abbreviations for other components, indicate the presence of the amino acid or component at a specific position within the peptide sequence. Each amino acid or component code is concatenated with a hyphen (usually representing an amide bond) to the codes of the next and / or previous amino acid or component in the sequence. When an amino acid contains multiple amino acids and / or carboxyls, all orientations of this amino acid are possible in principle, but in the case of α-amino acids, the use of α-amino and α-carboxyls is preferred, and other preferred orientations are clearly specified. In the case of amino acids, the first letter in their abbreviation represents the stereochemistry of the C-α-atom (if applicable). For example, a capital letter indicates the presence of an L-type amino acid in the peptide sequence, while a lowercase letter indicates the presence of the corresponding D-type amino acid in the peptide sequence. As used herein, aromatic L-α-amino acids refer to all types of L-α-amino acids that contain an aryl group. As used herein, heteroaromatic L-α-amino acids refer to all types of L-α-amino acids, including heteroaryl compounds. Unless otherwise stated, amino acid sequences in this specification are given in the direction from the N-terminus to the C-terminus. The amino acids in this invention may be ordinary amino acids (also called natural amino acids) or non-natural amino acids (containing amino and carboxyl, and not any kind of non-oligomeric compound of ordinary amino acids). The radioactive nuclide in this invention has a half-life that enables medical applications for diagnostic and / or therapeutic purposes. Specifically, the half-life is between 1 minute and 100 days. In preferred embodiments of the present invention, the radionuclides have decay energies that enable medical applications for diagnostic and / or therapeutic purposes. Specifically, for gamma-ray emitting isotopes, the decay energy for diagnostic applications is 0.004 to 10 MeV, preferably 0.05 to 4 MeV. For positron-emitting isotopes, the decay energy for diagnostic applications is 0.6 to 13.2 MeV, preferably 1 to 6 MeV. For particle-emitting isotopes, the decay energy for therapeutic applications is 0.039 to 10 MeV, preferably 0.4 to 6.5 MeV. In a preferred embodiment of the present invention, the radionuclide is industrially produced for use in medical applications. Specifically, the radionuclide can achieve GMP quality. In a preferred embodiment of the present invention, the daughter nuclides after the radioactive decay of a radionuclide are suitable for diagnostic and / or therapeutic medical applications. Furthermore, the daughter nuclides are stable or further decay in a way that does not interfere with, or rather supports, diagnostic and / or therapeutic medical applications.

[0035] Examples Reagents and models to be used The starting materials for the examples are commercially available and / or can be prepared by experts in the field of organic synthesis using various well-known methods. Experts in the field of organic synthesis will appropriately select the reaction conditions (including solvent, reaction atmosphere, reaction temperature, duration of experiment, and workup) from the synthesis methods described below. Experts in the field of organic synthesis will understand that the functional groups present in each part of the molecule should be compatible with the proposed reagents and reactions. All reagents and compounds used in the synthesis can be purchased through common commercial channels in China (excluding Hong Kong, Macau, and Taiwan), and suppliers include Shanghai Bide Pharmaceutical Technology Co., Ltd., J&K (Beijing, China), Inno-chem (Beijing, China), and Energy Chemical (Shanghai, China). Unless otherwise specified, none of these are further purified. SO2F2 gas is purchased from Shang Fluorine Co., Ltd. (Shanghai, China). All solvents used in the synthesis are purchased from Tongguang (Beijing, China), and HPLC-grade solvents are purchased from Fisher Scientific (Loughborough, UK). radionuclides: 68 GaCl3 is 68 Ge- 68 The name originates from the process of rinsing a Ga generator (iThemba LABS, South Africa) with 0.6M hydrochloric acid. 177 LuCl3 is found in 0.1 M hydrochloric acid and will be purchased from ITG GmbH (Germany). Recombinant protein: Human-derived recombinant protein FAP-His tag will be purchased from Jin'an Protein Co., Ltd. (China). Cell model: The FAP-high-expression human fibrosarcoma cell line (HT-1080-FAP) is constructed by transfecting the human fibrosarcoma cell line (HT-1080) with the FAP plasmid, manufactured by Wuxi Biotechnology (China). Mouse model: Nu / Nu mice (SPF grade) were purchased from Beijing Weitong Lihua Co., Ltd. (China), and HT-1080-FAP cells were subcutaneously injected into them to construct a tumor model with high FAP expression. Instruments to be used Compound preparation and identification: High-performance liquid chromatography (Waters), radioactive detector for high-performance liquid chromatography (Eckert & Ziegler Group), ultra-high-performance liquid chromatography-mass spectrometry (Waters), high-resolution mass spectrometry (Orbitrap Fusion Lumos or Bruker Solarix XR), nuclear magnetic resonance spectrometer (Bruker 400 / 500 / 600 MHz), Amersham Typhoon imaging system (Amersham Typhoon RGB). Animal experiments: Small animal PET / CT or SPECT / CT (Mediso nanoScanR PET122S or Eishin Medical inliView-3000B).

[0036] Example 1 Compound Synthesis [ka] The compound FAPI-CB-30 of the present invention can be synthesized by the above synthetic route, and some of the FAP-targeting compounds in the patent can be synthesized by a similar synthetic route.

[0037] Example 1a. Synthesis of FAPI-CB-30 The initial intermediate int 1a is prepared using the steps described in Albumin Binder Conjugated Fibroblast Activation Protein Inhibitor Radiopharmaceuticals for Cancer Therapy by Xu, M. et al. (J. Nucl. Med. 2021, jnumed.121.262533.), with the only difference being the replacement of the protected lysine used in that literature with protected (S)-2,3-diaminopropionic acid. To a solution of int 1a (450 mg, 0.5 mmol, 1.0 equivalent) in acetonitrile (10.0 ml), NHEt2 (973.0 mg, 13.34 mmol, 1.05 ml, 26.7 equivalents) is added, and the reaction mixture is stirred at 25°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC [eluent A: H2O (0.1% trifluoroacetic acid); eluent B: acetonitrile, from 10% B (2 mins) to 95% B (20 mins)], yielding int 2 (268.8 mg, 80%) as a white solid. To a solution of int 2a (336 mg, 0.5 mmol, 1.0 equivalent) in DMF (5.0 ml), DOTA-Tris(tBu) (0.5 g, 0.9 mmol, 1.8 equivalents), HATU (365 mg, 1.0 mmol, 2.0 equivalents), and DIEA (78 mg, 0.6 mmol, 105 μL, 1.2 equivalents) are added, and the mixture is stirred at 25°C for 12 hours. The reaction mixture is poured into methyl tert-butyl ether (200 ml) and stirred for 30 minutes to obtain a precipitate. The precipitate is dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) is added to the solution, and the mixture is reacted at 20°C for 30 minutes. The crude product is purified by HPLC [eluent A: H2O (0.1% trifluoroacetic acid); eluent B: ACN, from 20% B (2 mins) to 95% B (20 mins)], yielding int 3a (0.366 g, yield 65%) as a white solid. Dissolve int 3a (11.3 mg, 10 μmol, 1.0 equivalent) in DMF (200 μL), add commercially available 1a (1.7 mg, 12.2 μmol, 1.22 equivalents), DIPEA (3.9 mg, 30 μmol, 5.3 μL, 3.0 equivalents), and HBTU (9.9 mg, 12.0 μmol, 1.2 equivalents), and stir the reaction mixture at 25°C for 30 minutes. Then, separate by HPLC to obtain intermediate int 4a (10.32 mg, 80%), dissolve in acetonitrile (200 μL), replace the gas in the container with SO2F2 gas, add 4.0 equivalents of triethylamine, and react for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, then 1.0 mL of TFA was added, and the mixture was reacted at 25°C for 3 hours. The crude product was purified by HPLC [eluent A: H2O (0.1% TFA); eluent B: ACN, from 10% B (2 mins) to 60% B (20 mins)] to obtain FAPI-CB-30 (7.87 mg, 82%) as a white solid. UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C 181.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, eluent A: H2O (0.1% TFA); eluent B: MeOH; 0-0.2 min, 95% A; 0.2-3.0 min, 95%-5% A, curve 6; 3.0-4.0 min, 5% A; 4.0-4.5 min, 5%-95% A, curve 6; 4.5-5.0 min, 95% A. Calculated m / z is [M+H] + The value is 1162, and the holding time is 1.56 minutes.

[0038] Example 1b. Synthesis of FAPI-CB-31 [ka] Compound int 1b is prepared by the steps described in Albumin Binder Conjugated Fibroblast Activation Protein Inhibitor Radiopharmaceuticals for Cancer Therapy by Xu, M. et al. (J. Nucl. Med. 2021, jnumed.121.262533.). Add NHEt2 (1249.0 mg, 17.1 mmol, 1.343 ml, 26.7 equivalents) to a solution of int 1b (600 mg, 641.0 μmol, 1.0 equivalent) in acetonitrile (5.0 ml), and stir the reaction mixture at 25°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by HPLC [eluent A: H2O (0.1% trifluoroacetic acid); eluent B: acetonitrile, from 10% B (2 mins) to 95% B (20 mins)] to obtain int 2b (370.7 mg, yield 81%) as a white solid. To a solution of int 2b (357 mg, 0.5 mmol, 1.0 equivalent) in DMF (5.0 ml), DOTA-Tris(tBu) (0.5 g, 0.9 mmol, 1.8 equivalents), HATU (365 mg, 1.0 mmol, 2.0 equivalents), and DIEA (78 mg, 0.6 mmol, 105 μL, 1.2 equivalents) are added, and the mixture is stirred at 25°C for 12 hours. The reaction mixture is poured into methyl tert-butyl ether (200 ml) and stirred for 30 minutes to obtain a precipitate. The precipitate is dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) is added to the solution, and the mixture is reacted at 20°C for 30 minutes. The crude product is purified by HPLC [eluent A: H2O (0.1% trifluoroacetic acid); eluent B: ACN, from 20% B (2 mins) to 95% B (20 mins)], yielding int 3b (0.362 g, yield 62%) as a white solid. Dissolve int 3b (11.7 mg, 10.0 μmol, 1.0 equivalent) in DMF (200 μL), add 1b (3.9 mg, 12.0 μmol, 1.2 equivalents) easily obtained by oxidizing commercially available 1a with 35% hydrogen peroxide, DIPEA (3.9 mg, 30.0 μmol, 5.6 μL, 3.0 equivalents), and HBTU (4.6 mg, 12.0 μmol, 1.2 equivalents), add the reaction mixture, and stir at 25°C for 30 minutes. Then, separate by HPLC to obtain intermediate int 4b (8.8 mg, 67%), dissolve in acetonitrile (200 μL), replace the gas in the container with SO2F2 gas, add 4.0 equivalents of triethylamine, and react for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, then 1.0 mL of TFA was added and the mixture was reacted at 25°C for 3 hours. The crude product was purified by HPLC [eluent A: H2O (0.1% TFA); eluent B: ACN, from 10% B (2 mins) to 60% B (20 mins)] to obtain FAPI-CB-31 (6.5 mg) as a white solid. UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, eluent A: H2O (0.1% TFA); eluent B: MeOH; 0-0.2 min, 95% A; 0.2-3.0 min, 95%-5% A, curve 6; 3.0-4.0 min, 5% A; 4.0-4.5 min, 5%-95% A, curve 6; 4.5-5.0 min, 95% A. Calculated m / z is [M+H]. + The value is 1220, and the holding time is 1.32 minutes.

[0039] Example 1c. Synthesis of FAPI-CB-44 [ka] Compound int 1c is prepared using the steps described in "An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications" by Millul, J. et al. (PNAS 2021, 118 (16) e2101852118). To a 10.0 ml solution of int 1c (501 mg, 1.0 mmol, 1.0 equivalent) in DMF, commercially available 3A (468 mg, 1.0 mmol, 1.0 equivalent), DIPEA (390 mg, 3.0 mmol, 527 μL, 3.0 equivalent), and HATU (456.8 mg, 1.2 mmol, 1.2 equivalent) were added. The reaction mixture was stirred at 20°C for 60 minutes, and then analyzed by UPLC-MS to obtain a single major peak ([M+H]) with the desired mass. + The detection of (=952) is indicated. The reaction mixture is diluted to 20.0 ml with H2O and extracted with ethyl acetate (20.0 ml / round, 3 rounds). The combined organic layer is washed with 20.0 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product is used in the next step without further purification. Crude product int 2c (813 mg) is obtained as a yellow solid. To a solution of int 2c (1.0 mmol, 1.0 equivalent) in DMF (10.0 ml), NHEt2 (1950.2 mg, 26.7 mmol, 2.097 ml, 26.7 equivalents) was added, and the reaction mixture was stirred at 20°C for 60 minutes. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by prepared HPLC [eluent A: H2O (0.1% trifluoroacetic acid); eluent B: acetonitrile, from 10% B (2 mins) to 95% B (20 mins)], yielding int 3c (511.7 mg, yield 70.2%) as a white solid. To a solution of int 3c (364 mg, 0.5 mmol, 1.0 equivalent) in DMF (5.0 ml), DOTA-Tris(tBu) (0.5 g, 0.9 mmol, 1.8 equivalents), HATU (365 mg, 1.0 mmol, 2.0 equivalents), and DIEA (78 mg, 0.6 mmol, 105 μL, 1.2 equivalents) are added, and the mixture is stirred at 25°C for 12 hours. The reaction mixture is poured into methyl tert-butyl ether (200 ml) and stirred for 30 minutes to obtain a precipitate. The precipitate is dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) is added to the solution, and the mixture is reacted at 20°C for 30 minutes. The crude product is purified by HPLC [eluent A: H2O (0.1% trifluoroacetic acid); eluent B: ACN, from 20% B (2 / 10) to 95% B (20 / 10)], and int 4c (0.385 g, 65%) is obtained as a white solid. Dissolve int 4c (11.8 mg, 10.0 μmol, 1.0 equivalent) in DMF (200 μL), add commercially available 1a (3.9 mg, 12.0 μmol, 1.2 equivalents), DIPEA (3.9 mg, 30.0 μmol, 5.6 μL, 3.0 equivalents), and HBTU (4.6 mg, 12.0 μmol, 1.2 equivalents), add the reaction mixture, and stir at 25°C for 30 minutes. Then, separate by HPLC to obtain intermediate int 5c (9.7 mg, 75%), dissolve in acetonitrile (500 μL), replace the gas in the container with SO2F2 gas, add 4.0 equivalents of triethylamine, and react for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, then 1.0 mL of TFA was added and the mixture was reacted at 25°C for 3 hours. The crude product was purified by HPLC [eluent A: H2O (0.1% TFA); eluent B: ACN, from 10% B (2 mins) to 60% B (20 mins)] to obtain FAPI-CB-44 (7.4 mg, 81%) as a white solid. UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, eluent A: H2O (0.1% TFA); eluent B: MeOH; 0-0.2 min, 95% A; 0.2-3.0 min, 95%-5% A, curve 6; 3.0-4.0 min, 5% A; 4.0-4.5 min, 5%-95% A, curve 6; 4.5-5.0 min, 95% A. The calculated m / z is [M+H]. + The value is 1219, and the holding time is 1.43 minutes.

[0040] Example 1d. Synthesis of FAPI-CB-45 [ka] Compound int 1d is prepared by solid-phase synthesis with reference to the steps described in patent WO 2021 / 005125 A1 of the 3B Pharmaceuticals GmbH application. To a mixture of compound int 1d (200 mg, 174.53 mmol, 1.0 equivalent) and DOTA-NHS (131.3 mg, 261.80 mmol, 1.5 equivalents) in DMF (5 ml), DIEA (112.8 mg, 872.7 mmol, 152.0 μL, 5.0 equivalents) was added in one batch at 25°C, and the mixture was then stirred at 25°C for 0.5 hours. The main peak [M+H] was identified by LC-MS. + Confirm =1486.6. The mixture is purified by preparation HPLC (TFA conditions: A: 0.075% TFA in H2O, B: ACN) to obtain int 2d (143.3 mg, 119.22 umol, yield 51%). Dissolve int 2d (14.9 mg, 10.0 μmol) in water (500 μL), add DCM (500 μL), then replace the gas in the container with SO2F2 gas, add 4.0 equivalents of triethylamine, and react for 6 hours. Concentrate the reaction mixture under reduced pressure to remove the solvent, and purify the crude product by HPLC [eluent A: H2O (0.1% TFA); eluent B: ACN, from 10% B (2 mins) to 60% B (20 mins)] to obtain FAPI-CB-45 (13.5 mg, 86%) as a white solid. UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, eluent A: H2O (0.1% TFA); eluent B: MeOH; 0-0.2 min, 95% A; 0.2-3.0 min, 95%-5% A, curve 6; 3.0-4.0 min, 5% A; 4.0-4.5 min, 5%-95% A, curve 6; 4.5-5.0 min, 95% A. The calculated m / z is [M+H]. + The value is 1569, and the holding time is 1.71 minutes.

[0041] Example 1e. Synthesis of FAPI-CB-22 [ka] Following the method pathway in Example 1a, compound FAPI-CB-22 (10.5 mg, multi-step yield 27%) was obtained from the readily available intermediate int 2e and purified by HPLC [eluent A: H2O (0.1% TFA); eluent B: ACN, from 10% B (2 mins) to 60% B (20 mins)]. UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, eluent A: H2O (0.1% TFA); eluent B: MeOH; 0~0.2 min, 95% A; 0.2~3.0 min, 95%~5% A, curve 6; 3.0~4.0 min, 5% A; 4.0~4.5 min, 5%~95% A, curve 6; 4.5~5.0 min, 95% A. The calculated m / z is [M+H] + The value is 1204, and the holding time is 1.65 minutes.

[0042] Example 1f. Synthesis of FAPI-CB-28 [ka] Following the method pathway in Example 1a, compound FAPI-CB-28 (9.7 mg, multi-step yield 30%) was obtained from the readily available intermediate int 2f and purified by HPLC [eluent A: H2O (0.1% TFA); eluent B: ACN, from 10% B (2 mins) to 60% B (20 mins)]. UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, eluent A: H2O (0.1% TFA); eluent B: MeOH; 0~0.2 min, 95% A; 0.2~3.0 min, 95%~5% A, curve 6; 3.0~4.0 min, 5% A; 4.0~4.5 min, 5%~95% A, curve 6; 4.5~5.0 min, 95% A. The calculated m / z is [M+H] + The value is 1191, and the holding time is 1.62 minutes.

[0043] Example 1: Synthesis of FAPI-CB-47 [ka] Following the method route in Example 1a, compound FAPI-CB-47 (8.0 mg, multi-step yield 21%) was obtained from readily available intermediates int 2e and int 2g. Int 2g was obtained from Taijie Guo et al.'s publication, "A New Portal to SuFEx Click Chemistry: A Stable Fluorosulfuryl Imidazolium Salt Emerging as an F-SO2 + It is readily available by referring to the method described in "Profiling Sulfur(VI) Fluorides as Reactive Functionalities for Chemical Biology Tools and Expansion of the Ligandable Proteome" (ACS Chem. Biol. 2023, 18, 2, 285) by Donor of Unprecedented Reactivity, Selectivity, and Scope and Katharine E. Gilbert et al. Purification by HPLC [Eluting agent A: H2O (0.1% TFA); Eluting agent B: ACN, from 10% B (2 mins) to 60% B (20 mins)]. UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, Eluting agent A: H2O (0.1% TFA); Eluting agent B: MeOH; 0~0.2 min, 95% A; 0.2~3.0 min, 95%~5% A, curve 6; 3.0~4.0 min, 5% A; 4.0~4.5 min, 5%~95% A, curve 6; 4.5~5.0 min, 95% A. Calculated m / z is [M + H] + The value is 1177, and the holding time is 1.54 minutes.

[0044] Example 1h. Synthesis of FAPI-CB-50 [ka] Following the method pathway in Example 1a, compound FAPI-CB-50 was obtained from readily available intermediates int 2e and int 2h, where int 2h is the compound described in Taijie Guo et al.'s book, "A New Portal to SuFEx Click Chemistry: A Stable Fluorosulfuryl Imidazolium Salt Emerging as an F-SO2" + It is readily available by referring to the method described in "Donor of Unprecedented Reactivity, Selectivity, and Scope" (8.5 mg, multi-step yield 24%). Purification by HPLC [Eluting agent A: H2O (0.1% TFA); Eluting agent B: ACN, from 10% B (2 mins) to 60% B (20 mins)]. UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, Eluting agent A: H2O (0.1% TFA); Eluting agent B: MeOH; 0~0.2 min, 95% A; 0.2~3.0 min, 95%~5% A, curve 6; 3.0~4.0 min, 5% A; 4.0~4.5 min, 5%~95% A, curve 6; 4.5~5.0 min, 95% A. Calculated m / z is [M + H] + The value is 1167, and the holding time is 1.43 minutes.

[0045] Example 1i. Synthesis of FAPI-CB-36 [ka] Compound FAPI-CB-36 can be readily obtained from readily available intermediate int 2i following a method route similar to that of Example 1a (6.2 mg, multi-step yield 20%). Purification by HPLC [Eluting agent A: H2O (0.1% TFA); Eluting agent B: ACN, from 10% B (2 mins) to 60% B (20 mins)]. UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, Eluting agent A: H2O (0.1% TFA); Eluting agent B: MeOH; 0~0.2 min, 95% A; 0.2~3.0 min, 95%~5% A, curve 6; 3.0~4.0 min, 5% A; 4.0~4.5 min, 5%~95% A, curve 6; 4.5~5.0 min, 95% A. Calculated m / z is [M + H] + The value is 1061, and the holding time is 1.67 minutes.

[0046] Example 1j. Synthesis of FAPI-CB-53 [ka] Compound int 1j (5.00 g, 17.8 mmol, 1.00 equivalent) is dissolved in H2O (65.0 ml), and the pH is adjusted to 9-10 with NaOH (4 mol / L, 50 ml, 11.2 equivalents). The mixture is heated in an oil bath to 65 °C. Sodium nitropropyl (9.57 g, 32.1 mmol, 5.56 ml, 1.80 equivalents) is added in installments within 1 hour, while simultaneously maintaining the pH of the reaction mixture between 9 and 10 using NaOH (4.00 mol / L). The resulting mixture is heated for a further 3 hours, while simultaneously maintaining the pH between 9 and 10 by adding aqueous NaOH (4.00 mol / L) as needed. The mixture is filtered and extracted three times with ethyl acetate (250 ml). The combined organic layer is washed with brine (100 ml), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preliminary HPLC (under 0.1% TFA conditions) to obtain compound int 2j (2.90 g, 10.3 mmol, yield 57.8%) as a yellow oily substance. Compound int 2j (10.3 mmol, 1.00 equivalent) is dissolved in ACN, and K2CO3 (30.9 mmol, 3.00 equivalent) and BnBr (15.4 mmol, 1.50 equivalent) are added. The reaction mixture is stirred at 25°C for 12 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue is purified by silica gel column chromatography to obtain compound int 3j (2.10 g, 5.65 mmol, yield 54.8%). Dissolve DIAD (1.43 g, 7.07 mmol, 1.37 ml, 1.25 equivalents) in THF (25.0 ml), then add PPh3 (1.85 g, 7.07 mmol, 1.25 equivalents) at 0°C and stir for 1 hour. Then add compound 3j (2.10 g, 5.65 mmol, 1.00 equivalent) and AcSH (537 mg, 7.07 mmol, 505 μL, 1.25 equivalents) at 0°C. Stir the mixture at 20°C for 11 hours. Concentrate the mixture under vacuum. Purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 ~ 0:1, petroleum ether:ethyl acetate = 5:1, Rf = 0.15). Compound int 4j (2.00 g, 4.66 mmol, yield 82.3%) is obtained as a colorless oil. Compound int 4j (1.50 g, 3.49 mmol, 1.00 equivalent) is dissolved in glacial acetic acid (50.0 ml) and water (5.0 ml), and NCS (1.40 g, 10.4 mmol, 3.00 equivalent) is added. The reaction mixture is stirred at 25°C for 1 hour. The reaction mixture is poured into water (50 ml) and extracted with dichloromethane (100 ml). The organic layer is washed three times with water (100 ml) and brine (100 ml), dried over Na2SO4, and concentrated to obtain compound int 5j (1.50 g, crude product) as a colorless oil. Compound int 5j (1.50 g, 3.30 mmol, 1.00 equivalent) is dissolved in acetonitrile (42.0 ml) and water (21.0 ml), and KHF2 (1.03 g, 13.2 mmol, 435 μL, 4.00 equivalent) is added. The mixture is stirred at 25°C for 12 hours. The mixture is extracted three times with ethyl acetate (150 ml). The combined organic layer is concentrated to obtain the residue. The crude product is purified by preliminary HPLC. Compound int 6j (1.10 g, 2.51 mmol, yield 76.0%) is obtained as a colorless oil. Compound int 6j (1.10 g, 2.51 mmol, 1.00 equivalent) is dissolved in THF (20.0 ml), and Pd / C (220 mg, 206 μmol, 10% purity, 0.2 equivalent) is added under a nitrogen atmosphere. Bubbles are removed from the suspension, and the mixture is purified three times with H2. The mixture is stirred at 25°C for 12 hours under H2 (15 psi). The reaction mixture is filtered and concentrated to obtain compound int 7j (1.10 g, 2.51 mmol, yield 76.0%) as a white solid. Compound int 7j (100 mg, 468 μmol, 1.00 equivalent) is dissolved in THF (2.0 ml) and water (2.0 ml). NaHCO3 (39.4 mg, 468 μmol, 18.2 μL, 1.00 equivalent) and FmocOSu (158 mg, 468 μmol, 1.00 equivalent) are added, and the mixture is stirred at 25°C for 1 hour. The pH of the mixture is adjusted to 5, and it is extracted with ethyl acetate (100 ml). The organic layer is concentrated. The crude product is purified by preliminary HPLC. Compound int 8j (120 mg, 275 μmol, yield 58.7%) is obtained as a white solid. To a solution containing compound 9a (130 mg, 221.61 μmol, 1.00 equivalent) and acetonitrile (10.0 ml), p-toluenesulfonic acid (133 mg, 775 μmol, 3.50 equivalents) is added. The mixture is stirred at 40°C for 1 hour. The mixture is concentrated under vacuum to obtain compound 9b (100 mg, crude product) as a yellow solid. To a stirred solution containing compound 9b (95.5 mg, 196 μmol, 0.95 equivalents) and DMF (5.0 ml), compound int 8j (90.0 mg, 206 μmol, 1.00 equivalent), DIEA (53.4 mg, 413 μmol, 72.0 μL, 2.00 equivalents), HOBt (41.8 mg, 310 μmol, 1.50 equivalents), and EDCI (41.6 mg, 217 μmol, 1.05 equivalents) were sequentially added, and the reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under vacuum, and the crude product was purified by high-performance liquid chromatography (0.1% TFA conditions) to obtain compound int 9j (40.0 mg, 44.2 μmol, yield 21.4%) as a white solid. To a solution containing compound int 9j (40.0 mg, 44.2 μmol, 1.00 equivalent) and acetonitrile (16.0 ml), diethylamine (2.84 g, 38.8 mmol, 4.00 ml, 877 equivalents) is added, and the mixture is stirred at 25°C for 1 hour. The mixture is adjusted to pH 5 with citric acid (0.5 ml), extracted with ethyl acetate (10.0 ml), and the aqueous layer is freeze-dried to obtain the crude product. The crude product is purified by prepared high-performance liquid chromatography (0.1% TFA conditions) to obtain compound int 10j (10.0 mg, 14.6 μmol, yield 33.1%) as a colorless oil. To a 1.0 ml solution of acetonitrile containing compound int 10j (10.0 mg, 14.6 μmol, 1.00 equivalent) and DOTA-OSu (10.0 mg, 19.9 μmol, 1.36 equivalents), DIEA (4.74 mg, 36.6 μmol, 6.39 μL, 2.50 equivalents) is added, and the mixture is stirred at 25°C for 3 hours. The mixture is concentrated under a nitrogen atmosphere, and the crude product is purified by high-performance liquid chromatography (under 0.1% NH4HCO3 conditions) to obtain FAPI-FS-53 (6.0 mg, 5.09 μmol, yield 34.7%, purity 98.6%) as a white solid. [Eluting agent A: H2O (0.1% TFA); Eluting agent B: ACN, from 10% B (2 mins) to 60% B (20 mins)]. UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, eluent A: H2O (0.1% TFA); eluent B: MeOH; 0-0.2 min, 95% A; 0.2-3.0 min, 95%-5% A, curve 6; 3.0-4.0 min, 5% A; 4.0-4.5 min, 5%-95% A, curve 6; 4.5-5.0 min, 95% A. Calculated m / z is [M + H] + The value is 1069, and the holding time is 1.53 minutes.

[0047] Example 1k. Synthesis of FAPI-CB-59 [ka] Compound int 1k (5.30 g, 14.5 mmol, 1.00 equivalent) and compound 1a (1.94 g, 16.0 mmol, 1.10 equivalent) are dissolved in DMF (50.0 ml), and K2CO3 (2.01 g, 14.5 mmol, 1.00 equivalent) is added. The mixture is stirred at 25°C for 1 hour. The reaction is diluted with ethyl acetate (200 ml). The combined organic layer is washed three times with water (100 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound int 2k (5.80 g, 14.3 mmol, yield 98.0%, purity 99.4%) as a yellow oil. Compound int 2k (5.80 g, 14.3 mmol, 1.00 equivalent) is dissolved in DCM (10.0 ml), and TFA (35.4 g, 310 mmol, 23.1 ml, 21.8 equivalents) is added. The mixture is stirred at 25°C for 1 hour. The reaction mixture is concentrated under reduced pressure to obtain the residue. The residue is diluted with DCM (100 ml), the organic layer is adjusted to pH = 7 with saturated sodium bicarbonate aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound int 3k (4.00 g, 13.1 mmol, yield 92.2%) as a yellow oil. Compound int 4k (4.00 g, 21.2 mmol, 1.00 equivalent) and BnBr (3.62 g, 21.2 mmol, 2.51 ml, 1.00 equivalent) are dissolved in DMF (200 ml), and KHCO3 (3.18 g, 31.7 mmol, 1.50 equivalent) is added. The mixture is stirred at 40°C for 1 hour. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to obtain the residue. The filtrate is diluted with ethyl acetate (500 ml), the organic phase is washed three times with water (200 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound int 5k (4.60 g, 15.8 mmol, yield 74.8%, purity 96.0%) as a brown solid. Compound int 5k (4.60 g, 15.8 mmol, 1.00 equivalent) and compound 5a (9.58 g, 47.4 mmol, 4.84 ml, 3.00 equivalent) are dissolved in DMF (50.0 ml), and Cs2CO3 (10.3 g, 31.6 mmol, 2.00 equivalent) is added. The mixture is stirred at 60°C for 1 hour. The reaction mixture is filtered, and the filtrate is diluted with ethyl acetate (200 ml). The organic layer is washed three times with water (100 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue is purified by preliminary HPLC to obtain compound int 6k (4.00 g, 9.68 mmol, yield 61.2%, purity 96.9%) as a red oil. Compound int 6k (1.14 g, 3.75 mmol, 1.50 equivalents) is dissolved in ACN (50.0 ml), and K2CO3 (691 mg, 5.00 mmol, 2.00 equivalents) and KI (207 mg, 1.25 mmol, 0.50 equivalents) are added. The mixture is stirred at 70°C for 48 hours. The two batches of reaction mixtures are combined and processed. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to obtain the residue. The residue is purified by preliminary HPLC to obtain compound int 7k (2.00 g, 3.08 mmol, yield 61.7%, purity 96.1%) as a red oil. Compound int 7k (1.80 g, 2.77 mmol, 1.00 equivalent) is dissolved in DMF (2.00 ml), and Pd(PPh3)4 (480 mg, 415 μmol, 0.15 equivalent) and N-methylaniline (594 mg, 5.54 mmol, 602 μL, 2.00 equivalent) are added. The mixture is stirred at 25°C for 1 hour under an N2 atmosphere. The reaction mixture is concentrated under reduced pressure to obtain the residue. The residue is purified by preliminary HPLC to obtain compound int 8k (1.00 g, 1.60 mmol, yield 57.70%, purity 93.3%) as a yellow solid. Compound int 8k (750 mg, 1.20 mmol, 1.00 equivalent) and compound 8a (240.16 mg, 1.20 mmol, 1 equivalent) are dissolved in DCM (20.0 ml), and pyridine (474 ​​mg, 6.00 mmol, 484 μL, 5.00 equivalent) and POCl3 (221 mg, 1.44 mmol, 134 μL, 1.20 equivalent) are added at 0°C. The mixture is stirred at 25°C for 1 hour. The organic layer is washed three times with water (10.0 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue is purified by preliminary HPLC to obtain compound int 9k (500 mg, 646 μmol, yield 53.8%, purity 98.9%) as a yellow oil. Compound int 9k (200 mg, 258 μmol, 1.00 equivalent) is dissolved in methanol (2.00 ml), and Pd / C (55.0 mg, 51.7 μmol, 10% purity, 0.20 equivalent) is added under an N2 atmosphere. Bubbles are removed from the suspension under vacuum, and the mixture is purified several times with H2. The mixture is stirred at 25°C under H2 (15 psi) for 3 hours. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to obtain compound int 10k (50.0 mg, crude product) as a colorless oil. Compound int 10k (50.0 mg, 111 μmol, 1.00 equivalent) and DOTA-OSu (74.2 mg, 111 μmol, 1.00 equivalent) were dissolved in DMF (1.00 ml), and then DIEA (14.3 mg, 1115 μmol, 19.3 μL, 1.00 equivalent) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was added to stirred MTBE (100 ml), and then centrifuged to obtain compound int 11k (50.0 mg, 49.69 μmol, yield 44.9%, purity 100%) as a yellow oil. Compound int 11k (50.0 mg, 49.7 μmol, 1.00 equivalent) is dissolved in DMF (2.00 ml), and HBTU (28.3 mg, 74.5 μmol, 1.50 equivalent), HOBT (10.1 mg, 74.5 μmol, 1.50 equivalent), TEA (25.1 mg, 248 μmol, 34.6 μL, 5.00 equivalent), and compound 11a (47.0 mg, 74.5 μmol, 1.50 equivalent) are added. The mixture is stirred at 25°C for 12 hours. The reaction mixture was purified by preliminary HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-acetonitrile]; gradient: 14% - 44% B, sustained for 10 minutes) to obtain compound int 12k (25.0 mg, 18.5 μmol, yield 37.3%, purity 87.3%) as a white solid. 20.0 mg (14.8 μmol, 1.00 equivalent) of compound int 12k is dissolved in DCM (5.00 ml), and then TFA (6.14 g, 53.9 mmol, 4.00 ml, 3631 equivalents) and TIS (9.39 mg, 59.3 μmol, 12.2 μL, 4.00 equivalents) are added. The mixture is stirred at 25°C for 4 hours. The reaction mixture is filtered and concentrated under reduced pressure to obtain the residue. The residue (under TFA conditions) is purified by prep-HPLC to obtain compound int 13k (14.2 mg, 9.49 μmol, yield 64.0%, purity 99.4%, 4 TFA) as a white solid. Compound FAPI-CB-59 was obtained from 14.0 mg in 13k of compound (11.8 mg, yield 78%, purity 99.5%) following the same method and procedure as in Example 1d. It was purified by HPLC [eluent A: H2O (0.1% TFA); eluent B: ACN, from 10% B (2 mins) to 60% B (20 mins)]. UPLC-MS analysis conditions: separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, eluent A: H2O (0.1% TFA); eluent B: MeOH; 0-0.2 min, 95% A; 0.2-3.0 min, 95%-5% A, curve 6; 3.0-4.0 min, 5% A; 4.0-4.5 min, 5%-95% A, curve 6; 4.5-5.0 min, 95% A. The calculated m / z is [M+H]. + The value is 1092, and the holding time is 1.76 minutes.

[0048] Example 11. Synthesis of FAPI-CB-77 [ka] Compound int 2l can be readily prepared by polypeptide solid-phase synthesis. Compound FAPI-CB-77 is obtained from compound int 3l (5.5 mg, yield 32.6%, purity 98.2%) by purification by HPLC following the same method route as in Example 1a [eluent A: H2O (0.1% TFA); eluent B: ACN, from 10% B (2 mins) to 60% B (20 mins)]. UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, eluent A: H2O (0.1% TFA); eluent B: MeOH; 0-0.2 min, 95% A; 0.2-3.0 min, 95%-5% A, curve 6; 3.0-4.0 min, 5% A; 4.0-4.5 min, 5%-95% A, curve 6; 4.5-5.0 min, 95% A. The calculated m / z is [M+H]. + The value is 1577, and the holding time is 1.71 minutes.

[0049] Example 1: Synthesis of FAPI-CB-86 [ka] Compound FAPI-CB-86 was obtained from compound int 1m (3.5 mg, yield 12.0%, purity 97.2%) following the same method and route as in Example 1k. It was purified by HPLC [eluent A: H2O (0.1% TFA); eluent B: ACN, from 10% B (2 mins) to 60% B (20 mins)]. UPLC-MS analysis conditions: separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, eluent A: H2O (0.1% TFA); eluent B: MeOH; 0-0.2 min, 95% A; 0.2-3.0 min, 95%-5% A, curve 6; 3.0-4.0 min, 5% A; 4.0-4.5 min, 5%-95% A, curve 6; 4.5-5.0 min, 95% A. The calculated m / z is [M+H] + The value is 1221, and the holding time is 1.90 minutes.

[0050] Example 1n. Synthesis of FAPI-CB-93 [ka] Compound FAPI-CB-93 was obtained from int 1n (3.5 mg, yield 12.0%, purity 97.2%) following the same method and route as in Example 1k. It was purified by HPLC [eluent A: H2O (0.1% TFA); eluent B: ACN, from 10% B (2 mins) to 60% B (20 mins)]. UPLC-MS analysis conditions: separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, eluent A: H2O (0.1% TFA); eluent B: MeOH; 0-0.2 min, 95% A; 0.2-3.0 min, 95%-5% A, curve 6; 3.0-4.0 min, 5% A; 4.0-4.5 min, 5%-95% A, curve 6; 4.5-5.0 min, 95% A. The calculated m / z is [M+H]. + The value is 1164, and the holding time is 1.85 minutes.

[0051] Example 10. Synthesis of FAPI-CB-94 [ka] Compound int 5o is prepared using the steps described in "Phosphorus fluoride exchange: Multidimensional catalytic click chemistry from phosphorus connective hubs" by Sun, S. et al. (Chem 2023, 9, 2128-2143). Compound int 1o (6.0 g, 37.0 mmol) is dissolved in acetone (150 ml) and stirred. KF (17.1 g, 296 mmol) is added to the solution. The mixture is stirred at room temperature for 3 hours, then filtered through Celite. The solvent is evaporated under reduced pressure to obtain a sufficient amount of phosphorus amide difluoro compound int 2o in single yield. The int 2O and a commercially available int 3O reaction mixture were stirred at room temperature for 1 hour. Then, the reaction mixture was diluted with 200 ml of ethyl acetate, and the organic phase was sequentially washed with water (200 ml) and brine (200 ml). The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography (silica gel hexane: EA = 4:1) to obtain a colorless oily product int 3O (4.6 g, 60.9%). Add 100 mg of 10% Pd / C to a 50 ml round-bottom flask, then add 5 ml of methanol under an inert atmosphere (argon). Dissolve compound int 4o (1.0 g, 3.0 mmol) in methanol (5 ml) and add it to the flask, then seal with a rubber stopper. Elevate the round-bottom flask and fill with hydrogen gas using a hydrogen gas ball. Stir vigorously for 1 hour under a hydrogen atmosphere, then filter through diatomaceous earth. Remove the solvent under reduced pressure to obtain the white solid compound int 5o (627 mg, 84.6%). Compound int 5o (120 mg, 0.81 mmol, 1 equivalent), compound 5 (115 mg, 0.97 mmol, 1.2 equivalents), and EDCI (191 mg, 0.97 mmol, 1.2 equivalents) were dissolved in DCM (5 ml) and stirred at room temperature for 1 hour. LC-MS detected that the reaction was incomplete, so DMAP (9 mg, 0.08 mmol, 0.1 equivalents) was added and stirring continued for 2 hours. LC-MS indicated that the reaction was complete. Petroleum ether was added and recrystallization was performed to obtain the white solid compound int 6o (140 mg, 50% yield). Compound int 7o was obtained from int 3a following the same procedure as in Example 1d (yield 80.1%). Compound FAPI-CB-94 was obtained from int 7o by HPLC following the same procedure as in Example 1a [eluent A: H2O (0.1% TFA); eluent B: ACN, from 10% B (2 mins) to 60% B (20 mins)] (3.5 mg, yield 77.6%, purity 98.2%). UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, eluent A: H2O (0.1% TFA); eluent B: MeOH; 0-0.2 min, 95% A; 0.2-3.0 min, 95%-5% A, curve 6; 3.0-4.0 min, 5% A; 4.0-4.5 min, 5%-95% A, curve 6; 4.5-5.0 min, 95% A. The calculated m / z is [M+H]. + The value is 1190, and the holding time is 1.53 minutes.

[0052] Example 1p. Synthesis of FAPI-CB-95 [ka] Compound FAPI-CB-95 was obtained from the intermediate compound int 1p, which is readily available by polypeptide solid-phase synthesis, following the same method route as in Example 1a (3.6 mg, yield 11.9%, purity 98.5%). Purification by HPLC [Eluting agent A: H2O (0.1% TFA); Eluting agent B: ACN, from 10% B (2 mins) to 60% B (20 mins)]. UPLC-MS analysis conditions: Separation column, ACQUITY UPLC BEH C18 1.7 μm 2.1 × 50 mm. Method, flow rate 0.5 mL / min, Eluting agent A: H2O (0.1% TFA); Eluting agent B: MeOH; 0~0.2 min, 95% A; 0.2~3.0 min, 95%~5% A, curve 6; 3.0~4.0 min, 5% A; 4.0~4.5 min, 5%~95% A, curve 6; 4.5~5.0 min, 95% A. Calculated m / z is [M + H] + The value is 1203, and the holding time is 1.61 minutes.

[0053] Example 2: Preparation of nuclear drug molecules using nuclide-labeled precursor compounds in general, 68 Radiolabeling of Ga is performed after incubation with 10 nmol of FAPI-CB system precursor at pH = 4.0 and 90°C for 10 minutes. The product is C 18 The sample is purified using a Waters column, and its radiochemical purity is measured by high-performance liquid chromatography (radio-HPLC) equipped with a radioactive detector. Its stability in phosphate buffer (0.01 M, pH 7.4) and human serum is detected at 37°C (proteins in human serum need to be removed by acetonitrile precipitation). in general, 177 Radiolabeling of Lu is performed after incubation with several FAPI-CB system precursors at pH = 4.5 and 50-90°C for 10 minutes. The product is C 18 The sample is purified using a Waters column, and its radiochemical purity is measured by high-performance liquid chromatography (radio-HPLC) equipped with a radioactive detector. Its stability in phosphate buffer (0.01 M, pH 7.4) and human serum is detected at 37°C (proteins in human serum need to be removed by acetonitrile precipitation). Generally, Al 18 The radioactive labeling of F is performed as follows: Prepared using a commercially available accelerator. 18 After concentrating the F anion-containing aqueous solution to 10 μL using a nitrogen blow apparatus, add 6 mM Al 3+ Add 2 μL of 0.2 M sodium acetate solution (pH = 4.0, 12 nmol), 30 μL of acetonitrile, and 20 μL of 0.2 M sodium acetate buffer (pH = 4.0), and heat at 100°C for 5 minutes to [Al 18 F] 2+ Prepare the mixture, then add 20 nmol of the corresponding FAPI-CB precursor molecule and incubate at 100°C for 15 minutes. The product is C 18The sample is purified using a Waters column, and its radiochemical purity is measured by high-performance liquid chromatography (radio-HPLC) equipped with a radioactive detector. Its stability in phosphate buffer (0.01 M, pH 7.4) and human serum is detected at 37°C (proteins in human serum need to be removed by acetonitrile precipitation). RadioHPLC analysis conditions: Separation column, XBridgeR C 18 5 μm 4.6 × 150 mm; Elutate A: H2O (0.1% trifluoroacetic acid); Elutate B: Acetonitrile (0.1% trifluoroacetic acid); 0-2 min, 90% A phase; 2-10 min, 90%-40% A phase, linear mode 6; 10-12 min, 40% A phase; 12-13 min, 40%-90% A phase, linear mode 6; 13-15 min, 90% A phase; Retention time: Product 7.4 min, purity approx. 98.6%, hydrolysis by-product 6.1 min, approx. 1.4%. 68 Ga, 177 Lu, 86 Y and 225 FAPI-CB-22, FAPI-CB-28, FAPI-CB-30, FAPI-CB-31, FAPI-CB-44, FAPI-CB-45, FAPI-CB-4 labeled with Ac 7, FAPI-CB-50, FAPI-CB-53, FAPI-CB-59, FAPI-CB-77, FAPI-CB-86, FAPI-CB-93, FAPI-CB-94, and Al 18 FAPI-CB-36 and FAPI-CB-95 labeled with F are readily obtainable by the same method as described above and by the disclosed prior art. 68 The radioactive HPLC spectra of Ga-FAPI-CB-30 are shown in Figure 2. The left figure is the quality control diagram after labeling, the middle figure is the stability monitoring diagram after incubation with serum for 1 hour, and the right figure is the stability monitoring diagram after incubation with serum for 2 hours. 68 Ga-FAPI-CB-31, 68 Ga-FAPI-CB-50, Al 18 The radioactive HPLC spectra of F-FAPI-CB-36 are shown in Figure 3, left, middle, and right, respectively.

[0054] Example 3: Molecular Experiment - Co-incubation with target protein - Acid-base treatment - Gel electrophoresis - Autoradiography - Comasi brilliant blue staining experiment Total volume 20 μL, precursor molecule concentration 200 nM 177 Lu-FAPI-CB-30 is incubated with 4 μM of human recombinant FAP protein at pH 7.4 (serum pH) or pH 6.5 (tumor microenvironment pH) at 37°C for 1 hour. The sample is then denatured with a strong acid or strong alkali to remove reversible interactions, followed by SDS-PAGE to separate the protein and nuclear drug molecules on a polyacrylamide gel. The gel is then collected and subjected to phosphorescent screen autoradiography (Amersham Typhoon imaging) to obtain a radioactive band for the nuclear drug. Finally, the gel is stained with Comasi brilliant blue, and the target protein appears blue. By comparing the radioactive band with the Comasi brilliant blue staining results, a radioactive band is observed in the protein-colored region at the top of the gel if the nuclear drug and protein form an irreversible covalent bond. Figure 4 shows the results obtained after co-incubation with protein, gel electrophoresis, autoradiography, and Coomassie blue staining. 177 This shows the efficiency of covalent linkage between Lu-FAPI-CB-30 and human-derived recombinant FAP protein. The left figure shows a control incubated at pH 7.4 for 1 hour, while the right figure shows a sample treated with a strong acid after 1 hour of incubation, demonstrating the continued presence of covalent linkage.

[0055] Example 4: Molecular experiment - Long-term co-incubation with target protein - Gel electrophoresis - Autoradiography - Comasi brilliant blue staining experiment Precursor molecule concentration 150 nM 177Lu-FAPI-CB-30 is incubated with 3 μM of recombinant human FAP protein at pH 7.4 and 37°C. The same volume is then sampled at different time points, protein loading buffer is added and mixed uniformly, and the samples are denatured uniformly (95°C, 5 minutes) in a -80°C refrigerator. SDS-PAGE is performed to separate the protein and nuclear drug molecules on a polyacrylamide gel. The gel is then collected and subjected to phosphorescent screen autoradiography (Amersham Typhoon imaging) to obtain a radioactive band for the nuclear drug. Finally, the gel is stained with Comasi brilliant blue, and the target protein appears blue. By comparing the radioactive band with the Comasi brilliant blue staining results, a radioactive band is observed in the protein-colored region at the top of the gel if the nuclear drug and protein form an irreversible covalent bond. Figure 5 shows the results obtained after co-incubation with protein, gel electrophoresis, autoradiography, and Coomassie blue staining. 177 This figure shows the ratio of covalent linkage between Lu-FAPI-CB-30 molecules and human-derived recombinant FAP proteins. The left figure is an autoradiography diagram, and the right figure shows the grayscale values ​​of the bands quantified using an image quantification tool such as ImageJ, corresponding to the ratio of covalently linked molecules.

[0056] Example 5: Molecular experiment - Long-term co-incubation with target protein - Gel electrophoresis - Autoradiography - Comasi brilliant blue staining experiment Precursor molecule concentration 150 nM 177Lu-FAPI-CB molecules are incubated with 3 μM of human-derived recombinant FAP protein under conditions of pH 7.4 and 37°C. After a certain period, the same volume is sampled, protein loading buffer is added and mixed uniformly, and the sample is placed in a -80°C refrigerator to uniformly denaturate (95°C, 5 minutes). SDS-PAGE is then performed to separate the protein and nuclear drug molecules on a polyacrylamide gel. Subsequently, the gel is collected and phosphorescent screen autoradiography (Amersham Typhoon imaging) is performed to obtain a radioactive band of the nuclear drug. Finally, the gel is stained with Comasi brilliant blue, and the target protein appears blue. By comparing the radioactive band with the Comasi brilliant blue staining results, a radioactive band is observed in the protein-colored region at the top of the gel when the nuclear drug and protein form an irreversible covalent bond. Figure 6 shows the results obtained after co-incubation with protein, gel electrophoresis, autoradiography, and Coomassie blue staining. 177 The diagram shows the ratio of covalent linkage between Lu-FAPI-CB system molecules and FAP human-derived recombinant proteins. The courses in the diagram are, from left to right, respectively. 177 These are FAPI-CB-22, FAPI-CB-28, FAPI-CB-31, FAPI-CB-44, FAPI-CB-45, FAPI-CB-47, and FAPI-CB-50 labeled with Su.

[0057] Example 6: Animal Experiment - PET / CT Imaging and Biological Distribution All PET / CT scans are performed using the Mediso nanoScan(R) PET 122S small animal PET / CT scanner. A certain number of HT-1080-FAP tumor mice were given 7.4-18.5 MBq at a specified time. 68 Ga / 86After injecting Y-FAPI-04 (control) and a radionuclide-labeled -FAPI-CB molecule into the tail vein, imaging is performed at specified times. At a certain point, the mice are anesthetized, euthanized by severing the cervical vertebrae, and organs are collected by dissection. Radioactivity is measured, and the uptake and retention of the nuclear drug in the tumors are comprehensively quantitatively analyzed.

[0058] Example 7a: 68 Ga-FAPI-CB-30 and 68 Ga-FAPI-CB-02 or 68 PET / CT comparison images in the HT-1080-FAP tumor-bearing mouse model of Ga-FAPI-04 With 5 mL of 0.6 M high-purity hydrochloric acid 68 Ge- 68 The Ga generator (iThemba LABS, South Africa) is washed to obtain a Ga-68 hydrochloric acid solution. 1 mL of the washed Ga-68 solution is taken, and 100 μL of 3M sodium hydroxide and 130 μL of 3M sodium acetate are added to adjust the acidity to a final pH of 4.0. 12 μg of FAPI-CB-02 precursor (the structure is as shown in Figure 7a, and FAPI-CB-02 is synthesized by using essentially the same steps as in Example 1a, but by replacing the corresponding reactants) is added, and the reaction mixture is heated to 90°C and held for 10 minutes. The reaction solution is then converted to C 18 The solution is passed through a Waters column to remove free ions, and then treated with an ethanol solution. 18 Elute the column. Labeled 68 Obtain Ga-FAPI-CB-02. Labeled 68 Ga-FAPI-CB-02 was diluted with physiological saline, and approximately 3.7 MBq (volume: approximately 200 μL) was injected into each mouse. 90 minutes after injection, imaging was performed using PET scans, and the images were reconstructed using image processing software. Furthermore, control FAPI-CB-30 was labeled using the same process, and PET imaging was performed on the same mice at 24-hour intervals. The resulting images are shown in Figure 7b. 68 The Ga-FAPI-CB-30 probe is taken up at tumor sites. 68 It is equivalent to Ga-FAPI-CB-02, but the background of the blood pool is lower. In a similar process 68 Ga-FAPI-CB-30 and 68 Comparing Ga-FAPI-04, as shown in Figure 7c, 68 Tumor uptake of Ga-FAPI-CB-30 is improved, and there is no significant increase in background.

[0059] Example 7b: 68 Ga-FAPI-CB-31 and 68 PET / CT comparison images in the HT-1080-FAP tumor-bearing mouse model of Ga-FAPI-04 With 5 mL of 0.6 M high-purity hydrochloric acid 68 Ge- 68 The Ga generator (iThemba LABS, South Africa) is washed to obtain a Ga-68 hydrochloric acid solution. 1 mL of the washed Ga-68 solution is taken, and 100 μL of 3M sodium hydroxide and 130 μL of 3M sodium acetate are added to adjust the acidity to a final pH of 4.0. 9 μg of FAPI-04 precursor is added, and the reaction mixture is heated to 90°C and held for 10 minutes. The reaction solution is then converted to C 18 The solution is passed through a Waters column to remove free ions, and then treated with an ethanol solution. 18 Elute the column. Labeled 68 Obtain Ga-FAPI-04. Labeled 68 Ga-FAPI-04 was diluted with physiological saline, and approximately 3.7 MBq (volume: approximately 200 μL) was injected into each mouse. 90 minutes after injection, imaging was performed using PET scans, and the images were reconstructed using image processing software. Furthermore, control FAPI-CB-31 was labeled using the same process, and PET imaging was performed on the same mice at 24-hour intervals. The resulting images are shown in Figure 8. 68 The Ga-FAPI-CB-31 probe is taken up in tumor sites. 68 Compared to Ga-FAPI-04, it shows improvement, and the background of the blood pool is similar (the structure of FAPI-04 is shown in Figure 8a).

[0060] Example 7c: Al 18 F-FAPI-CB-36 and68 PET / CT comparison images in the HT-1080-FAP tumor-bearing mouse model of Ga-FAPI-04 Labeled by the method in Example 2 68 Ga-FAPI-04 was diluted with physiological saline, and approximately 3.7 MBq (volume: approximately 200 μL) was injected into each mouse. Imaging was performed by PET scan 90 minutes after injection, and the images were reconstructed using image processing software. Furthermore, the Al from Example 2 was also used. 18 Labeled using the F labeling process and controlled by Al 18 F-FAPI-CB-36 was obtained, and PET imaging was performed on the same mouse at 24-hour intervals. The resulting tumor uptake SUV max As shown in Figure 9, Al 18 The F-FAPI-CB-36 probe is taken up at tumor sites. 68 Compared to Ga-FAPI-04, it showed a significant improvement in SUV of mouse tumors. max The average value achieved was 2.08, and the mice in the same group... 68 Ga-FAPI-04 SUV max The average value is found to be only 0.78.

[0061] Example 7d: 68 Ga-FAPI-CB-50 and 68 PET / CT comparison images in the HT-1080-FAP tumor-bearing mouse model of Ga-FAPI-04 With 5 mL of 0.6 M high-purity hydrochloric acid 68 Ge- 68 The Ga generator (iThemba LABS, South Africa) is washed to obtain a Ga-68 hydrochloric acid solution. 1 mL of the washed Ga-68 solution is taken, and 100 μL of 3M sodium hydroxide and 130 μL of 3M sodium acetate are added to adjust the acidity to a final pH of 4.0. 9 μg of FAPI-04 precursor is added, and the reaction mixture is heated to 90°C and held for 10 minutes. The reaction solution is then converted to C 18 The solution is passed through a Waters column to remove free ions, and then treated with an ethanol solution. 18 Elute the column. Labeled 68 Obtain Ga-FAPI-04. Labeled 68Ga-FAPI-04 was diluted with physiological saline, and approximately 3.7 MBq (volume: approximately 200 μL) was injected into each mouse. PET scanning was performed 90 minutes after injection, and the images were reconstructed using image processing software. Furthermore, control FAPI-CB-50 was labeled using the same process, and PET imaging was performed on the same mice at 24-hour intervals. The resulting image 2 hours after injection is shown in Figure 10a. 68 The Ga-FAPI-CB-50 probe is taken up at tumor sites. 68 Compared to Ga-FAPI-04, improvement was observed, and the background of the blood pool was reduced to some extent, as shown in Figure 10b, with SUV of tumor and blood pool. max When considering the ratio, 68 Ga-FAPI-CB-50 exhibits a superior clearance rate.

[0062] Example 7e: 68 Ga-FAP-2286 and 68 PET / CT comparison images in the HT-1080-FAP tumor-bearing mouse model of Ga-FAPI-CB-45 In the method of Example 2, the labeled 68 Ga-FAP-2286 (precursor structure as shown in Figure 11A, commercially available or readily available by referring to patent WO 2021 / 005125 A1 of 3B Pharmaceuticals GmbH application) was diluted in physiological saline, and approximately 3.7 MBq (volume: approximately 200 μL) was injected into each mouse. Imaging was performed by PET scan 90 minutes after injection, and the images were reconstructed using image processing software. Furthermore, the mice were labeled using the same process and used as controls. 68 Ga-FAPI-CB-45 was obtained, and PET imaging was performed on the same mouse at 24-hour intervals. The obtained images are shown in Figure 11B. 68 The Ga-FAPI-CB-45 probe is taken up at tumor sites. 68 Compared to Ga-FAP-2286, it shows improvement, and there is no significant increase in background noise.

[0063] Example 7f: 68 Ga-FAPI-CB-53 and68 PET / CT comparison images in the HT-1080-FAP tumor-bearing mouse model of Ga-FAPI-04 With 5 mL of 0.6 M high-purity hydrochloric acid 68 Ge- 68 The Ga generator (iThemba LABS, South Africa) is washed to obtain a Ga-68 hydrochloric acid solution. 1 mL of the washed Ga-68 solution is taken, and 100 μL of 3M sodium hydroxide and 130 μL of 3M sodium acetate are added to adjust the acidity to a final pH of 4.0. 9 μg of FAPI-04 precursor is added, and the reaction mixture is heated to 90°C and held for 10 minutes. The reaction solution is then converted to C 18 The solution is passed through a Waters column to remove free ions, and then treated with an ethanol solution. 18 Elute the column. Labeled 68 Obtain Ga-FAPI-04. Labeled 68 Ga-FAPI-04 was diluted with physiological saline and injected into each mouse at a dose of approximately 3.7 MBq (volume: approximately 200 μL). One hour after injection, imaging was performed using PET scans, and the images were reconstructed using image processing software. Furthermore, control FAPI-CB-53 was labeled using the same process, and PET imaging was performed on the same mice at 24-hour intervals. The resulting images one hour after injection are shown in Figure 12. 68 The Ga-FAPI-CB-53 probe is taken up in tumor sites. 68 Compared to Ga-FAPI-04, this shows improvement, and the background level of the blood pool is maintained at a low level.

[0064] Example 7g: 68 Ga-FAPI-CB-59 and 68 PET / CT comparison images in the HT-1080-FAP tumor-bearing mouse model of Ga-FAPI-04 Labeled using the same process as in Example 2 68 PET imaging was performed using Ga-FAPI-CB-59 in HT-1080-FAP mice, and the images obtained at 1 hour and 3 hours post-injection are shown in Figure 13. 68The Ga-FAPI-CB-59 probe showed high uptake at the tumor site, with almost no change in tumor uptake after 3 hours compared to 1 hour, indicating good tumor retention.

[0065] Example 7h: Al 18 F-FAPI-CB-77 and Al 18 PET / CT comparison images in the HT-1080-FAP tumor-bearing mouse model of F-FAPI-74 In the method of Example 2, labeled Al 18 F-FAPI-74 (structure as shown in Figure 14a) is diluted with physiological saline, and approximately 7.4 MBq (volume: approximately 200 μL) is injected into each mouse. Two hours after injection, imaging is performed by PET scan, and the images are reconstructed using image processing software. Furthermore, Al in Example 2 18 Labeled using the F labeling process and controlled by Al 18 F-FAPI-CB-77 was obtained, and PET imaging was performed on the same mouse at 48-hour intervals. The obtained images are shown in Figure 14b. 18 The F-FAPI-CB-77 probe is uptaken at tumor sites. 18 While it is somewhat lower than F-FAPI-74, and background uptake in the bile duct and intestines is significantly reduced, it still appears to have some advantage in the screening of gastrointestinal tumors.

[0066] Example 7i: 68 Ga-FAPI-CB-86 and 68 PET / CT comparison images in the HT-1080-FAP tumor-bearing mouse model of Ga-FAPI-04 With 5 mL of 0.6 M high-purity hydrochloric acid 68 Ge- 68The Ga generator (iThemba LABS, South Africa) is washed to obtain a Ga-68 hydrochloric acid solution. 1 mL of the washed Ga-68 solution is taken, and 100 μL of 3M sodium hydroxide and 130 μL of 3M sodium acetate are added to adjust the acidity to a final pH of 4.0. 9 μg of FAPI-04 precursor is added, and the reaction mixture is heated to 90°C and held for 10 minutes. The reaction solution is then converted to C 18 The solution is passed through a Waters column to remove free ions, and then treated with an ethanol solution. 18 Elute the column. Labeled 68 Obtain Ga-FAPI-04. Labeled 68 Ga-FAPI-04 was diluted with physiological saline, and approximately 3.7 MBq (volume: approximately 200 μL) was injected into each mouse. PET scanning was performed 90 minutes after injection, and the images were reconstructed using image processing software. Furthermore, control FAPI-CB-50 was labeled using the same process, and PET imaging was performed on the same mice at 24-hour intervals. The resulting image 2 hours after injection is shown in Figure 15a. 68 The Ga-FAPI-CB-50 probe is taken up at tumor sites. 68 Compared to Ga-FAPI-04, improvement was observed, and the background of the blood pool was reduced to some extent, as shown in Figure 15b, with respect to the tumor and blood pool SUV. max When considering the ratio, 68 Ga-FAPI-CB-50 exhibits a superior clearance rate.

[0067] Example 7j: 68 Ga-FAPI-CB-93 and 68 PET / CT comparison images in the HT-1080-FAP tumor-bearing mouse model of Ga-FAPI-04 With 5 mL of 0.6 M high-purity hydrochloric acid 68 Ge- 68The Ga generator (iThemba LABS, South Africa) is washed to obtain a Ga-68 hydrochloric acid solution. 1 mL of the washed Ga-68 solution is taken, and 100 μL of 3M sodium hydroxide and 130 μL of 3M sodium acetate are added to adjust the acidity to a final pH of 4.0. 9 μg of FAPI-04 precursor is added, and the reaction mixture is heated to 90°C and held for 10 minutes. The reaction solution is then converted to C 18 The solution is passed through a Waters column to remove free ions, and then treated with an ethanol solution. 18 Elute the column. Labeled 68 Obtain Ga-FAPI-04. Labeled 68 Ga-FAPI-04 was diluted with physiological saline, and approximately 3.7 MBq (volume: approximately 200 μL) was injected into each mouse. PET scanning was performed 90 minutes after injection, and the images were reconstructed using image processing software. Furthermore, control FAPI-CB-50 was labeled using the same process, and PET imaging was performed on the same mice at 24-hour intervals. The resulting image 2 hours after injection is shown in Figure 16a. 68 The Ga-FAPI-CB-50 probe is taken up at tumor sites. 68 Compared to Ga-FAPI-04, improvement was observed, and the background of the blood pool was reduced to some extent, as shown in Figure 16b, with respect to the tumor and blood pool SUV. max When considering the ratio, 68 Ga-FAPI-CB-50 exhibits a superior clearance rate.

[0068] Example 7k: 68 Ga-FAPI-CB-94 and 68 PET / CT comparison images in the HT-1080-FAP tumor-bearing mouse model of Ga-FAPI-04 Labeled by the method of Example 2 68Ga-FAPI-04 was diluted with physiological saline, and approximately 3.7 MBq (volume: approximately 200 μL) was injected into each mouse. One hour after injection, imaging was performed using PET scanning, and the images were reconstructed using image processing software. Furthermore, control FAPI-CB-94 was labeled using the same process, and PET imaging was performed on the same mice at 24-hour intervals. The resulting images one hour after injection are shown in Figure 17. 68 Ga-FAPI-CB-94 is taken up at tumor sites. 68 Compared to Ga-FAPI-04, there is an improvement, and no significant increase is observed in the background of the blood pool.

[0069] Example 7l: Al 18 F-FAPI-CB-95 and Al 18 PET / CT comparison images in the HT-1080-FAP tumor-bearing mouse model of F-FAPI-74 According to the method of Example 2, labeled Al 18 F-FAPI-74 (structure as shown in Figure 18a) was diluted with physiological saline, and approximately 7.4 MBq (volume: approximately 200 μL) was injected into each mouse. Two hours after injection, imaging was performed by PET scan, and the images were reconstructed using image processing software. Furthermore, the Al from Example 2 was also used. 18 Labeled using the F labeling process and controlled by Al 18 F-FAPI-CB-95 was obtained, and PET imaging was performed on the same mouse at 48-hour intervals. The obtained images are shown in Figure 18b. 18 The F-FAPI-CB-95 probe is uptaken at tumor sites by Al 18 Compared to F-FAPI-74, there is a certain degree of improvement, and it can be seen that background uptake in the bile duct and intestines is significantly reduced.

[0070] Example 8: Tumor uptake values Mice with the same HT-1080-FAP tumor (4 mice per group) had 18.5 MBq at time 0. 68 After administering Ga-FAPI-04 via tail vein injection, a PET-CT scan was performed on day 1, and 24 hours later, 68When Ga has almost completely decayed, it has the same specific activity of 18.5 MBq. 68 After injecting Ga-FAPI-CB into the tail vein, a PET-CT scan is performed again to obtain image data. Tumor uptake can be semi-quantified using the Standard Uptake Value (SUV) obtained after analyzing the reconstructed image after the PET-CT scan with the instrument's built-in software. SUV refers to the ratio of the radioactivity of the contrast agent taken up by the local tissue to the average whole-body injected radioactivity (SUV = radioactivity concentration of the lesion (kBq / ml) / (injection dose (MBq) / body weight (kg))). Compared with the most relevant conventional technology, FAPI-04, the maximum standard tumor uptake value (SUV) of the FAPI-CB molecule in several embodiments of the present invention was obtained in the HT-1080-FAP mouse model. max ), average standard capture value (SUV mean The percentage of the injection dose (ID% / g) showed a significant improvement of more than three times at 1 hour (n=4, p < 0.0001, see Figure 19), and a significant improvement was also observed in the ratio of tumor to blood pool standard uptake values ​​(see Figure 20). Clear superiority was also shown in representative PET-CT images. Furthermore, in some examples, the FAPI-CB molecule did not show a significant difference in blood pool uptake at 1 hour compared to FAPI-04, but tumor uptake was higher (see Figure 21). In some embodiments, for example, 68 Ga-FAPI-CB-47 and 68 In the PET-CT results for Ga-FAPI-04, Figure 22a shows that 68 The tumor uptake level of Ga-FAPI-CB-47 significantly improved and increased over time, indicating a certain degree of improvement in tumor uptake. Figure 22b shows that 68 The clearance rate of Ga-FAPI-CB-47 from the blood pool is rapid, with blood pool uptake decreasing by approximately two-thirds at 2 hours compared to 0.5 hours, indicating that cumulative toxicity can be controlled. Therefore, the nuclide-labeled FAPI-CB compounds of the present invention exhibit significantly improved tumor uptake and controllable or reduced background uptake, thus having extremely important significance in improving clinical tumor detection rates or in the treatment of tumors.

[0071] Example 9: Cancer patients 68 Ga-FAPI-CB-50 PET / CT imaging 3 mL of 0.05 M high-purity hydrochloric acid, compliant with GMP standards, for clinical use. 68 Ge- 68 Wash the Ga generator to obtain a Ga-68 hydrochloric acid solution. Take the washed Ga-68 solution (pH 4.0), add 300 μL of FAPI-CB-50 precursor, heat the reaction mixture to 90°C and hold for 15 minutes. Dissolve the reaction solution in C 18 The solution is passed through a Waters column to remove free ions, and then chlorinated with an 80% ethanol solution. 18 Elute the column. Labeled 68 Obtain Ga-FAPI-CB-50. Labeled 68 Ga-FAPI-CB-50 was diluted with physiological saline filtered through a sterile filter, and approximately 188 MBq of the drug was injected into a forearm vein in patients with a confirmed cancer diagnosis. PET scans were performed 60 minutes and 180 minutes after injection, and the images were reconstructed using PET-CT image processing software. The resulting images are shown in Figure 23a. 68 The Ga-FAPI-CB-50 probe exhibits high uptake at tumor sites and has a maximum standard uptake value (SUV). max The uptake level can reach approximately 45, and it can be seen that uptake in the lesion hardly decreases over time, while uptake levels in non-target organs gradually decrease. Within one week, the patient 18 F-FDG imaging was performed, and the resulting image is shown in Figure 23b. 68 Ga-FAPI-CB-50 clearly shows superior tumor imaging effects in comparison.

[0072] Example 10 Cancer patients 177 Lu-FAPI-CB-30 SPECT / CT imaging The method of Example 2 yields clinically compliant carrier-free products that meet GMP standards. 177 Use Lu to label, 177 Lu-FAPI-CB-30 (radioactive yield >99%, radioactive purity >99%, molar activity ~37 MBq / nmol) is obtained. 177 Lu-FAPI-CB-30 was diluted with physiological saline filtered through a sterile filter, and approximately 1.11 GBq of the drug was injected into a forearm vein in patients with a confirmed cancer diagnosis. SPECT / CT scans were performed at 24, 48, and 120 hours after injection, and the images were reconstructed using SPECT / CT image processing software. The resulting images are shown in Figure 24. 177 Lu-FAPI-CB-30 was found to have high uptake at tumor sites (the area enclosed by the dashed line is the peritoneal metastasis), and uptake at the lesion site decreased slowly over time, while uptake at non-target organs decreased more rapidly, thus providing a high target-to-background ratio. This suggests that the candidate molecule has a broad therapeutic window.

[0073] Example 11 Tumor model mouse 177 Lu-FAPI-CB-86 SPECT / CT imaging In the method of Example 2, the labeled 177 Lu-FAPI-CB-86 was diluted with physiological saline and approximately 25.9 MBq (molar activity ~29.6 MBq / nmol, volume approximately 200 μL) was injected via tail vein into HT-1080-FAP tumor-bearing mice. PET scans were performed 90 minutes after injection, and the images were reconstructed using SPECT / CT image processing software. The results are shown in Figure 25; Figure 25a is a representative SPECT / CT image of a mouse, and Figure 25b is the tumor SUV-time curve. The results indicate that the radionuclide molecule can remain in high-FAP-expressing tumor sites for an extended period, demonstrating a clear therapeutic effect (tumor reduction).

[0074] Example 12 Tumor model mouse 177 Treatment of Lu-FAPI-CB-30 The average tumor size is approximately 100 mm. 3If this is achieved (day 0), HT-1080-FAP tumor mice from the same lot will be randomly divided into three groups: a negative control group (injected with saline, n = 8 mice), a low-dose group ( 177 Lu-FAPI-CB-30 was injected at a dose of 22.2 MBq (number of mice n = 6), high-dose group ( 177 Lu-FAPI-CB-30 was injected at a dose of 44.4 MBq (number of mice n = 6). Treatment was administered only once on day 0. 177 Lu-labeled FAPI-CB-30 was prepared using the method described in Example 2 (radioactive yield >99%, radioactive purity >99%, molar activity ~29.6 MBq / nmol). Tumor size and body weight of mice were monitored every two or three days. As shown in Figure 26, Figure 26a is a schematic diagram of the treatment protocol, Figure 26b is the averaged tumor growth curve, Figure 26c is the tumor growth curve for each individual mouse in each group, and Figure 26d is the averaged normalized body weight curve. Compared to the saline control group, 177 Lu-FAPI-CB-30 exhibits a significant tumor-suppressing effect and is shown to be dose-dependent, and its toxicity can be controlled based on changes in mouse body weight.

[0075] Example 13 68 Ga-FAPI-CB-30 and 68 PET / CT comparative images in a mouse model of renal fibrosis using Ga-FAPI-04 Unilateral ureteral obstruction (UUO method) was used to induce left renal infarction in mice, and a mouse model of left renal fibrosis (high FAP expression in the fibrotic site) was created. On the 14th day of model creation, the mice were labeled using the method of Example 2. 68 Ga-FAPI-04 was diluted with physiological saline, and 11.2 MBq (approximately 200 μL in volume, n = 4 mice) was injected into each mouse model. One hour after injection, imaging was performed using PET scans, and the images were reconstructed using image processing software. Furthermore, the same process was used for control groups. 68Ga-FAPI-CB-30 was labeled, and PET imaging was performed on four other mouse models. The representative images (coronal plane) obtained one hour after injection are shown in Figure 27a. 68 Ga-FAPI-CB-30 shows high uptake in the left kidney with severe renal fibrosis, 68 Ga-FAPI-04 is the opposite. Figure 27b shows the quantitative results of the kidney SUV value. This example is used in the monitoring and staging of renal fibrosis. 68 This explains the advantages of Ga-FAPI-CB-30.

[0076] Unless otherwise specified in the context, the singular forms “a,” “an,” and “the” in this specification and the appended claims include the plural forms. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that ordinarily understood by those skilled in the art. Except for the specific order disclosed herein, the methods described herein may be carried out in any logically possible order.

[0077] Representative examples are provided for illustrative purposes only and should not be construed as limiting the scope of the invention. In practice, various modifications and many other embodiments of the invention will become apparent to those skilled in the art beyond those shown and described herein. These include examples and references to scientific and patent documents cited herein. The examples contain important additional information, illustrations, and guidance on how the invention can be practically adopted in its various embodiments and equivalents.

Claims

1. A trifunctional compound comprising at least one target substance T, at least one payload P, a pharmaceutically acceptable salt, stereoisomer or solvate thereof, In addition to any covalent warheads that may be present in the target material T itself, the trifunctional compound comprises at least one of the following covalent warheads C: The payload P is any optical functional group, radiolabeling functional group, radiolabelable functional group, or functional group of a small molecule cytotoxic drug that can be used for optical imaging, positron emission tomography, single-photon emission computed tomography, chemotherapy, or radiotherapy. The target substance T comprises a targeting group capable of targeting proteins or tissues, and the targeting group is a small molecule. The covalent warhead C can form a reversible or irreversible covalent bond with the protein or tissue targeted by the target substance T. Here, the covalent warhead C is 【Chemical 408】 、 【Chemical 409】 、 【Chemical 410】 、 【Chemical 411】 、 【Chemical 412】 、 【Chemical 413】 、 【Chemical 414】 、 【Chemical 415】 、 【Chemical 416】 、 【Chemical 417】 、 【Chemical 418】 、 【Chemical 419】 、 【Chemical 420】 、 【Chemistry 421】 、 【Chemistry 422】 、 【Chemistry 423】 、 【Chemistry 424】 、 【Chemical 425】 、 【Chemistry 426】 、 【Chemistry 427】 、 【Chemistry 428】 、 【Chemistry 429】 、 【Chemistry 430】 、 【Chemistry 431】 、 【Chemistry 432】 、 【Chemistry 433】 、 【Chemistry 434】 、 【Chemical 435】 、 【Chemistry 436】 、 【Chemistry 437】 、 【Chemistry 438】 、 【Chemistry 439】 、 【Chemical 440】 、 【Chemistry 441】 、 【Chemistry 442】 、 【Chemistry 443】 、 【Chemistry 444】 、 【Chemistry 445】 Selected from the group consisting of, Here: Y is O, S and NR 1 Selected from the group consisting of, LG is a release group that can be substituted with a protein residue, preferably a halogen or OTs, and Ts is p-toluenesulfonyl. R, R', and R'' are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, optionally substituted mercapto, optionally substituted seleno, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino. R 1 This is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. Het is an optionally substituted heterocyclic group or heteroaryl group, and if the heteroaryl group contains an N atom, the N atom may exist in a free form or in the form of an onium salt. Hal is a halogen, preferably F or Cl. Each p is an independent integer between 0 and 12. A trifunctional compound, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, characterized in that the at least one target substance T, at least one payload P, and at least one covalent warhead C are linked via a linking group portion.

2. The covalent warhead C is 【Chemistry 446】 、 【Chemistry 447】 、 【Chemistry 448】 、 【Chemistry 449】 、 [Chemical 450] 、 【Chemistry 451】 、 【Chemistry 452】 、 【Chemistry 453】 、 【Chemical 454】 Selected from the group consisting of, Here: Het is an arbitrarily substituted C 4 -C 12 Heterocyclic groups, or optionally substituted C 5 -C 12 If a heteroaryl compound contains an N atom, the N atom may exist in a free form or in the form of an onium salt. Hal is F, Each p is an independent integer between 0 and 6. R 1 The trifunctional compound according to claim 1, characterized in that is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

3. C is 【Chemistry 455】 、 【Chemistry 456】 、 【Chemistry 457】 、 【Chemistry 458】 Selected from the group consisting of, Here: It is C 4 , C 5 or C 6 a heterocyclic group, or C 5 or C 6 a heteroaryl, wherein the heterocyclic group or heteroaryl contains one or two heteroatoms selected from N, O or S, and when the heteroaryl contains an N atom, the N atom may exist in a free form or in the form of an onium salt, preferably exists in a free form, and more preferably, Het is azetidinyl, pyridyl, pyrrolyl or N-oxypyridinyl, Hal is F, The trifunctional compound according to claim 1, characterized in that each p is an independent integer between 0 and 4, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

4. A trifunctional compound comprising at least one target substance T, at least one payload P, a pharmaceutically acceptable salt, stereoisomer or solvate thereof, In addition to any covalent warheads that may be present in the target material T itself, the trifunctional compound comprises at least one of the following covalent warheads C: The payload P is any optical functional group, radiolabeling functional group, radiolabelable functional group, or functional group of a small molecule cytotoxic drug that can be used for optical imaging, positron emission tomography, single-photon emission computed tomography, chemotherapy, or radiotherapy. The target substance T comprises a targeting group capable of targeting proteins or tissues, and the targeting group is a small molecule. The covalent warhead C can form a reversible or irreversible covalent bond with the protein or tissue targeted by the target substance T. Here, the covalent warhead C is 【Chemistry 459】 、 【Chemical 460】 、 【Chemistry 461】 、 【Chemistry 462】 、 【Chemical Formula 463】 、 【Chemical 464】 、 【Chemical 465】 、 【Chemical 466】 、 【Chemistry 467】 、 【Chemical 468】 、 【Chemistry 469】 、 【Chemical 470】 、 【Chemistry 471】 、 【Chemistry 472】 、 【Chemistry 473】 、 【Chemistry 474】 、 【Chemistry 475】 、 【Chemistry 476】 、 【Chemistry 477】 、 【Chemistry 478】 、 【Chemistry 479】 、 【Chemical 480】 、 【Chemistry 481】 、 【Chemistry 482】 、 【Chemistry 483】 、 【Chem.484】 、 【Chemistry 485】 、 【Chemical 486】 、 【Chemistry 487】 、 【Chemical 488】 、 【Chemistry 489】 、 【Chemistry 490】 、 【Chemistry 491】 、 【Chemistry 492】 、 【Chemistry 493】 、 【Chem.494】 、 【Chemical 495】 、 【Chemistry 496】 、 【Chemistry 497】 、 【Chem.498】 Selected from the group consisting of, Here: Y is O, S and NR 1 Selected from the group consisting of, LG is a release group that can be substituted with a protein residue, preferably a halogen or OTs, and Ts is p-toluenesulfonyl. R, R', and R'' are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, optionally substituted mercapto, optionally substituted seleno, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino. R 1 This is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. Het is an optionally substituted heterocyclic group or heteroaryl group, and if the heteroaryl group contains an N atom, the N atom may exist in a free form or in the form of an onium salt. Hal is a detaching group, preferably a halogen, OH, or NH. 2 It is more F or Cl, Each p is an independent integer between 0 and 12. A trifunctional compound, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, characterized in that the at least one target substance T, at least one payload P, and at least one covalent warhead C are linked via a linking group portion.

5. The covalent warhead C is 【Chem.499】 、 [500] 、 【Chemical 501】 、 【Chemical 502】 、 【Chemical 503】 、 【Chemical 504】 、 【Chemical 505】 、 【Chemical 506】 、 【Chemical 507】 、 【Chemical 508】 、 【Chemical 509】 Selected from the group consisting of, Here: Het is an arbitrarily substituted C 4 -C 12 Heterocyclic groups, or optionally substituted C 5 -C 12 If a heteroaryl compound contains an N atom, the N atom may exist in a free form or in the form of an onium salt. Hal is F, Each p is an independent integer between 0 and 6. R 1 The trifunctional compound according to claim 4, characterized in that is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

6. C is 【Chemical 510】 、 【Chemical 511】 、 【Chemical 512】 、 【Chemical Formula 513】 、 【Chemical 514】 、 【Chemical 515】 Selected from the group consisting of, Here: Het is C 4 , C 5 or C 6 Heterocyclic group, or C 5 or C 6 The heteroaryl is a heteroaryl compound, wherein the heterocyclic group or heteroaryl compound comprises one or two heteroatoms selected from N, O, or S, and if the heteroaryl compound contains an N atom, the N atom may exist in a free form or in the form of an onium salt, preferably in a free form, and more preferably Het is azetidinyl, pyridyl, pyrrolyl, or N-oxypyridinyl. Hal is F, The trifunctional compound according to claim 4, characterized in that each p is an independent integer between 0 and 4, a pharmaceutically acceptable salt, stereoisomer or solvate thereof.

7. A trifunctional compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a stereoisomer or solvate thereof, The trifunctional compound comprises one to three payloads P, for example one or two payloads P, and one to three target substances T, for example one or two target substances T, and in addition to covalent warheads that may be present in the target substance T itself, the trifunctional compound comprises one to three covalent warheads C, for example one or two target substances C, and each linking group portion independently comprises 0 to 6 linking group units, and the linking group units may be divalent linking groups, for example single bonds, or trivalent linking groups, characterized in that the trifunctional compound, a pharmaceutically acceptable salt, stereoisomer or solvate thereof.

8. A trifunctional compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt, stereoisomer or solvate thereof, The aforementioned trifunctional compound has the structure of general formula (I), general formula (II), or general formula (III), 【Chemical 516】 General formula (I) 【Chemical Formula 517】 General formula (II) 【Chemical 518】 General formula (III) Here: Payloads P and P' are, independently, groups containing the same or different radionuclides, chelating groups capable of chelating radionuclides, optical dye groups, or small molecule cytotoxic drug groups. Target substances T and T' are each independently targeting groups capable of targeting the same or different proteins or tissues, and the targeting groups are small molecules. In general formulas (I), (II), and (III), in addition to the covalent warheads that may be present in the target material T itself, there are further one, two, or three identical or different covalent warheads C, each of which independently comprises the same or different linking base portion L 4 P, T, L are expressed by the general formula via 1 , connected to T' or P', Each L 1 , L 2 and L 3 The three functional compounds, their pharmaceutically acceptable salts, stereoisomers, or solvates, are characterized by being linking group portions, each independently containing 0 to 6 linking group units.

9. A trifunctional compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, stereoisomer or solvate thereof, The aforementioned trifunctional compound has the structure of general formula (Ia), general formula (Ib), general formula (Ic), general formula (IIa), or general formula (IIIa), 【Chemical 519】 General formula (Ia) 【Chemical 520】 General formula (Ib) 【Chem.521】 General formula (Ic) 【Chemical 522】 General formula (IIa) 【Chemical 523】 General formula (IIIa) Here: Each L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 , L 12 , L 13 , L 14 , L 15 , L 16 and L 17 Each is an independent linking group portion, and each independently contains 0 to 6 linking group units. a, b, c, d, e, and f are each independently either 0 or 1, and if they are 0, it indicates that the base in parentheses represented by that number does not exist, where the sum of a, b, and c is at least 1, and the sum of c, d, and e is at least 1. A trifunctional compound, a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof, characterized in that C, C', and C'' each independently have the meanings defined in claims 1 to 6.

10. The trifunctional compound according to any one of claims 1 to 9, characterized in that the targeting group targets fibroblast-activating protein-α (FAP-α), a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof.

11. The targeting group has general formula (IV), preferably general formula (IVa), more preferably general formula (IVc), general formula (IVd), general formula (IVe), or general formula (IVf). 【Chemical Formula 524】 General formula (IV) Here, in general formula (IV), A is O, S, NR A Selected from, R A H, C 1 -C 6 Selected from alkyl groups, Multiple R f There is a base, and each R f The groups are H, F, Cl, -CN, and -B(OH) respectively, independently. 2 , C 1 -C 6 Selected from alkyl and α-chloroketone groups, any two R groups on adjacent carbons f The groups can link together to form a cycloalkyl group, preferably C 3 -C 7 It is a cycloalkyl, B 1 and B 2 It is independently selected from O or S, R f1 and R f2 These are independently H, D and C 1 -C 4 Selected from alkyl groups, Ar is a carbon atom containing one N atom. 6 -C 10 It is a heteroaryl, 【Chemical Formula 525】 General formula (IVa), Here, in general formula (IVa), A is O, S, NR A Selected from, R A H, C 1 -C 6 Selected from alkyl groups, Multiple R f There is a base, and each R f The groups are H, F, Cl, -CN, and C, respectively, independently. 1 -C 6 Selected from alkyl and α-chloroketone groups, any two R groups on adjacent carbons f The groups can link together to form a cycloalkyl group, preferably C 3 -C 7 It is a cycloalkyl, 【Chemical 526】 General formula (IVb), 【Chemical Formula 527】 General formula (IVc), 【Chemical 528】 General formula (IVd), 【Chemical 529】 General formula (IVe), Here, in general formulas (IVb), (IVc), (IVd), or (IVe), A is O, S, NR A Selected from, R A The trifunctional compound according to any one of claims 1 to 10, characterized in that is selected from H, methyl, ethyl, n-propyl, and isopropyl, a pharmaceutically acceptable salt thereof, stereoisomer, or solvate thereof.

12. The aforementioned targeting group has general formula (V), 【Chemical 530】 General formula (V), The peptide sequence is drawn from left to right, in the direction from the N-terminus to the C-terminus. Xaa1 is an amino acid residue of general formula (VI), 【Chemistry 531】 General formula (VI) Here: R 1a is -NH-R 1a’ And R 1a’ is a protecting group or an amino acid, preferably the protecting group is R 1a’’ -C(O)- or R 1a’’ -S(O 2 )- and R 1a’’ C 1 -C 6 It is an alkyl group, where optionally one -CH group. 2 - The group is substituted with -S- or -O-, R 1b is H or methyl, g is either 0 or 1. The carbonyl group of Xaa1 is covalently bonded to the nitrogen of Xaa2. The sulfur atom of Xaa1 is covalently bonded to Yc as a thioether. Xaa2 and Xaa3 are independently selected from amino acid residues of general formula (VII) or general formula (VIII). 【Chemical 532】 General formula (VII), 【Chemical 533】 General formula (VIII), Here, h is 0, 1, or 2. i is either 1 or 2. j is 1, 2, or 3. The amino acid of the general formula (VII) has methyl, OH, and NH at the indicated ring positions 3 and 4. 2 It may be substituted with one or two substituents selected from F, Xaa4 is an amino acid residue of general formula (IX), 【Chemistry 534】 General formula (IX), Here, R 4a is selected from H, OH, COOH and CONH 2 and q is 1, 2, or 3, where q is any one of the 1, 2, or 3 CH 2 One or two hydrogen atoms in the group are independently substituted with methyl or ethyl atoms. R 4b is H or methyl, Xaa5 is an amino acid residue of general formula (X), 【Chemical 535】 General formula (X), Here: R 5a is OH or NH 2 And, m is 1, 2, or 3. R 5b is H or methyl, Xaa6 is an amino acid selected from aromatic La-amino acids, preferably a residue of an amino acid of general formula (XI). 【Chemical 536】 General formula (XI), Here, R 6a and R 6b are each independently selected from H, methyl, ethyl, propyl and isopropyl, preferably H, R 6c The 'x' represents 0 to 3 substituents, and each substituent is independently F, Cl, Br, NO 2 NH 2 , CN, CHF 3 , OH, OR 6d and C 1 -C 4 Selected from alkyl groups, R 6d It is selected from methyl, ethyl, propyl and isopropyl, l is 0 or 1, preferably 0. The CR shown here 6a R 6b (CH 2 ) l PhR 6c The portion can constitute part of the covalent warhead C in general formula (I), (II), or (III), Xaa7 is an aminothiol or amino acid residue of general formula (XII), 【Chemical Formula 537】 General formula (XII), Here, R 7a H, -COOH, -CONH 2 or CH 2 It is OH, n is either 1 or 2. Yc has the structure of general formula (XIII), 【Chemical 538】 General formula (XIII), When two thioether bonds are formed, the sulfur atom of Xaa1 and the sulfur atom of Xaa7 are linked, thereby forming a cyclic structure of general formula (XIV). 【Chemical 539】 General formula (XIV), Here, the substitution patterns of the aromatic group in general formula (XIII) are ortho, para, or meta. g is either 0 or 1. n is either 1 or 2. Y 1 is CH or N, Y 2 CR L1 And, R L1 is a linking unit that is linked to the other parts in general formula (I), The targeting group is preferably 【Chemical 540】 A trifunctional compound according to any one of claims 1 to 9, characterized by having formula (Va), a pharmaceutically acceptable salt, stereoisomer or solvate thereof.

13. The payload P includes at least one base selected from the following base group: Group 1: A group having at least one radionuclide, 【Chemistry 541】 、 【Chemistry 542】 、 【Chemistry 543】 、 【Chemical 544】 、 【Chemical 545】 、 【Chemical 546】 、 【Chemical 547】 、 【Chemical 548】 、 【Chemistry 549】 、 【Chemical Formula 550】 、 【Chemistry 551】 , and 【Chemical Formula 552】 Selected from, Here, R 2 , R 3 , R 4 and R 5 These are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. X is 18 F, 123 I, 124 I, 125 I, 131 I and 211 Selected from At or its non-radioactive isotopes, q and r are independent integers between 0 and 4. The nitrogen atom on the triazole ring at the linking site shown here is not present on the payload P, but may be located on the linking unit. Group 2: Chelate groups capable of chelating radionuclides, 【Chemical 553】 、 【Chemical 554】 、 【Chemical 555】 、 【Chemical Formula 556】 、 【Chemical 557】 、 【Chemical Formula 558】 、 【Chemical 559】 、 【Chemical 560】 、 【Chemical 561】 、 【Chemical 562】 、 【Chemical Formula 563】 、 【Chemical 564】 、 【Chemical 565】 、 【Chemical 566】 、 【Chemical 567】 、 【Chemical Formula 568】 、 【Chemical 569】 、 【Chemical 570】 、 【Chemistry 571】 、 【Chemistry 572】 , and 【Chemistry 573】 Selected from, Group 3: Optical dye groups, 【Chemistry 574】 、 【Chemical 575】 、 【Chemical 576】 、 【Chemical 577】 、 【Chemical 578】 、 【Chemistry 579】 、 【Chemical 580】 、 【Chemistry 581】 、 【Chemical Formula 582】 、 【Chemical 583】 、 【Chemical 584】 、 【Chemical 585】 , and 【Chemical 586】 Selected from, Group 4: Small molecule cytotoxic drug groups, 【Chemical 587】 【Chemical 588】 and 【Chemical 589】 A trifunctional compound according to any one of claims 1 to 12, characterized by being selected from, a pharmaceutically acceptable salt, stereoisomer or solvate thereof.

14. L 1 When is a trivalent linking group, that is, when the covalent warhead C is linked, or L 4 Independently, 【Chemical 590】 ， 【Chemistry 591】 ， 【Chem.592】 and 【Chem.593】 If selected from, L 1 ~L 17 The divalent linking units contained within are independently, single bond, 【Chem.594】 、 【Chemical Formula 595】 、 【Chemical 596】 、 【Chem.597】 、 【Chemical 598】 、 【Chemical 599】 、 【Chemical 600】 、 【Chemical 601】 、 【Chemical 602】 、 【Chemical 603】 、 【Chemical 604】 、 【Chemical 605】 , and 【Chemical 606】 Selected from, The methylene in the divalent linking group unit described herein is one or more -COR L2 Base or -COOR L2 It can be substituted with a base, where each R L2 H and C are independent of each other. 1 -C 6 Alkyl, C 6 -C 10 Ariel, C 6 -C 10 C replaced by aryl 1 -C 6 Selected from alkyl groups, L 18 This is a single bond, -CH 2 -, -NHCH 2 -, or 【Chemical 607】 And, Church 【Chemical 608】 、 【Chemical 609】 、 【Chemical 610】 、 【Chemical 611】 、 【Chemical 612】 and 【Chemical 613】 Selected from, u, u1, u2, u3, u4, u5, u6, u7, u8, u9, u10, u11, v and o are independently 1, 2, 3, 4 or 5. Each R 6 and R 7 These are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. * indicates a site that is linked to the target substance T. ** is the part connected to the covalent warhead C, The condition is, L 1 ~L 17 A trifunctional compound according to any one of claims 1 to 13, characterized in that the heteroatoms are not directly linked via covalent bonds, and the heteroatoms are selected from N, O, and S, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

15. L 1 This is when the linking group is trivalent, that is, when the covalent warhead C is linked, or L 4 Independently, 【Chemical Formula 614】 、 【Chemical 615】 、 【Chemical 616】 、 【Chemical 617】 , and 【Chemical Formula 618】 If selected from, L 1 ~L 17 The divalent linking units contained within are independently, single bond, 【Chemical 619】 、 【Chemical 620】 、 【Chemical 621】 、 【Chemical Formula 622】 、 【Chemical 623】 、 【Chemical 624】 、 【Chemical 625】 、 【Chemical Formula 626】 、 【Chemical Formula 627】 、 【Chemical Formula 628】 、 【Chemical Formula 629】 、 【Chemical 630】 、 【Chemistry 631】 and 【Chemical 632】 Selected from, The methylene in the divalent linking group unit described herein is one or more -COR L2 Base or -COOR L2 It can be substituted with a base, where each R L2 H and C are independent of each other. 1 -C 6 Alkyl, C 6 -C 10 Ariel, C 6 -C 10 C replaced by aryl 1 -C 6 Selected from alkyl groups, L 18 This is a single bond, -CH 2 -, -NHCH 2 -, or 【Chemical Formula 633】 And, Church 【Transformation 634】 、 【Chemical 635】 、 【Chemical 636】 、 【Chemical Formula 637】 、 【Chemical 638】 and 【Chemistry 639】 Selected from, u, u1, u2, u3, u4, u5, u6, u7, u8, u9, u10, u11, u12, v and o are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Each R 6 and R 7 These are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. * indicates a site that is linked to the target substance T. ** is the part connected to the covalent warhead C, The condition is, L 1 ~L 17 A trifunctional compound according to any one of claims 1 to 13, characterized in that the heteroatoms are not directly linked via covalent bonds, and the heteroatoms are selected from N, O, and S, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

16. A trifunctional compound according to any one of claims 1 to 11 and 13 to 15, a pharmaceutically acceptable salt, stereoisomer or solvate thereof, The aforementioned trifunctional compound has the structure of general formula (Ia), L 4 teeth, 【Chemical 640】 or 【Chemistry 641】 And, L 4 Preferably 【Chemistry 642】 、 【Chemistry 643】 、 【Chemical Formula 644】 , or 【Chemistry 645】 Having a structure, Here, R 6 , R 7 , L 18 A trifunctional compound, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, characterized in that Cy, o, and u have the definitions described in claim 14 or 15.

17. A trifunctional compound according to claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof, The aforementioned trifunctional compound has the structure of general formula (Ia) or general formula (Ib), 【Chemical Formula 646】 General formula (Ia) 【Transformation 647】 General formula (Ib) Here: The L shown 4 This is a trivalent linking group portion, Each indicated L 5 , L 6 , L 7 and L 8 These are independently divalent linking group portions, each independently containing 0 to 6, preferably 0 to 3, linking group units. The indicated C is a covalent warhead, 【Chemical 648】 、 【Chemical Formula 649】 、 【Chemical 650】 、 【Chemical 651】 、 【Chemical 652】 、 【Chemical 653】 、 【Chemical 654】 、 【Chemical Formula 655】 、 【Chemical 656】 Selected from the group consisting of, Het is an arbitrarily substituted C 4 -C 12 Heterocyclic groups, or optionally substituted C 5 -C 12 If a heteroaryl compound contains an N atom, the N atom may exist in a free form or in the form of an onium salt. Hal is either F or Cl. Y is O, S and NR 1 Selected from the group consisting of, Each p is an independent integer between 0 and 6. Each R 1 These are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. Each R is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, optionally substituted mercapto, optionally substituted seleno, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino. The indicated T is a targeting group that targets fibroblast-activating protein-α (FAP-α), The P shown is a chelating group capable of chelating radionuclides, and the compound is a trifunctional compound, a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof.

18. A trifunctional compound according to claim 17, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, The aforementioned trifunctional compound has the structure of general formula (Ia) or general formula (Ib), Here: Said L 4 teeth, 【Chemical Formula 657】 、 【Chemical Formula 658】 、 【Chemistry 659】 and 【Chemical Formula 660】 A trivalent linking group selected from, Each said L 5 , L 6 , L 7 and L 8 Each is an independently divalent linking group portion, each independently containing 0 to 3, preferably 0 or 1, linking group units, and each linking group unit independently single bond, 【Chemical Formula 661】 、 【Chemical 662】 、 【Chemical Formula 663】 、 【Chemical Formula 664】 、 【Chemical Formula 665】 、 【Chemical 666】 、 【Chemical 667】 、 【Chemical Formula 668】 、 【Chemical 669】 、 【Transformation 670】 、 【Chemistry 671】 、 【Transformation 672】 , and 【Chemistry 673】 Selected from, The methylene in the divalent linking group unit described herein is one or more -COR L2 Base or -COOR L2 It can be substituted with a base, where each R L2 H and C are independent of each other. 1 -C 6 Alkyl, C 6 -C 10 Ariel, C 6 -C 10 C replaced by aryl 1 -C 6 Selected from alkyl groups, L 18 This is a single bond, -CH 2 -, -NHCH 2 -, or 【Transformation 674】 And, Church 【Chemistry 675】 、 【Chemical Formula 676】 、 【Chemical 677】 、 【Chemical 678】 、 【Transformation 679】 and 【Chemical 680】 Selected from, u, u1, u2, u3, u4, u5, u6, u7, u8, u9, u10, u11, v and o are independently 1, 2, 3, 4 or 5. Each R 6 and R 7 These are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. * indicates a part connected to T, ** is the part connected to C, The condition is, L 5 , L 6 , L 7 and L 8 In this configuration, the heteroatoms are not directly linked via covalent bonds, and the heteroatoms are selected from N, O, and S. C is 【Chemistry 681】 、 【Chemical 682】 、 【Chemical Formula 683】 、 【Chemical Formula 684】 Selected from the group consisting of, Here: Het is C 4 , C 5 or C 6 Heterocyclic group, or C 5 or C 6 A heteroaryl compound, wherein the heterocyclic group or heteroaryl compound comprises one or two heteroatoms selected from N, O, or S, and if the heteroaryl compound contains an N atom, the N atom may exist in a free form or in the form of an onium salt, preferably in a free form, and preferably Het is C 4 , C 5 or C 6 Heterocyclic group, or C 5 or C 6 It is a heteroaryl compound, and the heterocyclic group or heteroaryl compound contains one N, O, or S atom, preferably a heteroatom of N, and more preferably Het is azetidinyl, pyridyl, pyrrolyl, or N-oxypyridinyl. Hal is F, Each p is an independent integer between 0 and 4. The indicated T is a targeting group that targets fibroblast-activating protein-α (FAP-α), The P shown is a chelating group capable of chelating radionuclides. 【Chemical 685】 、 【Chemical 686】 、 【Chemical 687】 、 【Chemical Formula 688】 、 【Chemical 689】 、 【Chemical 690】 、 【Chemistry 691】 、 【Chemistry 692】 、 【Chemistry 693】 、 【Chemical 694】 、 【Chemical 695】 、 【Chemical 696】 、 【Transformation 697】 、 【Chemical Formula 698】 、 【Chemical Formula 699】 、 【Chemical 700】 、 【Chemical 701】 、 【Chemical 702】 , and 【Chemical 703】 A trifunctional compound characterized by being a group selected from, a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof.

19. A trifunctional compound according to claim 17 or 18, a pharmaceutically acceptable salt, stereoisomer or solvate thereof, The aforementioned trifunctional compound has the structure of general formula (Ia), Here: C and P are as defined in claim 18, L 4 teeth, 【Chemical 704】 、 【Chemical 705】 、 【Chemical 706】 , or 【Chemical 707】 Having a structure, Each said L 5 and L 6 Independently, single bond, 【Chemical 708】 、 【Chemical 709】 、 【Chemical 710】 、 【Chem.711】 、 【Chemical 712】 、 【Chemical 713】 、 【Chemical Formula 714】 、 【Chemical 715】 、 【Chemical 716】 、 【Chemical 717】 、 【Chemical 718】 、 【Chemical 719】 , and 【Chemical 720】 And, Here, u, u1, u2, u3, u4, u5, u6, u7, u8, u9, u10, u11, v and o are independently 1, 2, 3, 4 or 5. Each R 6 and R 7 These are, independently of each other, hydrogen, and optionally substituted C 1 -C 4 Selected from the group consisting of, * indicates a part connected to T, ** is the part connected to C, The condition is, L 5 and L 6 In this configuration, the heteroatoms are not directly linked via covalent bonds, and the heteroatoms are selected from N, O, and S. T is general formula (IV), preferably having general formula (IVa), and more preferably having general formula (IVc), general formula (IVd), general formula (IVe), or general formula (IVf). 【Chem.721】 General formula (IV) Here, in general formula (IV), A is O, S, NR A Selected from, R A H, C 1 -C 6 Selected from alkyl groups, Multiple R f There is a base, and each R f The groups are H, F, Cl, -CN, and -B(OH) respectively, independently. 2 , C 1 -C 6 Selected from alkyl and α-chloroketone groups, any two R groups on adjacent carbons f The groups can link together to form a cycloalkyl group, preferably C 3 -C 7 It is a cycloalkyl, B 1 and B 2 It is independently selected from O or S, R f1 and R f2 These are independently H, D, or C 1 -C 4 Selected from alkyl groups, Ar is a carbon atom containing one N atom. 6 -C 10 It is a heteroaryl, 【Chemical 722】 General formula (IVa), Here, in general formula (IVa), A is O, S, NR A Selected from, R A H, C 1 -C 6 Alkyl is selected, Multiple R f There is a base, and each R f The groups are H, F, Cl, -CN, and C, respectively, independently. 1 -C 6 Selected from alkyl groups, any two R groups on adjacent carbons f The groups can link together to form a cycloalkyl group, preferably C 3 -C 7 It is a cycloalkyl, 【Chemical 723】 General formula (IVb), 【Chemical 724】 General formula (IVc), 【Chemical 725】 General formula (IVd), 【Chemical 726】 General formula (IVe), Here, in general formulas (IVb), (IVc), (IVd), or (IVe), A is O, S, NR A Selected from, R A The invention relates to a trifunctional compound characterized by being selected from H, methyl, ethyl, n-propyl, and isopropyl, a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof.

20. A trifunctional compound according to claim 17 or 18, a pharmaceutically acceptable salt, stereoisomer or solvate thereof, The aforementioned trifunctional compound has the structure of general formula (Ib), Here: In general formula (Ib), C and P have the same meanings as those described in claim 18. Each said L 7 and L 8 Independently, single bond, 【Chemical 727】 、 【Chemical Formula 728】 、 【Chemical 729】 、 【Chemical 730】 、 【Chemistry 731】 、 【Chemical 732】 、 【Chemical 733】 、 【Chemistry 734】 、 【Chemical 735】 、 【Chemical 736】 、 【Chemical 737】 、 【Chemical 738】 , and 【Chemical 739】 And, Here, u, u1, u2, u3, u4, u5, u6, u7, u8, u9, u10, u11, v and o are independently 1, 2, 3, 4 or 5. Each R 6 and R 7 These are, independently of each other, hydrogen, and optionally substituted C 1 -C 4 Selected from, The condition is, L 7 and L 8 In this configuration, the heteroatoms are not directly linked via covalent bonds, and the heteroatoms are selected from N, O, and S. T has the general formula (V), 【Chemical 740】 General formula (V), The peptide sequence is drawn from left to right, in the direction from the N-terminus to the C-terminus. Xaa1 is an amino acid residue of general formula (VI), 【Chemistry 741】 General formula (VI) Here: R 1a is -NH-R 1a’ And R 1a’ is a protecting group or an amino acid, preferably the protecting group is R 1a’’ -C(O)- or R 1a’’ -S(O 2 )- and R 1a’’ C 1 -C 6 It is an alkyl group, where optionally one -CH group. 2 - The group is substituted with -S- or -O-, R 1b is H or methyl, g is either 0 or 1. The carbonyl group of Xaa1 is covalently bonded to the nitrogen of Xaa2. The sulfur atom of Xaa1 is covalently bonded to Yc as a thioether. Xaa2 and Xaa3 are independently selected from amino acid residues of general formula (VII) or general formula (VIII). 【Chemistry 742】 General formula (VII), 【Chemical 743】 General formula (VIII), Here, h is 0, 1, or 2. i is either 1 or 2. j is 1, 2, or 3. The amino acid of the general formula (VII) has methyl, OH, and NH at the indicated ring positions 3 and 4. 2 It may be substituted with one or two substituents selected from F, Xaa4 is an amino acid residue of general formula (IX), 【Chemical 744】 General formula (IX), Here, R 4a H, OH, COOH and CONH 2 Selected from, q is 1, 2, or 3, where optionally the 1, 2, or 3 CH 2 One or two hydrogen atoms in the group are independently substituted with methyl or ethyl atoms. R 4b is H or methyl, Xaa5 is an amino acid residue of general formula (X), 【Chem.745】 General formula (X), Here: R 5a is OH or NH 2 And, m is 1, 2, or 3. R 5b is H or methyl, Xaa6 is an amino acid selected from aromatic La-amino acids, preferably a residue of an amino acid of general formula (XI). 【Chemical 746】 General formula (XI), Here, R 6a and R 6b Each of these is independently selected from H, methyl, ethyl, propyl, and isopropyl, and is preferably H. R 6c The 'x' represents 0 to 3 substituents, and each substituent is independently F, Cl, Br, NO 2 NH 2 , CN, CHF 3 , OH, OR 6d and C 1 -C 4 Selected from alkyl groups, R 6d It is selected from methyl, ethyl, propyl and isopropyl, l is 0 or 1, preferably 0. The CR shown here 6a R 6b (CH 2 ) l PhR 6c This part can constitute a part of C in general formula (Ib), Xaa7 is an aminothiol or amino acid residue of general formula (XII), 【Chemical 747】 General formula (XII), Here, R 7a H, -COOH, -CONH 2 or CH 2 It is OH, n is either 1 or 2. Yc has the structure of general formula (XIII), 【Chemical 748】 General formula (XIII), When two thioether bonds are formed, the sulfur atom of Xaa1 and the sulfur atom of Xaa7 are linked, thereby forming a cyclic structure of general formula (XIV). 【Chemical 749】 General formula (XIV), Here, the substitution patterns of the aromatic group in general formula (XIII) are ortho, para, or meta. g is either 0 or 1. n is either 1 or 2. Y 1 is CH or N, Y 2 CR L1 And, R L1 A trifunctional compound, a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof, characterized in that is a linking group unit linked to the other parts of general formula (Ib).

21. A trifunctional compound according to claim 17 or 18, a pharmaceutically acceptable salt, stereoisomer or solvate thereof, The aforementioned trifunctional compound has the structure of general formula (Ib), Here: L 7 , L 8 C and P are the same as those described in claim 20. T has the general formula (V), 【Chemical 750】 General formula (V), The peptide sequence is drawn from left to right, in the direction from the N-terminus to the C-terminus. Xaa1 is an amino acid residue of general formula (VI), 【Chemistry 751】 General formula (VI) Here: R 1a is -NH-R 1a’ And R 1a’ is a protecting group or an amino acid, preferably the protecting group is R 1a’’ -C(O)- or R 1a’’ -S(O 2 )- and R 1a’’ C 1 -C 6 It is an alkyl group, where optionally one -CH group. 2 - The group is substituted with -S- or -O-, R 1b is H or methyl, g is either 0 or 1. The carbonyl group of Xaa1 is covalently bonded to the nitrogen of Xaa2. The sulfur atom of Xaa1 is covalently bonded to Yc as a thioether. Xaa2 and Xaa3 are independently selected from amino acid residues of general formula (VII) or general formula (VIII). 【Chem.752】 General formula (VII), 【Chemical 753】 General formula (VIII), Here, h is 0, 1, or 2. i is either 1 or 2. j is 1, 2, or 3. The amino acid of the general formula (VII) has methyl, OH, and NH at the indicated ring positions 3 and 4. 2 It may be substituted with one or two substituents selected from F, Xaa4 is an amino acid residue of general formula (IX), 【Chem.754】 General formula (IX), Here, R 4a H, OH, COOH and CONH 2 Selected from, q is 1, 2, or 3, where optionally the 1, 2, or 3 CH 2 One or two hydrogen atoms in the group are independently substituted with methyl or ethyl atoms. R 4b is H or methyl, Xaa5 is an amino acid residue of general formula (X), 【Chemical 755】 General formula (X), Here: R 5a is OH or NH 2 And, m is 1, 2, or 3. R 5b is H or methyl, Xaa6 is an amino acid residue of general formula (XI), 【Chemical 756】 General formula (XI), Here, R 6a and R 6b Each of these is independently selected from H, methyl, ethyl, propyl, and isopropyl, and is preferably H. R 6c represents 0 to 1 substituent, and each substituent is independently F, Cl, NO 2 NH 2 , CN, CHF 3 , OH and C 1 -C 4 Selected from alkyl groups, R 6d It is selected from methyl, ethyl, propyl and isopropyl, l is 0 or 1, preferably 0. The CR shown here 6a R 6b (CH 2 ) l PhR 6c This part can constitute a part of C in general formula (Ib), Xaa7 is an aminothiol or amino acid residue of general formula (XII), 【Chemical 757】 General formula (XII), Here, R 7a is H or -COOH, n is either 1 or 2. Yc has the structure of general formula (XIII), 【Chemical 758】 General formula (XIII), When two thioether bonds are formed, the sulfur atom of Xaa1 and the sulfur atom of Xaa7 are linked, thereby forming a cyclic structure of general formula (XIV). 【Chemical 759】 General formula (XIV), Here, the substitution patterns of the aromatic group in general formula (XIII) are ortho, para, or meta. g is either 0 or 1. n is either 1 or 2. Y 1 is CH or N, Y 2 CR L1 And, R L1 is a linking unit that is linked to the other parts in general formula (Ib), The aforementioned T is preferably, 【Chemical 760】 A trifunctional compound characterized by having formula (Va), a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof.

22. A trifunctional compound according to claim 4, a pharmaceutically acceptable salt thereof, stereoisomer, or solvate thereof, The aforementioned trifunctional compound has the structure of general formula (Ia) or general formula (Ib), 【Chemistry 761】 General formula (Ia) 【Chemical 762】 General formula (Ib) Here: The L shown 4 This is a trivalent linking group portion, Each indicated L 5 , L 6 , L 7 and L 8 These are independently divalent linking group portions, each independently containing 0 to 6, preferably 0 to 3, linking group units. The indicated C is a covalent warhead, 【Chemical Formula 763】 、 【Chemical 764】 、 【Chemical 765】 、 【Chemical Formula 766】 、 【Chemical 767】 、 【Chemical Formula 768】 、 【Chemical 769】 、 【Chemical 770】 、 【Chemistry 771】 、 【Chemical 772】 、 【Chemical 773】 Selected from the group consisting of, Het is an arbitrarily substituted C 4 -C 12 Heterocyclic groups, or optionally substituted C 5 -C 12 If a heteroaryl compound contains an N atom, the N atom may exist in a free form or in the form of an onium salt. Hal is either F or Cl. Y is O, S and NR 1 Selected from the group consisting of, Each p is an independent integer between 0 and 6. Each R 1 These are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. Each R is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, optionally substituted mercapto, optionally substituted seleno, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amino. The indicated T is a targeting group that targets fibroblast-activating protein-α (FAP-α), The P shown is a chelating group capable of chelating radionuclides, and the compound is a trifunctional compound, a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof.

23. A trifunctional compound according to claim 22, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, The aforementioned trifunctional compound has the structure of general formula (Ia) or general formula (Ib), Here: Said L 4 teeth, 【Chemical 774】 、 【Chemistry 775】 、 【Chemical 776】 、 【Chemical 777】 , and 【Chemical 778】 A trivalent linking group selected from, Each said L 5 , L 6 , L 7 and L 8 Each is an independently divalent linking group portion, each independently containing 0 to 3, preferably 0 or 1, linking group units, and each linking group unit independently single bond, 【Chemical 779】 、 【Chemical 780】 、 【Chemistry 781】 、 【Chemical 782】 、 【Chemical 783】 、 【Chemical 784】 、 【Chemical 785】 、 【Chemical 786】 、 【Chemical 787】 、 【Chemical 788】 、 【Chemical 789】 、 【Chemical Formula 790】 、 【Chemistry 791】 and 【Chemical 792】 It is a base selected from, The methylene in the divalent linking group unit described herein is one or more -COR L2 Base or -COOR L2 It can be substituted with a base, where each R L2 H and C are independent of each other. 1 -C 6 Alkyl, C 6 -C 10 Ariel, C 6 -C 10 C replaced by aryl 1 -C 6 Selected from alkyl groups, L 18 This is a single bond, -CH 2 -, -NHCH 2 -, or 【Chemical 793】 And, Church 【Chemical 794】 、 【Chem.795】 、 【Chemical 796】 、 【Chemical 797】 、 【Chemical 798】 and 【Chemical 799】 Selected from, u, u1, u2, u3, u4, u5, u6, u7, u8, u9, u10, u11, u12, v and o are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Each R 6 and R 7 These are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. * indicates a part connected to T, ** is the part connected to C, The condition is, L 5 , L 6 , L 7 and L 8 In this configuration, the heteroatoms are not directly linked via covalent bonds, and the heteroatoms are selected from N, O, and S. C is 【Chemical 800】 、 【Chemical 801】 、 【Chemical 802】 、 【Chemical 803】 Selected from the group consisting of, Here: Het is C 4 , C 5 or C 6 Heterocyclic group, or C 5 or C 6 A heteroaryl compound, wherein the heterocyclic group or heteroaryl compound comprises one or two heteroatoms selected from N, O, or S, and if the heteroaryl compound contains an N atom, the N atom may exist in a free form or in the form of an onium salt, preferably in a free form, and preferably Het is C 4 , C 5 or C 6 Heterocyclic group, or C 5 or C 6 It is a heteroaryl compound, and the heterocyclic group or heteroaryl compound contains one N, O, or S atom, preferably a heteroatom of N, and more preferably Het is azetidinyl, pyridyl, pyrrolyl, or N-oxypyridinyl. Hal is F Each p is an independent integer between 0 and 4. The indicated T is a targeting group that targets fibroblast-activating protein-α (FAP-α), The P shown is a chelating group capable of chelating radionuclides. 【Chemical 804】 、 【Chemical 805】 、 【Chemical 806】 、 【Chemical 807】 、 【Chemical 808】 、 【Chemical 809】 、 【Chemical 810】 、 【Chemical 811】 、 【Chemical 812】 、 【Chemical 813】 、 【Chemical Figure 814】 、 【Chemical 815】 、 【Chemical Formula 816】 、 【Chemical 817】 、 【Chemical 818】 、 【Chemical 819】 、 【Chemical 820】 、 【Chemical 821】 , and 【Chemical 822】 A trifunctional compound characterized by being a group selected from, a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof.

24. A trifunctional compound according to claim 22 or 23, a pharmaceutically acceptable salt, stereoisomer or solvate thereof, The aforementioned trifunctional compound has the structure of general formula (Ia), Here: C and P are as defined in claim 23, L 4 teeth, 【Chemical 823】 、 【Chemical 824】 、 【Chemical 825】 、 【Chemical 826】 , or 【Chemical 827】 Having a structure, Each said L 5 and L 6 Independently, single bond, 【Chemical 828】 、 【Chemical 829】 、 【Chemical 830】 、 【Chemical 831】 、 【Chemical 832】 、 【Chemical 833】 、 【Chemical 834】 、 【Chemical 835】 、 【Chemical 836】 、 【Chemical 837】 、 【Chemical 838】 、 【Chemical 839】 、 【Chemical 840】 and 【Chemical 841】 And, Here, u, u1, u2, u3, u4, u5, u6, u7, u8, u9, u10, u11, u12, v and o are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Each R 6 and R 7 These are, independently of each other, hydrogen, and optionally substituted C 1 -C 4 Selected from, * indicates a part connected to T, ** is the part connected to C, The condition is, L 5 and L 6 In this configuration, the heteroatoms are not directly linked via covalent bonds, and the heteroatoms are selected from N, O, and S. T is general formula (IV), preferably having general formula (IVa), and more preferably having general formula (IVc), general formula (IVd), general formula (IVe), or general formula (IVf). 【Chemical 842】 General formula (IV) Here, in general formula (IV), A is O, S, NR A Selected from, R A H, C 1 -C 6 Selected from alkyl groups, Multiple R f There is a base, and each R f The groups are H, F, Cl, -CN, and -B(OH) respectively, independently. 2 , C 1 -C 6 Selected from alkyl and α-chloroketone groups, any two R groups on adjacent carbons f The groups can link together to form a cycloalkyl group, preferably C 3 -C 7 It is a cycloalkyl, B 1 and B 2 It is independently selected from O or S, R f1 and R f2 These are independently H, D, or C 1 -C 4 Selected from alkyl groups, Ar is a carbon atom containing one N atom. 6 -C 10 It is a heteroaryl, 【Chemical 843】 General formula (IVa), Here, in general formula (IVa), A is O, S, NR A Selected from, R A H, C 1 -C 6 Selected from alkyl groups, Multiple R f There is a base, and each R f The groups are H, F, Cl, -CN, and C, respectively, independently. 1 -C 6 Selected from alkyl groups, any two R groups on adjacent carbons f The groups can link together to form a cycloalkyl group, preferably C 3 -C 7 It is a cycloalkyl, 【Chemical 844】 General formula (IVb), 【Chemical 845】 General formula (IVc), 【Chemical 846】 General formula (IVd), 【Chemical 847】 General formula (IVe), Here, in general formulas (IVb), (IVc), (IVd), or (IVe), A is O, S, NR A Selected from, R A The invention relates to a trifunctional compound characterized by being selected from H, methyl, ethyl, n-propyl, and isopropyl, a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof. 【Request Item 25】 【Chemistry 848】 、 【Chemical 849】 、 【Chemical 850】 、 【Chemical 851】 、 【Chemical 852】 、 【Chemical 853】 、 【Chemical 854】 、 【Chemical 855】 、 【Chemical 856】 、 【Chemical 857】 、 【Chemical 858】 、 【Chemical 859】 、 【Chemical 860】 、 【Chemistry 861】 、 【Chemical 862】 、 【Chemical 863】 A trifunctional compound according to claim 1 or 4, characterized by having one of the structures of, a pharmaceutically acceptable salt, stereoisomer or solvate thereof.

26. The trifunctional compound according to any one of claims 13 to 25, characterized in that the payload P is a chelating group capable of chelating a radionuclide, and the chelating group chelates a radionuclide, a pharmaceutically acceptable salt thereof, stereoisomer or solvate thereof.

27. A trifunctional compound according to any one of claims 13 to 26, a pharmaceutically acceptable salt thereof, stereoisomer or solvate thereof The radioactive nuclides contained in or chelated by the aforementioned trifunctional compound are positron nuclides, beta-ray emitters, alpha-ray emitters, Auger electron-emitting isotopes, X-ray-emitting isotopes, fluorescence-emitting isotopes, or stable metal / nonmetal elements coordinated with radioactive nuclides, preferably, 11 C, 13 N, 15 O, 18 F and its coordinating elements, 47 Sc, 51 Cr, 67 Ga, 68 Ga, 86 Y, 90 Y, 64 Cu, 67 Cu, 72 As, 72 Se, 89 Zr, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 142 Pr, 151 EU, 153 EU, 169 EU, 159 Gd, 161 Tb, 177 Lu, 198 Au, 199 Ag, 201 Tl, 211 At, 203 Pb, 212 Pb, 212 Bi, 213 Bi, 225 Ac, 99m Tc, 111 In, 149 PM, 153 Sm, 165 Dy, 169 Er, 186 Re, 188 Re, 197 Hg, 227 Th, 67 Ga, 68 Ga, 86 Y, 90 Y, 55 Co, 139 La, 140 La, 149 Tb, 152 Tb, 155 Tb, 166 Ho, 175 Yb, 226 Th, 223 Ra and 230 A trifunctional compound characterized by being U, a pharmaceutically acceptable salt thereof, stereoisomer, or solvate.

28. A drug composition comprising a trifunctional compound according to any one of claims 1 to 27, a pharmaceutically acceptable salt, stereoisomer or solvate thereof, and a pharmaceutically acceptable carrier.

29. A reagent kit comprising or comprising a trifunctional compound according to any one of claims 1 to 27, a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a drug composition according to claim 28, and instructions for diagnosing a disease.

30. A method for diagnosing or treating a disease, preferably a disease related to FAP, The method comprises administering to a subject a therapeutically effective amount of a trifunctional compound described in any one of claims 1 to 27, a pharmaceutically acceptable salt thereof, a stereoisomer, or a solvate thereof, wherein the disease is preferably a central nervous system disorder, a metabolic disorder (preferably a cardiovascular metabolic disorder), or cancer.

31. The method according to 30, characterized in that the cancer is selected from prostate cancer, breast cancer, pancreatic cancer, liver cancer, lung cancer, stomach cancer, kidney cancer, ovarian cancer, bladder cancer, esophageal cancer, head and neck cancer, thymic cancer, cervical cancer, endometrial cancer, neuroendocrine tumor, thyroid cancer, colorectal cancer, glioma, and bone metastasis cancer.

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