New ligand-targeted compound, chelate, composition and use thereof

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein W is oxygen or sulfur; X1 is -L1-R1; Y1 is -L1-R2; Z1 is L2-R3-L1-R4; L1 is independently a bond or a linking group at each occurrence; L2 is O, S or NH; R3 is optionally substituted arylene, heteroarylene, cycloalkylene or heterocyclylene; one of R1, R2 and R4 is a targeting group, and the remaining two are independently a targeting group, a drug molecule group, an isotope chelating agent or a labeling precursor group, a fluorescent or molecular tag group or a capping group. Further provided in the present disclosure are a chelate, a pharmaceutical composition and the use thereof as diagnostic agents or therapeutic agents for the diagnosis and treatment of diseases.

Description

New ligand-targeted compounds, chelates, compositions and uses thereof Technical Field

[0001] The present disclosure relates to the fields of medical treatment and diagnosis, and in particular to a novel ligand-targeted compound, a chelate, a composition and uses thereof. Background Art

[0002] Targeted drug delivery strategies are methods for precisely and controllably releasing drugs at specific locations to achieve therapeutic effects. Targeted drug delivery systems primarily consist of a targeting ligand, a linker (controlled-release structure), and a payload. Depending on the targeting ligand and payload, targeted drug delivery systems are categorized into antibody-drug conjugates (ADCs), peptide-drug conjugates (PDCs), small-molecule drug conjugates (SMDCs), aptamer-drug conjugates (ApDCs), and radionuclide-drug conjugates (RDCs). A cleavable structure is crucial for achieving controlled drug release. These linkers are primarily classified into two categories: chemically cleavable linkers and enzymatically cleavable linkers. Among chemically cleavable linkers, the hydrazine structure is a classic acid-sensitive linker. Hydrazine linkers are generally stable in the bloodstream, but once internalized by target cancer cells, the acidic environment in lysosomes (pH 4.8) and endosomes (pH 5.5-6.2) hydrolyzes the hydrazine structure, releasing the cytotoxic drug. Marketed ADCs such as Mylotarg and Besponsa utilize hydrazine as a controlled-release structure. Disulfide linkers are another classic chemically cleavable linker that is sensitive to reduced glutathione (GSH). The concentration of GSH in blood is significantly lower than that within cancer cells. Therefore, this type of linker can maintain stability in the blood system while enabling controlled release of the active payload in cancer cells where GSH levels are elevated. Among marketed ADCs, Elahere used disulfide bonds as controlled-release structures. Various peptidyl linkers within the enzymatically cleavable linker family are sensitive to lysosomal proteases and have been used in numerous ADCs. Lysosomal proteases, such as cathepsin B, are often overexpressed in cancer cells, enabling precise drug release near tumors. Among marketed ADCs, 9 out of 15 drugs utilize enzymatically cleavable linkers. However, current controlled-release strategies lack specificity, resulting in significant off-target toxicity during the long-term circulation of ADCs in vivo.

[0003] Therefore, there is still a need to develop a ligand-targeted compound to address one or more of the above-mentioned deficiencies. Summary of the Invention

[0004] The present disclosure provides a ligand-targeted compound with a specific structural type of phosphoryl as the core to improve the specificity of drug delivery and / or reduce off-target toxicity.

[0005] One aspect of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, isomer or solvate thereof,

[0006] in

[0007] W is oxygen or sulfur, preferably oxygen;

[0008] X1 is -L1-R1;

[0009] Y1 is -L1-R2;

[0010] Z1 is -L2-R3-L1-R4;

[0011] L1 is independently a bond or a linker at each occurrence;

[0012] L2 is O, S or NH, preferably oxygen;

[0013] R3 is an optionally substituted arylene, heteroarylene, cycloalkylene or heterocyclylene, such as phenylene; the substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, cyano;

[0014] One of R1, R2, and R4 is a targeting group, and the other two are independently targeting groups, drug molecule groups, isotope chelators or labeling precursor groups, fluorescent or molecular tag groups, or capping groups.

[0015] In some embodiments, one of R1, R2, R4 is an isotope chelator or a labeling precursor group.

[0016] Another aspect of the present disclosure provides a chelate or radionuclide label comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof and a radionuclide.

[0017] Yet another aspect of the present disclosure provides a pharmaceutical composition comprising or consisting of:

[0018] (a) the compound of formula (I) above or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; or the chelate or radionuclide labeling substance above,

[0019] (b) optionally, and pharmaceutically acceptable excipients.

[0020] Another aspect of the present disclosure also provides the diagnostic or therapeutic use of the above-mentioned compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer or solvate, or the diagnostic or therapeutic use of the above-mentioned chelate or radionuclide label; or the diagnostic or therapeutic use of the above-mentioned pharmaceutical composition; or a kit thereof.

[0021] Another aspect of the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, which can be used as an intermediate in preparing a compound of formula (I). BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the technical solutions of the embodiments of the present disclosure, the drawings of the embodiments will be briefly introduced below. Obviously, the drawings in the following description only relate to some embodiments of the present disclosure, and are not intended to limit the present invention.

[0023] FIG1 shows that LDP-FAP-MMAE releases MMAE drug molecules only in the presence of FAP protein, and the release can be inhibited by the addition of FAPI-04.

[0024] FIG2 shows that LDP-FAP-MMAE can release MMAE drug molecules in FAP-positive cells, which is significantly different from that in FAP-negative cells.

[0025] Figure 3 shows 68 Photographs of the distribution of Ga-LDP-FAP-MMA in HT1080-FAP tumor-bearing mice.

[0026] FIG4 shows the MMAE release of LDP-FAP-MMAE in different tissues of HT1080-FAP tumor-bearing mice.

[0027] FIG5 shows the tumor volume of HT1080-FAP tumor-bearing mice after treatment with LDP-FAP-MMAE.

[0028] Figure 6 shows 177 SDS-PAGE and autoradiography results of co-incubation of Lu-labeled LDP-FAPI-DOTA and FAP protein.

[0029] Figure 7 shows the administration of drugs to mice 68 Ga-FAPI-04 and 68 PET-CT imaging results of Ga-LDP-FAPI-DOTA.

[0030] Figure 8 shows the percentage of MMAE molecules released by LDP-FAP-H-FITC, LDP-B-FAP-H-MMAE, LDP-B-FAP-F-MMAE, LDP-B-FAP-F-NIR-DOTA, LDP-B-FAP-H-MMAE-DOTA and LDP-B-FAP-F-MMAE-DOTA in the presence of FAP protein.

[0031] FIG9 shows fluorescence confocal microscopy imaging after LDP-FAP-H-FITC and LDP-B-FAP-F-NIR-DOTA were co-incubated with HT1080 cells and HT080-FAP-expressing cells, respectively.

[0032] FIG10 shows the administration mode of LDP-B-FAP-F-MMAE-DOTA in the PDX tumor model, tumor volume change, body weight change, and tumor change curve information for each mouse.

[0033] FIG11 shows in vivo near-infrared fluorescence imaging of LDP-FAP-PEG0-S0456, LDP-FAP-PEG2-S0456, LDP-FAP-PEG5-S0456, and LDP-FAP-F-PEG5-S0456 in HT1080-FAP tumor-bearing mice.

[0034] FIG12 shows the results of autoradiography in SDS-PAGE experiments after co-incubation of LDP-FAP-S0456-DOTA and FAP protein.

[0035] Figure 13 shows 68 PET-CT imaging of Ga-radiolabeled LDP-FAP-S0456-DOTA in HT1080-FAP tumor-bearing mice.

[0036] FIG14 shows near-infrared fluorescence imaging of LDP-FAP-S0456-DOTA in HT1080-FAP tumor-bearing mice.

[0037] FIG15 shows that after the addition of FAP protein, FAP-Cy5-Quencher and FAP-Cy5-Quencher-DOTA release the quenching group, and the fluorescence signal increases significantly.

[0038] FIG16 shows fluorescence confocal microscopy imaging of FAP-Cy5-Quencher and FAP-Cy5-Quencher-DOTA co-incubated with HT1080 cells and HT080-FAP-expressing cells at time points of 6 to 24 hours.

[0039] FIG17 shows near-infrared fluorescence imaging of FAP-Cy5-Quencher and FAP-Cy5-Quencher-DOTA in HT1080-FAP tumor-bearing mice.

[0040] FIG18 shows the percentage of drug molecules released by LDP-Dox, LDP-Exatecan, and LDP-Dxd in the presence of FAP protein.

[0041] FIG19 shows that CA-P-1 and CA-P-2 release fluorescent molecules in the presence of carbonic anhydrase 1 protein, and the fluorescence signal increases. DETAILED DESCRIPTION

[0042] To make the purpose, technical solutions, and advantages of the embodiments of the present disclosure more clear, the technical solutions of the embodiments of the present disclosure will be clearly and completely described below in conjunction with the drawings of the embodiments of the present disclosure. Obviously, the described embodiments are part of the embodiments of the present disclosure, not all of the embodiments. Based on the described embodiments of the present disclosure, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0043] The present invention may be embodied in other specific forms without departing from the essential attributes of the present invention. It should be understood that, without conflict, any and all embodiments of the present invention may be combined with the technical features of any other embodiment or multiple other embodiments to produce additional embodiments. The present invention includes such combinations to produce additional embodiments.

[0044] All publications and patents mentioned in this disclosure are hereby incorporated into the present disclosure in their entirety by reference. If the purposes or terms used in any publications and patents incorporated by reference conflict with the purposes or terms used in this disclosure, then the purposes and terms of this disclosure shall prevail.

[0045] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0046] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly used in the art to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0047] Unless otherwise indicated, when any type of range is disclosed or claimed, it is intended to disclose or claim individually every possible value that the range may reasonably encompass, including any subranges encompassed therein. For example, the number of substituents is 1 to 5, indicating integers within the range, where 1-5 is understood to include 1, 2, 3, 4, 5, and also includes subranges of 1-4 and 1-3.

[0048] The description of the present disclosure should be interpreted in accordance with the laws and principles of chemical bonding.In some cases, it may be possible to remove a hydrogen atom in order to accommodate a substituent at a given position.

[0049] As used in this disclosure, words such as "include," "comprising," or "including" mean that the elements preceding the word include the elements listed after the word and their equivalents, without excluding unlisted elements. The terms "comprising" or "including" as used herein may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0050] The term "pharmaceutically acceptable" as used herein means that the compound or composition is chemically and / or toxicologically compatible with the other ingredients constituting the formulation and / or with humans or mammals for the prevention or treatment of a disease or condition.

[0051] The term "subject" or "patient" as used in this application includes humans and mammals.

[0052] In the context of this application, the term "treatment" may also include prophylaxis, unless specifically stated to the contrary.

[0053] The term "solvate" as used herein refers to a complex formed by combining a compound of formula (I) or a pharmaceutically acceptable salt thereof and a solvent. It should be understood that any solvate of a compound of formula (I) used in the diagnosis or treatment of a disease or condition described herein, although potentially providing different properties (including pharmacokinetic properties), will yield the compound of formula (I) once absorbed into a subject, such that use of a compound of formula (I) encompasses the use of any solvate of the compound of formula (I).

[0054] The term "hydrate" refers to the above-mentioned term "solvate" in which the solvent is water.

[0055] It should be further understood that the compound of formula (I) or its pharmaceutically acceptable salt can be isolated in the form of a solvate, and therefore any such solvate is included within the scope of the present invention. For example, the compound of formula (I) or its pharmaceutically acceptable salt can exist in an unsolvated form as well as in a solvated form with a pharmaceutically acceptable solvent (such as water, ethanol, etc.).

[0056] The term "pharmaceutically acceptable salts" refers to relatively non-toxic addition salts of the compounds of the present disclosure. See, for example, SM Berge et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0057] Suitable pharmaceutically acceptable salts of the disclosed compounds may be acid addition salts of compounds of the disclosed compounds having a nitrogen atom in a chain or ring and having sufficient basicity, such as acid addition salts formed with inorganic or organic acids.

[0058] Alternatively, another suitable pharmaceutically acceptable salt of a sufficiently acidic compound of the present invention is an alkali metal salt, an alkaline earth metal salt, or a salt with an organic base which provides a physiologically acceptable cation.

[0059] Those skilled in the art will also recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid by any of a variety of known methods. Alternatively, alkali metal and alkaline earth metal salts of the acidic compounds of the present disclosure can be prepared by reacting them with a suitable base by various known methods.

[0060] The present invention includes all possible salts of the disclosed compounds, either as a single salt or as any mixture of such salts in any ratio.

[0061] It should be understood that the term "compounds of the present disclosure" used in this application may include, depending on the context, the compound represented by formula (I), its pharmaceutically acceptable salts, its solvates, its pharmaceutically acceptable salt solvates, and mixtures thereof.

[0062] The compounds of the present disclosure may contain one or more asymmetric centers, depending on the position and properties of the various substituents desired. Asymmetric carbon atoms can exist in the (R) or (S) configuration, resulting in racemic mixtures in the case of one asymmetric center and diastereomeric mixtures in the case of multiple asymmetric centers. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, such as where the central bond connects two substituted aromatic rings of a particular compound.

[0063] Preferred compounds are those that produce more desirable biological activity. Isolation, purification or partial purification of isomers and stereoisomers, or racemic mixtures or diastereomeric mixtures of the disclosed compounds are included within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.

[0064] The term "optionally" is used herein to describe a situation that may or may not occur. For example, the term "optionally substituted" refers to a situation that is unsubstituted or has at least one non-hydrogen substituent that does not destroy the intended property possessed by the unsubstituted analog. For example, with respect to a pharmaceutical composition, the phrase "optionally, and a pharmaceutically acceptable excipient" as used herein means that a pharmaceutically acceptable excipient may or may not be present in the pharmaceutical composition.

[0065] In the present disclosure, unless otherwise specified, the number of "substituted" may be one or more; when it is multiple, it may be 2, 3 or 4. Moreover, when the number of "substituted" is multiple, the "substituted" may be the same or different.

[0066] In the present disclosure, the position of “substitution” can be any position unless otherwise specified.

[0067] The term "alkyl" as used herein refers to a straight or branched alkane chain containing 1 to 14 carbon atoms. 14 Representative examples of alkyl include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), and isobutyl (C4). 14 Representative examples of alkyl groups include, but are not limited to, n-pentyl (C5), 3-pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "lower alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms. "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. The term "haloalkyl" refers to an alkyl group having one or more halogen substituents, including, but not limited to, groups such as -CH2Br, -CH2I, -CH2Cl, -CH2F, -CHF2, and -CF3.

[0068] The term "optionally substituted alkyl" as used herein means that the alkyl group may be unsubstituted or substituted. Substituted alkyl groups include, but are not limited to, groups selected from C 1-4 Alkyl, C 1-4 C substituted with one or more substituents selected from alkoxy, hydroxy, amino, mercapto, halogen, nitro and -CN 1-5 alkyl.

[0069] As used herein, the term "alkylene" refers to a divalent hydrocarbon group as described above for "alkyl," but with two points of attachment. For example, a methylene group is a -CH2- group and an ethylene group is a -CH2-CH2- group.

[0070] As used herein, the terms "alkoxy" and "alkylthio" refer to an alkyl group as described above attached via an oxygen bond (-O-) or a sulfur bond (-S-), respectively. The terms "substituted alkoxy" and "substituted alkylthio" refer to substituted alkyl groups attached via an oxygen bond or a sulfur bond, respectively. "Lower alkoxy" is a group OR where R is a lower alkyl group (an alkyl group containing 1 to 4 carbon atoms).

[0071] As used herein, the term "halogen" refers to fluorine, chlorine, iodine, or bromine.

[0072] The term "cycloalkyl" as used herein refers to a saturated cycloalkyl group derived by removing one hydrogen atom from a single carbon atom of a parent cycloalkane. 3-14Cycloalkyl groups include, but are not limited to, groups such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groups can be described by the number of carbon atoms in the ring. For example, a cycloalkyl group having 5-7 ring atoms can be referred to as a (C5-C7)cycloalkyl group. In certain embodiments, a cycloalkyl group can be a (C5-C7)cycloalkyl group. 14 )cycloalkyl, (C5-C8)cycloalkyl, (C5-C7)cycloalkyl, (C5-C6)cycloalkyl, and these may be referred to using alternative language as C5-C 14 Cycloalkyl, C5-C8 cycloalkyl, C5-C7 cycloalkyl, C5-C6 cycloalkyl or C5-C7 cycloalkyl.

[0073] The term "cycloalkylene" as used herein refers to a general term for a divalent group remaining after removing two hydrogen atoms from any position of a cycloalkyl carbon ring. Typical cycloalkylene groups include, but are not limited to, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, and the like.

[0074] As used herein, the term "heterocycloalkyl" and interchangeably "heterocyclyl" refers to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one, preferably 1 to 3, heteroatoms as ring members, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur, wherein each ring is preferably a 5- to 8-membered ring, preferably a 5- to 6-membered ring. Typical heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, dioxanyl, piperazinyl, pyrazinyl, morpholinyl, dioxanyl, and the like.

[0075] As used herein, the term "heterocycloalkylene" refers to a general term for a divalent group remaining after removing two hydrogen atoms from any position on the heterocycloalkyl ring. Typical heterocycloalkylene groups include, but are not limited to, tetrahydrofuranylene, tetrahydropyrrolylene, tetrahydrothiophenylene, tetrahydropyranylene, piperidinylene, tetrahydrothiopyranylene, dioxanylene, piperazinylene, 1,4-piperazinylene, pyrazinylene, morpholinylene, and dioxanylene.

[0076] The term "arylene" as used herein refers to a general term for a divalent group remaining after removing two hydrogen atoms from the carbon at any position of the aromatic nucleus of an aromatic hydrocarbon molecule, such as phenylene, naphthylene, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,5-naphthylene or 1,6-naphthylene or 2,6-naphthylene, etc.

[0077] As used herein, the term "optionally substituted arylene" includes unsubstituted arylene, as well as substituted arylene, for example, substituted by C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4Arylene substituted with one or more substituents selected from the group consisting of alkoxy, hydroxy, amino, mercapto, halogen, nitro and -CN.

[0078] As used herein, the term "heteroaryl" refers to an arbitrarily substituted monovalent aromatic group containing about 5 to about 14 skeleton ring atoms, one to three of which are heteroatoms independently selected from, but not limited to, oxygen, nitrogen, and sulfur, provided that the ring of the group does not contain two adjacent O or S atoms. In embodiments where two or more heteroatoms are present in the ring, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other. The term heteroaryl includes optionally substituted monovalent fused or non-fused heteroaryls having at least one heteroatom. In addition, the term heteroaryl also includes fused and non-fused heteroaryls containing 5 to about 14 skeleton ring atoms, and fused and non-fused heteroaryls containing 5 to about 10 skeleton ring atoms. Heteroaryl groups may be bound by carbon atoms or heteroatoms. Thus, for example, an imidazole can be attached to the parent molecule via any of its carbon atoms (imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl) or its nitrogen atom (imidazol-1-yl or imidazol-3-yl). Similarly, the heteroaryl group can be further substituted via any or all of its carbon atoms and / or any or all of its heteroatoms. A fused heteroaryl group can comprise 2-4 fused rings of aromatic heterocycles, the other individual rings being alicyclic, heterocyclic, aromatic, aromatic heterocyclic, or any combination thereof. Non-limiting examples of monocyclic heteroaryls include pyridyl; fused ring heteroaryls include benzimidazolyl, quinolinyl, acridinyl, and non-fused biheteroaryls include bipyridinyl.Other examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl, indolizinyl, isothiazolyl,

[0014] Examples of the present invention include oxadiazolyl, thiazolyl, triazinyl, thiazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazolyl, purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl, and thiadiazolyl, and oxides thereof, such as pyridyl-N-oxide.

[0079] The term "heteroarylene" as used herein refers to a general term for a divalent group remaining after removing two hydrogen atoms from any carbon position of the heteroaromatic nucleus of a heteroaryl molecule, such as furanylene, thienylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene or pyridazinylene. The term "optionally substituted heteroarylene" as used herein includes unsubstituted heteroarylene and substituted heteroarylene, such as C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Heteroarylene substituted with one or more substituents selected from alkoxy, hydroxy, amino, mercapto, halogen, nitro and -CN.

[0080] In the compounds provided herein, any atom not specifically limited to a particular isotope represents any stable isotope of that atom. Isotopic substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. As a non-limiting general example, deuterium ( 2 H) and tritium ( 3 Isotopes of hydrogen, such as H), can be used anywhere in the structure to achieve the desired result. Alternatively, isotopes of carbon, such as 13 C and 14 C.

[0081] In certain embodiments, the isotope is at least about 90, 95, or 99% or more isotopically enriched at any of the positions involved. In one non-limiting embodiment, deuterium is at least about 90, 95, or 99% enriched at the desired position.

[0082] In some non-limiting embodiments, the substitution of a deuterium atom for a hydrogen atom occurs in a 1 、R 2 、R 3 、R 4 、R a 、R b 、R c Or any other substituent group defined herein. In other non-limiting embodiments, R 1 、R 2 、R 3 、R 4 、R a 、R b 、R c At least one of the groups is deuterium-enriched. For example, when any group is, or contains, a substituent such as a methyl, ethyl, or methoxy group, the alkyl residue may be deuterated (e.g., CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In certain other embodiments, when two substituents are combined to form a ring, the unsubstituted carbon may be deuterated.

[0083] It is to be understood that as used in this disclosure, singular forms such as "a," "an," and "the" may include plural referents unless otherwise specified.

[0084] Unless otherwise indicated, this disclosure employs standard nomenclature and standard laboratory procedures and techniques in analytical chemistry, synthetic organic chemistry, and coordination chemistry. Unless otherwise indicated, this disclosure employs conventional methods of mass spectrometry and elemental analysis, and each step and condition may refer to conventional procedures and conditions in the art.

[0085] The reagents and starting materials used in the present disclosure are commercially available or can be prepared by conventional chemical synthesis methods.

[0086] As used herein, the term "targeting group" refers to a ligand group that specifically binds to a targeting protein. For example, a targeting group is a ligand group that has a high affinity for a tumor or tissue-specific biomarker.

[0087] As used herein, the term "drug molecule group" refers to a group derived from a drug molecule. For example, the drug molecule has one or more of cytotoxicity, immunomodulatory function, protein degradation function, and antimicrobial function. For example, the drug molecule is a cytotoxic drug, an immunomodulator, an antibiotic, a protein degrader, or a molecular glue. In one embodiment, the drug molecule is a DNA crosslinker, a microtubule inhibitor, a DNA alkylating agent, a topoisomerase inhibitor, or a combination thereof. For example, the drug molecule is selected from vinca alkaloids, laulimalide, taxane, colchicine, tubulysin, Cryptophycin, Hemiasterlin, Cemadotin, Rhizoxin, Discodermolide, taccalonolide A or B or AF or AJ, taccalonolide AI-epoxide, CA-4, epothilone A and B, paclitaxel, docetaxel, doxorubicin, camptothecin, iSGD-1882, centanamycin, PNU-159682, uncialamycin, indolebenzodiazepine Dimer, β-amanitin, amatoxin (Amatoxin), thailanstatin (thailanstatin) or its derivatives or analogs, or its combination.Immunomodulator, for example, can be selected from: cytokine, chemokine, stem cell growth factor, lymphotoxin, hematopoietic factor, colony stimulating factor (CSF), interferon, erythropoietin, thrombopoietin, tumor necrosis factor (TNF), interleukin (IL), granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), stem cell growth factor called "S1 factor", activator of costimulatory molecules (for example, OX40 agonist), immune checkpoint molecules (for example, PD-1, PD-L1, LAG-3, TIM-3, CEACAM or CTLA-4, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGFRβ inhibitor.

[0088] As used herein, the term "isotope chelator or labeling precursor group" refers to a group derived from an isotope chelator or labeling precursor molecule. The isotope chelator or labeling precursor can be an isotope chelator or labeling precursor that can chelate a metal nuclide or label a medical nuclide, such as HYNIC, DTPA, DOTA, NOTA, and derivatives thereof.

[0089] The term "fluorescent or molecular tag group" as used herein refers to a group derived from a fluorescent or molecular tag. The fluorescent or molecular tag can be, for example, a fluorescent dye, quantum dots, biotin, or a radionuclide (e.g. 18 F. 51 Cr, 67 Ga, 68 Ga, 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, 165 Dy, 169 Second, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As、 72 Se, 97 Such as 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, 67 Cu, 188 Re、 186 Re、 198 Au,225 Ac, 227 Th and 199 Ag).

[0090] The term "capping group" as used herein refers to a low molecular weight monovalent group that does not readily undergo chemical transformation under typical synthetic reaction conditions. Capping groups include, for example, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0091] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof,

[0092] in

[0093] W is oxygen or sulfur, preferably oxygen;

[0094] X1 is -L1-R1;

[0095] Y1 is -L1-R2;

[0096] Z1 is -L2-R3-L1-R4;

[0097] L1 is independently a bond or a linker at each occurrence;

[0098] L2 is O, S or NH, preferably oxygen;

[0099] R3 is an optionally substituted arylene, heteroarylene, cycloalkylene or heterocyclylene; the substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, cyano

[0100] One of R1, R2, and R4 is a targeting group, and the other two are independently targeting groups, drug molecule groups, isotope chelators or labeling precursor groups, fluorescent or molecular tag groups, or capping groups.

[0101] In one embodiment, R3 is optionally substituted C 5-14 Arylene, C 5-14 Heteroarylene, C 5-14 Cycloalkylene or C 5-14 Heterocyclylene.

[0102] In one embodiment, R3 is selected from:

[0103] Optionally substituted C 5-14 arylene;

[0104] The optionally substituted C 5-14 heteroarylene;

[0105] An optionally substituted divalent saturated or partially unsaturated fused, bridged or spirocyclic cycloalkylene group containing a single ring or multiple rings, C 5-14 cycloalkylene;

[0106] An optionally substituted divalent saturated or partially unsaturated fused, bridged or spirocyclic C 5- 14 cycloalkylene; or

[0107] An optionally substituted divalent saturated or partially unsaturated fused, bridged or spirocyclic C 5- 14 Heterocycloalkylene containing 1 to 3 heteroatoms independently selected from N, O or S;

[0108] The substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.

[0109] In other embodiments, R3 is selected from optionally substituted 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 2,6-naphthylene, furylene, thienylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene, tetrahydropyrrolylene, tetrahydrothienylene, tetrahydropyranylene, piperidinylene, tetrahydrothiopyranylene, dioxaneylene, piperazinylene, 1,4-piperazinylene, pyrazinylene, morpholinylene, dioxaneylene; and the substituents are selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.

[0110] In other embodiments, R3 is selected from 3-X-1,4-phenylene, 2-X-1,4-phenylene, 2-X-1,5-phenylene, 3-X-1,5-phenylene, 3-X-1-phenylene, 2-X-1-phenylene, 4-X-1-phenylene (structures shown below), and X is selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.

[0111] L1 being a bond means that the groups on both sides of L1 are directly connected. For example, when describing X1 as -L1-R1, L1 being a bond means that X1 is -R1.

[0112] In the present disclosure, a linker refers to a divalent group that connects the groups on both sides. Each time a linker appears in L1, it can be selected independently. For example, the linkers appearing in X1, Y1, and Z1 can be the same, partially the same, or different. Linkers include, but are not limited to, -C(O)-, -O-, -S-, -SS-, -NH-, -N(CH3)-, -CH2-, -CH(CH3)-, -CH2CH2-, -CH2O-, Or they are selected from C 1-4 Alkyl, C 1-4 The form in which the substituents are substituted by one or more substituents selected from alkoxy, hydroxy, amino, mercapto, halogen, nitro and -CN.

[0113] In one embodiment, each occurrence of L1 is independently selected from a bond or -L a -(L b ) m -L c -(L d ) n -L e -L f -, where L a , L b , L c , L d , L e , L f Each occurrence is independently selected from a bond, -O-, -S-, -SS-, -S(=O)2-, -NH-, -N(CH3)-, -C(R a )(R b )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NH-, -NHC(=O)-, -C(=O)-N(CH3)-, -N(CH3)-C(=O)-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -CH=NO-, -C(CH3)=N-NH-, -C(CH3)=N-NH-C(=O)-, -NH-CH2-C(=CH-COOH)-, a divalent peptide group containing 1 to 4 amino acids, a cyclohexylene group, a phenylene group, a heterocyclylene group (e.g., piperazine-1,4-diyl) or R a and R b Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, phenyl, -OH, -SH, -NH2, -NH(CH3) or -NH(CH3)2, and the subscripts m and n are each an integer from 0 to 4.

[0114] In some embodiments, after the targeting group of the compound of formula (I) of the present disclosure or its pharmaceutically acceptable salt, stereoisomer or solvate recognizes and binds to the target protein, the adjacent nucleophilic amino acid residues (lysine, cysteine, tyrosine, etc.) in the protein pocket will react with it. N 2 reactions, the group -R3-L1-R4 leaves.

[0115] In one embodiment, one of R1, R2, and R4 is a targeting group for a targeting protein, and the other two are independently drug molecule groups, isotope chelators or labeling precursor groups, fluorescent or molecular tag groups, or capping groups. For example, R4 is a targeting group for a targeting protein, R1 is a drug molecule group, isotope chelators or labeling precursor groups, or fluorescent or molecular tag groups, and R2 is a capping group; or R4 is a targeting group for a targeting protein, R2 is a drug molecule group, isotope chelators or labeling precursor groups, or fluorescent or molecular tag groups, and R1 is a capping group. In another embodiment, two of R1, R2, and R4 are independently targeting groups of targeting proteins, and the remaining one is a drug molecule group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group, or a capping group. For example, R1 and R2 are independently targeting groups of targeting proteins, and R4 is a drug molecule group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group, or a capping group; or R1 and R4 are independently targeting groups of targeting proteins, and R2 is a drug molecule group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group, or a capping group; or R2 and R4 are independently targeting groups of targeting proteins, and R1 is a drug molecule group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group, or a capping group.

[0116] In one embodiment, R4 is a targeting group or a drug molecule group, and R1 and R2 are each independently a targeting group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group, or a capping group.

[0117] In one embodiment, R4 is a targeting group, and R1 and R2 are each independently a drug molecule group, an isotope chelator or labeling precursor group, a fluorescent or molecular tag group, or a capping group.

[0118] In one embodiment, R4 is a targeting group, one of R1 and R2 is a drug molecule group, an isotope chelator or a labeling precursor group, or a fluorescent or molecular tag group, and the other is a capping group.

[0119] In one embodiment, R4 is a targeting group for targeting proteins, and one of R1 and R2 is an isotope chelator or a labeling precursor group and the other is a capping group.

[0120] When R4 is a targeting group of a target protein, after R4 recognizes and binds to the target protein, the adjacent nucleophilic amino acid residues (lysine, cysteine, tyrosine, etc.) in the protein pocket will bind to the electrophilic linker S with a cleavable reaction site. N 2 reactions, the functional molecule is covalently modified to the target protein and the targeting ligand will leave at the same time, achieving "traceless" labeling of the target protein.

[0121] In one embodiment, R4 is a targeting group that targets a protein, R1 and R2 are one of a drug molecule group, an isotope chelator or a labeling precursor group or a fluorescent or molecular tag group, and the other is a blocking group. The compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof binds to the protein with high specificity through R4, and quickly and specifically releases the drug molecule, isotope chelator or labeling precursor or fluorescent or molecular tag, thereby achieving the diagnosis and treatment of diseases such as tumors.

[0122] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof satisfies one or more of the following conditions:

[0123] (a) Each occurrence of L1 is independently a bond or -L a -(L b ) m -L c -(L d ) n -L e -L f -, where L a , L b , L c , L d , L e , L f Each occurrence is independently selected from a bond, -O-, -S-, -SS-, -S(=O)2-, -NH-, -N(CH3)-, -C(R a )(R b)-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NH-, -NHC(=O)-, -C(=O)-N(CH3)-, -N(CH3)-C(=O)-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -CH=NO-, -C(CH3)=N-NH-, -C(CH3)=N-NH-C(=O)-, -NH-CH2-C(=CH-COOH)-, a divalent peptide group containing 1 to 4 amino acids, a cyclohexylene group, a phenylene group, a heterocyclylene group (e.g., piperazine-1,4-diyl) or R a and R b Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, phenyl, -OH, -SH, -NH2, -NH(CH3)2, and the subscripts m and n are each an integer from 0 to 4;

[0124] (b) the end-capping group is selected from -L g -(L h ) n -L i -R c , where L g , L h , L i Each occurrence is independently selected from a bond, -O-, -S-, -C(R a )(R b )-, -NH-, -N(CH3)-, -C(=O)-, -CH2O- or -OCH2-, subscript n is an integer from 0 to 4, R a and R b Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, phenyl, -OH, -SH, -NH2, -NH(CH3) or -NH(CH3)2, R c Selected from methyl, ethyl, hydroxyl or mercapto;

[0125] (c) the drug molecule group is derived from a cytotoxic drug, an immunomodulator, an antibiotic, a protein degrader, or a molecular glue;

[0126] (d) isotope chelators or labeling precursor groups are selected from or

[0127] (e) the fluorescent or molecular tag group is selected from a fluorescent or molecular tag group, an isotopic fluorescent or molecular tag group, an affinity purification tag group, or a click chemistry tag group;

[0128] (f) The targeting group is selected from a ligand group having high affinity for FAP, FOLR1, integrin, folate hydrolase, carbonic anhydrase or Nectin4.

[0129] In one embodiment, L1 is selected from -NH-, -CH2-, -N(CH3)-, -C(=O)-, -C(=O)-PEP-, -NH-PEP-, wherein subscripts m and n are integers of 0-4, subscript c is an integer of 1-10, and PEP represents a divalent peptide group comprising 1 to 4 amino acids.

[0130] In one embodiment, the end-capping group is selected from methyl, methoxy, or The subscript n is an integer from 1 to 4.

[0131] In one embodiment, L1 in Z1 is selected from -NH-, -CH2-, -N(CH3)-, -C(=O)-, -C(=O)-PEP-, -NH-PEP-, wherein the subscript n is an integer of 1-4, and PEP represents a divalent peptide group containing 1 to 4 amino acids.

[0132] In one embodiment, L1 in X1 or Y1 is selected from or wherein subscripts m and n are integers of 0-4, respectively, and subscript c is an integer of 1-10.

[0133] In one embodiment, the drug molecule group is selected from: or

[0134] In one embodiment, the isotope chelator or label precursor group or fluorescent or molecular tag group is selected from:

[0135] In one embodiment, the targeting group of the targeting protein is selected from or

[0136] In a preferred embodiment, the targeting group of the targeting protein is

[0137] In some embodiments, one of R1, R2, and R4 is an isotope chelator or a labeling precursor group, preferably R1 or R2 is an isotope chelator or a labeling precursor group.

[0138] For example, the compound of formula (I) is

[0139] or

[0140] The small molecule conjugate drug LDP-FAP-MMAE targeting FAP protein can specifically bind to FAP protein and then release the drug molecule MMAE.

[0141] The compound of formula (I) can be prepared by the reaction shown below or a similar reaction.

[0142] The present disclosure also provides a chelate or radionuclide label, comprising:

[0143] (i) a compound of the above formula (I) or a pharmaceutically acceptable salt, isomer or solvate thereof, and

[0144] (ii) Radionuclides.

[0145] In some embodiments, in the chelate or radionuclide label, the isotope chelator or label precursor unit is directly chelated to the radionuclide (e.g., 68 Ga is chelated with an isotope chelator or labeling precursor unit derived from DOTA), or the radionuclide is indirectly introduced by chelating with other metals (e.g., Al 3+ Sc 3+ Chelated with an isotope chelator unit derived from DOTA, radionuclides 18 F is introduced into the chelate in the form of coordination with the metal ion).

[0146] In some embodiments, the radionuclide is selected from: 18 F. 51 Cr, 67 Ga, 68 Ga, 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, 165 Dy, 169 Second, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As、 72 Se, 97 Such as 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, 67 Cu, 188 Re、 186 Re、 198 Au, 225 Ac, 227 Th and 199 Ag. For example, the radionuclide is 68 Ga.

[0147] The present disclosure also provides a pharmaceutical composition comprising or consisting of:

[0148] (1) the compound of formula (I) above or its pharmaceutically acceptable salt, stereoisomer or solvate; or the above chelate or radionuclide labeling substance,

[0149] (2) Optionally, and pharmaceutically acceptable excipients.

[0150] In one embodiment, the pharmaceutical composition comprises or consists of (1) a compound of formula (I) above, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; or a chelate or radionuclide labeling agent as described above. In another embodiment, the pharmaceutical composition comprises or consists of (1) a compound of formula (I) above, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; or a chelate or radionuclide labeling agent as described above; and (2) a pharmaceutically acceptable excipient.

[0151] The compositions of the present disclosure may necessarily or optionally further comprise pharmaceutically acceptable excipients for formulating the chelate or radionuclide label for the intended route of administration.

[0152] In another aspect, the present invention provides a kit comprising or consisting of:

[0153] (i) a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; or a chelate or radionuclide label according to any one of claims 18 to 20; or a pharmaceutical composition according to claim 21, and

[0154] (ii) instructions for use in diagnosing or treating a disease.

[0155] In some embodiments, the present invention provides a kit comprising or consisting of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, or a chelate or radionuclide label, or a pharmaceutical composition, and instructions for diagnosing or treating a disease. In a preferred embodiment, the disease is characterized by overexpression of fibroblast activation protein.

[0156] Another aspect of the present disclosure relates to the compound of formula (I) above or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a chelate or radionuclide label, or a composition thereof for use in diagnosing or treating a disease in a mammal or a human.

[0157] Another aspect of the present disclosure relates to the use of the compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer or solvate, or chelate or radionuclide label, or composition in a drug for achieving targeted therapy or diagnosis.

[0158] In some embodiments, the diseases targeted by the targeted therapy are malignant proliferative diseases, immune diseases, and infectious diseases.

[0159] In some embodiments, the malignant proliferative disease is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, bile duct cell carcinoma, clear cell renal carcinoma, neuroendocrine tumor, carcinogenic osteomalacia, sarcoma, cancer of unknown primary, thymic cancer, glioma, glioma, astrocytoma, cervical cancer, prostate cancer, thyroid cancer, gastric cancer, bone cancer, lung cancer, lymphoma, uterine corpus cancer, gallbladder cancer, oral cancer, and testicular cancer.

[0160] In some embodiments, the immune disease is selected from: rheumatoid arthritis (RA), ankylosing spondylitis (AS), juvenile idiopathic arthritis (JIA), non-radiographic axial spondyloarthritis (nr-AxSpA), psoriasis, psoriatic arthritis (PsA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), lupus nephritis (LN), multiple sclerosis (MS), bronchial asthma, etc.

[0161] Another aspect of the present disclosure relates to a method for achieving targeted therapy or diagnosis, comprising administering to a subject in need thereof the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate, or chelate or radionuclide label, or composition thereof.

[0162] Another aspect of the present disclosure relates to a method for inhibiting overexpression of fibroblast activation protein in a subject in need thereof, comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate, or chelate or radionuclide label, or composition thereof.

[0163] Another aspect of the present disclosure relates to a method for diagnosing or treating a disease characterized by overexpression of fibroblast activation protein, comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate, or chelate or radionuclide label, or composition thereof.

[0164] Another aspect of the present disclosure relates to the use of the compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer or solvate, or chelate or radionuclide label, or composition for preparing a medicament for inhibiting overexpression of fibroblast activation protein in a subject in need thereof.

[0165] Another aspect of the present disclosure relates to the use of the compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer or solvate, or chelate or radionuclide label, or composition for preparing a drug for diagnosing or treating a disease characterized by overexpression of fibroblast activation protein.

[0166] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a chelate or radionuclide label thereof, which targets fibroblast activation protein (FAP), can be used to diagnose or treat a disease characterized by overexpression of fibroblast activation protein. For example, a disease characterized by overexpression of fibroblast activation protein (FAP) is selected from cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and scar disease, preferably, wherein the cancer is selected from breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, bile duct cell carcinoma, clear cell renal carcinoma, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, cancer of unknown primary (CUP), thymic cancer, glioma, glioma, astrocytoma, cervical cancer and prostate cancer.

[0167] Another aspect of the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, which can be used as an intermediate in the preparation of a compound of formula (I).

[0168] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof has the following structure:

[0169] in

[0170] W is oxygen or sulfur, preferably oxygen;

[0171] X1 is -L1-R1;

[0172] Y1 is -L1-R2;

[0173] Z1 is -L2-R3-L1-R4;

[0174] L1, at each occurrence, is independently a bond, a linker, or absent;

[0175] L2 is O, S or NH, preferably oxygen;

[0176] R3 is an optionally substituted arylene, heteroarylene, cycloalkylene or heterocyclylene, wherein the substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, cyano;

[0177] R1, R2, and R4 are end-capping groups;

[0178] The end-capping group is selected from -L g -(L h ) n -L i -R c , where L g , L h, L i Each occurrence is independently selected from a bond, -O-, -S-, -C(R a )(R b )-, -NH-, -N(CH3)-, -C(=O)-, -CH2O- or -OCH2-, subscript n is an integer from 0 to 4, R a and R b Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, phenyl, -OH, -SH, -NH2, -NH(CH3) or -NH(CH3)2, R c Selected from methyl, ethyl, hydroxyl or mercapto.

[0179] In some embodiments, the definitions of each group or fragment of the structure of compound (II) are the same as the corresponding group or fragment in compound (I).

[0180] In some embodiments, R3 in the compound structure of (II) is selected from:

[0181] Optionally substituted C 5-14 arylene;

[0182] The optionally substituted C 5-14 heteroarylene;

[0183] An optionally substituted divalent saturated or partially unsaturated fused, bridged or spirocyclic C 5- 14 cycloalkylene; or

[0184] An optionally substituted divalent saturated or partially unsaturated fused, bridged or spirocyclic C 5- 14 Heterocycloalkylene containing 1 to 3 heteroatoms independently selected from N, O or S;

[0185] The substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.

[0186] In some embodiments, R3 in the compound structure of (II) is specifically selected from: optionally substituted 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 2,6-naphthylene, furylene, thienylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrazinylene, pyrimidinylene, pyridazinylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene, tetrahydropyrrolylene, tetrahydrothienylene, tetrahydropyranylene, piperidylene, tetrahydrothiopyranylene, dioxaneylene, piperazinylene, 1,4-piperazinylene, pyrazinylene, morpholinylene, dioxaneylene, and the substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.

[0187] In some embodiments, R3 is preferably 3-X-1,4-phenylene, 2-X-1,4-phenylene, 2-X-1,5-phenylene, 3-X-1,5-phenylene, 3-X-1-phenylene, 2-X-1-phenylene, 4-X-1-phenylene, wherein X is selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.

[0188] Yet another aspect of the present disclosure relates to the use of the compound of formula (II) as an intermediate in the preparation of the compound of formula (I).

[0189] Another aspect of the present disclosure relates to a method for preparing the compound of formula (I), comprising using the compound of formula (II) as an intermediate. Another aspect of the present disclosure relates to the use of the compound of formula (II) in preparing a drug for achieving targeted therapy or diagnosis.

[0190] Example

[0191] The starting materials of the embodiments are commercially available and / or can be prepared by a variety of methods known to those skilled in the art of organic synthesis. Those skilled in the art of organic synthesis will appropriately select reaction conditions (including solvent, reaction atmosphere, reaction temperature, duration of experiment and aftertreatment) in the following synthetic methods. Those skilled in the art of organic synthesis will appreciate that the functional groups present in each part of the molecule should be compatible with the proposed reagents and reactions.

[0192] Example 1: LDP-FAP-MMAE

[0193] Preparation of LDP-FAP-MMAE

[0194] LDP-FAP-MMAE can be prepared by the aforementioned reaction scheme (1), and the specific reaction is shown below.

[0195] 1-1 (1 equivalent) was dissolved in DMF, and N-Fmoc-ethylenediamine (1.2 equivalents), HBTU (1.2 equivalents), and DIPEA (3 equivalents) were added. The mixture was allowed to react at room temperature for 30 minutes. The solvent was then dried and dissolved in aqueous NaOH. The product was washed three times with ethyl acetate, and the aqueous phase was acidified with dilute hydrochloric acid. The precipitate was filtered to obtain 1-2. UPLC-MS analysis revealed a molecular weight of 404.11.

[0196] 1-2 (1 equivalent) was dissolved in DMF, and tert-butyl 3-hydroxypropionate (1 equivalent), DCC (2.2 equivalents), and DMAP (0.05 equivalents) were added. After reacting for 1 hour, the filtrate was filtered. The solvent was dried, and aqueous NaOH was added to dissolve the mixture. The mixture was washed three times with ethyl acetate, and the aqueous phase was adjusted to acidity with dilute hydrochloric acid. The precipitate was filtered to obtain 2-3. The product was characterized by UPLC-MS, and the measured molecular weight was 532.20.

[0197] 1-3 (1 equivalent) was dissolved in DMF, and p-hydroxybenzyl alcohol (1.2 equivalents), PyBop (1.2 equivalents) and DIPEA (3 equivalents) were added. The reaction was carried out at room temperature for 30 min. 1-4 was obtained by separation on a silica gel column with MeOH:DCM = 1:20. The product was characterized by UPLC-MS, and the measured molecular weight was 638.24.

[0198] 1-4 (1 equivalent) was dissolved in DMF, and DSC (1.1 equivalents) and DIPEA (3 equivalents) were added. After reacting at room temperature for 5 hours, MMAE (1 equivalent) was added. After reacting at room temperature for 30 minutes, 1-5 was separated by reverse HPLC. The product was characterized by UPLC-MS, and the measured molecular weight was 1381.72.

[0199] 1-5 (1 equivalent) was dissolved in MeCN, TFA was added, and the reaction was continued for 30 minutes before spun down to dryness. TsOH was added to FAP-int (1 equivalent) to remove the protecting group, which was then dissolved in MeCN and mixed with the deprotected 1-5. HBTU (1.2 equivalents) and DIPEA (3 equivalents) were added, and the reaction was continued for 30 minutes before separation by reverse-phase HPLC to yield 1-6. UPLC-MS characterization revealed a molecular weight of 1793.87.

[0200] FAP-int: 1H NMR(400MHz,DMSO-d6)δppm 1.41(s,9H),2.27-2.33(m,2H),3.27-3.29(m,5H),3.43-3.55(m,2H), 3.93-4.21(m,10H),5.19(dd,J=9.26,2.75Hz,1H),7.59(dd,J=9.26,2. 63Hz,1H),7.69(d,J=4.63Hz,1H),7.87-8.00(m,1H),8.14(d,J=9.26Hz,1H),8.95(d,J=4.63Hz,1H),9.24(t,J=5.82Hz,1H),11.00(brs,1H).

[0201] Diethylamine was added to 1-6 (1 equivalent) for deprotection and then dried in a rotary evaporation cycle. DOTA (10 equivalents), HATU (2 equivalents) and DIPEA (3 equivalents) were added and reacted for 1 hour. LDP-FAP-MMAE was obtained by reverse HPLC separation. The product was characterized by UPLC-MS and high-resolution mass spectrometry. The molecular weight of the product was [C 94 H 139 F2KN 17 O 24 P] 2+ =998.97,t R =2.04 min. The analytical column model for the UPLC-MS instrument was ACQUITY UPLC BEH C18 1.7 μm 2.1×50 mm throughout the document. The method was 90% H2O (0.1% FA) + 10% MeCN from 0 to 0.2 min, linearly changing to 100% MeCN from 0.2 to 3 min, 100% MeCN from 3 to 4 min, linearly changing to 90% H2O (0.1% FA) + 10% MeCN from 4 to 4.5 min, and linearly changing to 90% H2O (0.1% FA) + 10% MeCN from 4.5 to 5 min.

[0202] LDP-FAP-MMAE specifically releases MMAE through FAP protein

[0203] 5 μM FAP protein was incubated with 250 nM LDP-FAP-MMAE in PBS at pH 7.4 at 37°C, and the amount of MMAE released was detected by UPLC-MS (SIR M / Z = 719) at 0 min, 30 min, 90 min, 5 h, 11 h, and 24 h. 500 nM LDP-FAP-MMAE was incubated in PBS at pH 7.4 at 37°C, and the amount of MMAE released was detected by UPLC-MS (SIR M / Z = 719) at 0 h, 1 h, 2 h, 4 h, 6 h, 18 h, and 24 h. 5 μM FAP protein, 250 nM LDP-FAP-MMAE, 100 μM FAPI-04 were incubated at 37 ° C in PBS at pH 7.4, and the release of MMAE (SIR M / Z = 719) was detected by UPLC-MS at 0 h, 1 h, 2 h, 5 h, 11 h, and 24 h. 5 μM FAP protein, 250 nM LDP-FAP-MMAE, human serum albumin HSA (45 g / L), 5 μM DPP IV (FAP homologous protein), and 5 μM alkaline phosphatase ALP were incubated at 37 ° C in PBS at pH 7.4, and the release of MMAE (SIR M / Z = 719) was detected by UPLC-MS at 0 h, 2 h, 5 h, and 24 h. The experiment showed that LDP-FAP-MMAE only released MMAE rapidly when FAP protein was added, and the release was rapid and specific. The test results are shown in Figure 1.

[0204] LDP-FAP-MMAE releases MMAE in FAP-positive cells to kill cells

[0205] LDP-FAP-MMAE was prepared into a concentration gradient of 0, 0.5, 1, 5, 10, 20, 50, 100, 200, 500, 1000 nM and 0, 0.05, 0.1, 0.2, 0.5, 1, 2, 5, 10, 50 nM, and incubated with HT1080-FAP cells and HT1080 cells in 96-well plates for 48 hours (5000 cells per well). MMAE was prepared into a concentration gradient of 0, 0.05, 0.1, 0.2, 0.5, 1, 2, 5, 10, 50, 100 nM and incubated with HT1080-FAP cells. After 48 hours, the culture medium was replaced with 10% CCK-8 medium. After incubation for 1 hour, the absorbance at 450 nM was measured using a microplate reader. Cell viability was calculated using the CCK-8 formula: Cell proliferation rate (%) = (OD experimental group - OD blank group) / (OD control group - OD blank group) × 100%. The EC50 values ​​for LDP-FAP-MMAE against HT1080-FAP were 1.4 nM, MMAE against HT1080-FAP was 1.1 nM, and LDP-FAP-MMAE against HT1080 cells was 35.6 nM. See Figure 2 for the test results.

[0206] LDP-FAP-MMAE specifically releases MMAE in vivo

[0207] The gallium germanium generator was eluted with 5 mL of 0.6 M high-purity hydrochloric acid to obtain a Ga-68 hydrochloric acid solution. 1 mL of the eluted Ga-68 solution was added, 100 microliters of 3 M sodium hydroxide and 130 microliters of 3 M sodium acetate to adjust the acidity to a final pH of 4.0. 50 micrograms of TEFAPI-06 precursor were added, and the reaction mixture was heated to 90°C for 10 minutes. The reaction solution was passed through a C18 column to remove free ions, and then the C18 column was eluted with an ethanol solution. The labeled 68 Ga-LDP-FAP-MMAE. 37 MBq of labeled product was diluted with 200 μL of saline and withdrawn using an insulin syringe. The ethanol content of the drug should not exceed 5%. Healthy mice were anesthetized and placed on the PET / CT acquisition bed. An indwelling cannula was placed in the tail vein. A syringe was connected to the cannula, and PET data acquisition began at time zero of needle insertion. Acquisition times were 30 minutes, 90 minutes, and 4 hours. See Figure 3 for test results.

[0208] The tumor size of HT1080-FAP-bearing mice reached 200-300 mm 3Afterwards, each mouse was administered LDP-FAP-MMAE (0.2 mg / kg). Mice (n=5 per group) were dissected at 1, 6, 24, and 48 hours. Plasma, liver, and tumor samples were ground and extracted with methanol. MMAE content in the tissues was measured by UPLC-MS. The results showed that LDP-FAP-MMAE released significant amounts of MMAE only in the tumors. The liver took up LDP-FAP-MMAE significantly but did not release MMAE, demonstrating specific MMAE release. See Figure 4 for the test results.

[0209] LDP-FAP-MMAE for the treatment of HT1080-FAP tumor-bearing mice

[0210] When the tumor size is 50-100 mm 3 HT1080-FAP tumor-bearing mice and HT1080 tumor-bearing mice were treated (n=5, single dose of 0.78 mg / kg) on ​​days 0 and 4, respectively. It can be seen that after treatment, the growth of FAP-positive tumors was significantly inhibited. The test results are shown in Figure 5.

[0211] Example 2: LDP-FAPI-DOTA

[0212] LDP-FAPI-DOTA can be prepared by the aforementioned reaction scheme (1).

[0213] Synthesis steps:

[0214] 5-1 (50 mg, 1 equivalent) was dissolved in MeCN, and HBTU (134 mg, 1.2 equivalents), DIPEA (114 mg, 3 equivalents) and reactant g (100 mg, 1.2 equivalents) were added. After reaction at room temperature for 30 min, the mixture was separated on a silica gel column (DCM:MeOH = 10:1) and dried to give 5-2 with a yield of 81%.

[0215] 5-2 (95 mg) was dissolved in MeCN, and LiBr was added. The mixture was heated at 100°C under nitrogen for 5 h. A white precipitate gradually precipitated during the reaction and was filtered to obtain the product 5-3 with a yield of 40%.

[0216] 5-3 (36 mg, 1 equivalent) was dissolved in DMF, and reaction material i (19.4 mg, 1.2 equivalents), PyBop (52 mg, 1.2 equivalents) and DIPEA (32 mg, 3 equivalents) were added. The reaction was carried out at room temperature for 1 h. The product was separated by silica gel column (DCM:MeOH=20:1) and dried to give the product 5-4 with a yield of 83%.

[0217] 5-4 (43 mg) was dissolved in DCM, TFA was added for deprotection and the product 5-5 was obtained by spin drying with a yield of 95%.

[0218] 5-5 (6.8 mg, 1.2 eq) was dissolved in MeCN, and 1-2 (5 mg, 1 eq), HBTU (4.3 mg, 1.2 eq), and DIPEA (4 mg, 3 eq) were added. The mixture was allowed to react at room temperature for 30 min, followed by HPLC separation and lyophilization to afford 5-6 in a 62% yield. (Method: 0 min: 90% H2O + 10% MeCN, 12 min: 50% H2O + 50% MeCN, 15 min: 10% H2O + 90% MeCN, 17 min: 90% H2O + 10% MeCN).

[0219] 5-6 (6.5 mg, 1 equivalent) was dissolved in MeCN, and NHEt2 was added. After deprotection, HPLC separation and lyophilization, 5-7 was obtained in a 75% yield. (Method: 0 min: 90% H2O + 10% MeCN, 12 min: 50% H2O + 50% MeCN, 15 min: 10% H2O + 90% MeCN, 17 min: 90% H2O + 10% MeCN).

[0220] 5-7 (3.8 mg, 1 eq) was dissolved in DMF, and DOTA-NHS (2.9 mg, 1.2 eq) and DIPEA (3.1 mg, 5 eq) were added. The mixture was reacted at room temperature for 1 h. The mixture was then separated and lyophilized by HPLC to obtain 5-8 (LDP-FAPI-DOTA). (Method: 0 min: 90% H2O + 10% MeCN, 12 min: 50% H2O + 50% MeCN, 15 min: 10% H2O + 90% MeCN, 17 min: 90% H2O + 10% MeCN, separation column type: C18 5μm 4.6×150mm). UPLC-MS characterization of the product showed that the molecular weight was [C 53 H 72 F2K2N 12 O 15 P] 2+ =612.22,t R =1.56min.

[0221] Experiments have found that LDP-FAPI-DOTA can bind to FAP protein and then covalently label DOTA on the FAP protein, achieving covalent delivery of nuclides, increasing the uptake of small molecule nuclear drugs at the tumor site, and prolonging the retention time of retained nuclides at the tumor site.

[0222] LDP-FAPI-DOTA can be covalently linked to FAP protein

[0223] FAP protein: 177Lu-labeled LDP-FAPI-DOTA (5:1) was co-incubated at 37°C, pH 7.4. Samples were taken at 1, 3, 10, 24, 32, and 53 hours for SDS-PAGE. Autoradiography revealed significant radioactivity within the protein bands (see Figure 6), demonstrating covalent attachment to the FAP protein. The covalent site was identified by MS / MS.

[0224] LDP-FAPI-DOTA molecules can enhance tumor uptake

[0225] For the same HT1080-FAP tumor-bearing mouse, the tail vein was administered first. 68 PET imaging of Ga-FAPI-04 was performed 24 hours later 68 The PET imaging results of Ga-LDP-FAPI-DOTA are shown in FIG7 . It can be seen that the tumor uptake of LDP-FAPI-DOTA is significantly higher than that of FAPI-04.

[0226] Example 3: LDP-FAP-H-FITC, LDP-B-FAP-H-MMAE, LDP-B-FAP-F-MMAE, LDP-B-FAP-F-NIR-DOTA, LDP-B-FAP-H-MMAE-DOTA and LDP-B-FAP-F-MMAE-DOTA

[0227] LDP-FAP-H-FITC

[0228] LDP-FAP-H-FITC was prepared by the following reaction scheme.

[0229] Synthesis steps:

[0230] Diethylphosphinoacetic acid (50 mg, 1 equivalent) and FAP int (124 mg, 1 equivalent) were dissolved in DMF, DIEA 50 μL and HBTU (116 mg, 1.2 equivalents) were added, and the mixture was reacted at room temperature for 30 min. The product was separated by reverse HPLC to obtain 120 mg of the product with a yield of 74%.

[0231] The product from the previous step was dissolved in MeCN, and LiBr (200 mg, >10 equivalents) was added. The reaction was carried out at 80° C. overnight. The product was separated and purified by reverse HPLC to obtain 93 mg of the product with a yield of 80%.

[0232] The product from the previous step and p-hydroxybenzyl alcohol were dissolved in DMF, 1.2 equivalents of PyBop and 3 equivalents of DIEA were added, and the mixture was reacted at room temperature for half an hour. After purification by reverse HPLC, the product was obtained with a yield of 65%.

[0233] The product from the previous step was pre-activated with 1.2 equivalents of DSC for 1 hour, followed by the addition of amino FITC and DIEA, and heated at 60°C. The yield was 20%, and the product was purified by HPLC. UPLC-MS characterization of the final product [M+H] + =1114.35, purity 98%, t R =2.54min.

[0234] LDP-B-FAP-H-MMAE

[0235] Synthesis and characterization:

[0236] The synthetic route is the same as that of LDP-FAP-H-FITC, except that FITC is replaced with MMAE. UPLC-MS characterization of the final product [M+H] + =1469.78,t R =2.43min.

[0237] LDP-B-FAP-F-MMAE

[0238] Synthesis and characterization:

[0239] The synthetic route is the same as that of LDP-FAP-H-FITC, except that FITC is replaced by MMAE and p-hydroxybenzyl alcohol is replaced by 3-F-p-hydroxybenzyl alcohol. UPLC-MS characterization of the final product [M+H] + =1487.77,t R =2.43min.

[0240] LDP-B-FAP-F-NIR-DOTA

[0241] Synthesis and characterization:

[0242] The synthetic route is the same as that of LDP-FAP-MMAE, except that MMAE is replaced by NIR, NFmoc-ethylenediamine is replaced by NFmoc-PEG2-ethylenediamine, and p-hydroxybenzyl alcohol is replaced by 3-F-p-hydroxybenzyl alcohol. UPLC-MS characterization of the final product [M] + =1712.76,t R =2.12min.

[0243] LDP-B-FAP-H-MMAE-DOTA

[0244] Synthesis and characterization:

[0245] The synthetic route is the same as LDP-FAP-MMAE, except that NFmoc-ethylenediamine is replaced with NFmoc-PEG2-ethylenediamine. UPLC-MS characterization of the final product [M+H] + =2030.06,t R =2.03min.

[0246] LDP-B-FAP-F-MMAE-DOTA

[0247] Synthesis and characterization:

[0248] The synthetic route is the same as that of LDP-FAP-MMAE, except that NFmoc-ethylenediamine is replaced with NFmoc-PEG2-ethylenediamine and p-hydroxybenzyl alcohol is replaced with 3-F-p-hydroxybenzyl alcohol. UPLC-MS characterization of the final product [M+H] + =2048.05,t R =2.04min.

[0249] Biological test data

[0250] (1) 5 μM FAP protein was incubated with 250 nM of the above molecules in PBS at pH 7.4 at 37°C. The release of MMAE (SIR M / Z = 719) was detected by UPLC-MS at different times. The test data showed that the above molecules could release functional molecules in the presence of FAP protein. The test results are summarized in Figure 8.

[0251] (2) 1 μM LDP-FAP-H-FITC and LDP-B-FAP-F-NIR-DOTA were co-incubated with HT1080 cells and HT080-FAP-expressing cells for 6, 12, and 24 hours, respectively. Fluorescence confocal microscopy was used to image the cells at the corresponding time points. LDP-FAP-H-FITC used the AF488 fluorescence channel, and LDP-B-FAP-F-NIR used the Cy5 fluorescence channel. Fluorescence signals were observed in FAP-expressing cells, while FAP-negative cells showed almost no fluorescence signals. The test results are summarized in Figure 9; the left side of Figure 9 shows green fluorescence, and the right side shows red fluorescence.

[0252] (3) LDP-B-FAP-F-MMAE-DOTA mouse treatment test. A PDX tumor model was constructed in BNDG mice. When the tumor was 50 mm 3 Each mouse received a single dose of 10 nmol, administered three times at 3-day intervals. While the treated group showed no significant weight loss, it demonstrated a significant tumor therapeutic effect. The control groups were FAP-Val-Cit-PAB-MMAE and saline. The dosing pattern, changes in tumor volume and weight, and the tumor progression curves for each mouse are summarized in Figure 10.

[0253] Example 4: LDP-FAP-PEG0-S0456, LDP-FAP-PEG2-S0456, LDP-FAP-PEG5-S0456, LDP-FAP-F-PEG5-S0456

[0254] LDP-FAP-PEG0-S0456

[0255] Synthesis and characterization:

[0256] The synthetic route is the same as that of LDP-FAPI-DOTA, except that DOTA is replaced by S0456. For all the example molecules containing the S0456 fluorescent molecular module, the HPLC and UPLC-MS in the synthesis, separation and analytical characterization were performed, and H2O (0.1%) was replaced by H2O (10 mM ammonium acetate). The final product M was characterized by UPLC-MS. + =1780.59,t R =1.66min.

[0257] LDP-FAP-PEG2-S0456

[0258] Synthesis and characterization:

[0259] The synthetic route is the same as LDP-FAPI-DOTA, except that NFmoc-ethylenediamine is replaced by NFmoc-PEG2-ethylenediamine and DOTA is replaced by S0456. UPLC-MS characterization of the final product [M] + =1868.64,t R =1.65min.

[0260] LDP-FAP-PEG5-S0456

[0261] Synthesis and characterization:

[0262] The synthetic route is the same as LDP-FAPI-DOTA, except that NFmoc-ethylenediamine is replaced by NFmoc-PEG5-ethylenediamine and DOTA is replaced by S0456. UPLC-MS characterization of the final product [M] + =2000.72,t R =1.66min.

[0263] LDP-FAP-F-PEG5-S0456

[0264] Synthesis and characterization:

[0265] The synthetic route is the same as that of LDP-FAP-MMAE, except that DOTA is replaced by S0456, NFmoc-PEG2 ethylenediamine is replaced by NFmoc-PEG5 ethylenediamine, and p-hydroxybenzyl alcohol is replaced by 3-F-phenol. UPLC-MS characterization of the final product [M] + =2018.71,t R =1.67min.

[0266] Biological test data:

[0267] The aforementioned molecules were used for in vivo near-infrared fluorescence imaging in HT1080-FAP tumor-bearing mice. Each mouse was injected with 10 nmol of the molecules via the tail vein (4 mice per molecule, n=4). Imaging was performed 6 hours after administration using imaging parameters of Ex = 720 nm and Em = 790 nm. The test results are summarized in Figure 11.

[0268] Example 5: LDP-FAP-S0456-DOTA

[0269] Synthesis and characterization:

[0270] Diethylphosphinoacetic acid (5 g, 1 equivalent) and N-Fmoc ethylenediamine (8.6 g, 1.2 equivalents) were dissolved in DMF, DIEA 4.7 mL and HBTU (14.5 mg, 1.5 equivalents) were added, and the mixture was reacted at room temperature for 30 min. The product was purified by reverse phase column separation to obtain 8 g of the product with a yield of 69%.

[0271] The product from the previous step was dissolved in MeCN, and LiBr (9 g, excess) was added. The reaction was carried out at 80°C overnight, and the product was separated and purified by reverse phase column to obtain 6 g of the product with a yield of 80%.

[0272] The product from the previous step and tert-butyl 3-hydroxypropionate (1.2 eq) were dissolved in MeCN, 1.5 equivalents of PyBop and 2 equivalents of DIEA were added, and the mixture was reacted at room temperature for half an hour. The mixture was purified by reverse phase column to obtain 5 g of product with a yield of 65%.

[0273] The product from the previous step was dissolved in MeCN, and TFA was added to make the concentration 50%. The reaction was carried out at room temperature for 20 min, and the product was purified by reverse phase column to obtain 4.28 g of the product with a yield of 95%.

[0274] The product from the previous step was dissolved in MeCN, and LiBr (9 g, excess) was added. The reaction was allowed to proceed at 80°C overnight. The product was separated and purified by reverse phase column to obtain 3.64 g of the product with a yield of 90%. This product was named P1.

[0275] (5 g, 1 eq) and (4.2 g, 1.1 eq) were dissolved in MeCN, a small amount of DIEA was added, and the mixture was reacted at room temperature for 40 min to obtain 6.61 g of the product with a yield of 90%.

[0276] The product from the previous step was added to a TFA-MeCN solution and reacted at room temperature for 20 min to obtain 5.15 g of product with a yield of 95%. This product was named P2.

[0277] P1 and P2 were mixed and dissolved in MeCN, DIEA 2.8 mL and HBTU (4.4 g, 1.5 equivalents) were added, and the mixture was reacted at room temperature for 50 min. The mixture was purified by reverse phase column to obtain 5.0 g of the product with a yield of 72%.

[0278] The product from the previous step was mixed with 1.2 eq of tert-butyl p-hydroxybenzoate and dissolved in MeCN. 2 mL of DIEA and 3.0 g of HBTU (1.5 eq) were added. The mixture was reacted at room temperature for 50 min and purified by reverse phase column to obtain 3.87 g of the product with a yield of 65%.

[0279] The product from the previous step was dissolved in MeCN and irradiated with a UV lamp at 365 nm overnight to obtain 1.91 g of product with a yield of 59%.

[0280] 100 mg of the product from the previous step was dissolved with S0456 (1 equivalent) in MeCN, 50 μL of DIEA and 1.5 equivalents of HBTU were added, and the mixture was reacted at room temperature for 50 min. The product was purified by reverse phase column to obtain 167 mg of the product with a yield of 80%.

[0281] The product from the previous step was added to a TFA-MeCN solution and reacted at room temperature for 20 min to obtain 146 mg of the product with a yield of 90%.

[0282] The product from the previous step and FAP int (50 mg, 1 equivalent) were dissolved in DMF, DIEA 30 μL and HBTU (57.5 mg, 2 equivalents) were added, and the mixture was reacted at room temperature for 30 min. The product was separated by reverse phase HPLC to obtain 150 mg of the product with a yield of 78%.

[0283] The product from the previous step was added to a TEA-MeCN solution and reacted at room temperature for 20 min to obtain 123 mg of the product with a yield of 90%.

[0284] DOTA (excess) was dissolved in DMF, and 30 μL of DIEA and 40 mg of HBTU (2 equivalents) were added. The mixture was reacted at room temperature for 30 min. The product from the previous step was added and reacted at room temperature for 30 min. The product was separated by reverse-phase HPLC to obtain 70 mg of the product with a yield of 50%.

[0285] The product from the previous step was added to 4M HCl and reacted at room temperature for 20 min to obtain 40 mg of the final product with a yield of 60%. UPLC-MS analysis showed that the purity of the final product was >95%, [M+H] 2+ =1253.46,t R =1.68min.

[0286] Biological test data:

[0287] (1) The above molecules were subjected to covalent SDS-PAGE experiments to separate the FAP protein: 177 Lu-labeled molecules were co-incubated at 37°C, pH 7.4 in a ratio of 5:1. Samples were taken at 12 and 30 hours (n=2) for SDS-PAGE experiments. Autoradiography revealed obvious radioactivity on the protein bands, indicating that covalent linkage with the FAP protein was possible. The left figure in Figure 12 shows the results of autoradiography. The upper band corresponds to the protein band stained with Coomassie Brilliant Blue in the right figure in Figure 12, and the lower band represents the non-covalent small molecule.

[0288] (2) The above molecules are carried out 68 Ga radiolabeled, 10 nmol of the molecule and 10 mCi 68 GaCl3 was dissolved in sodium acetate buffer at pH 4, and 0.5 mg of gentisic acid was added. The mixture was heated at 90°C for 10 minutes and then purified using a C18 column. The labeled product was injected into the tail vein of HT1080-FAP tumor-bearing mice for PET-CT imaging. The molecular specific activity was 400 μCi / nmol. The test results are summarized in Figure 13, showing that the molecule is specifically enriched in the tumor site.

[0289] (2) Near-infrared fluorescence imaging was performed on HT1080-FAP tumor-bearing mice. Each mouse (n=4) was administered 1 nmol via the tail vein, and imaging was performed at different time points using imaging parameters of Ex = 720 nm and Em = 790 nm. The test results are summarized in Figure 14, showing that the molecule is enriched in the tumor site and has high tumor retention.

[0290] Example 6: FAP-Cy5-Quencher and FAP-Cy5-Quencher-DOTA

[0291] FAP-Cy5-Quencher

[0292] Synthesis and characterization: The synthetic route was the same as that of LDP-FAP-S0456-DOTA. During the synthesis, the FAP target head was replaced by NFmoc-PEG2 ethylenediamine-QSY-21, DOTA was replaced by NFmoc-PEG2 ethylenediamine-Cy5, and NFmoc ethylenediamine was replaced by NFmoc-PEG2 ethylenediamine.

[0293] UPLC-MS characterization of the final product [M+H] 2+ =1182.45,t R =2.35min.

[0294] FAP-Cy5-Quencher-DOTA

[0295] Synthesis and characterization: The synthetic route was the same as that of FAP-Cy5-Quencher, except that NFmoc-PEG2 ethylenediamine-Cy5 was replaced by Lys-DOTA-Cy5.

[0296] UPLC-MS characterization of the final product [M] 2+ =1518.64,t R =2.13min.

[0297] Biological test data:

[0298] (1) 500 nmol of the above molecules and 5 μM protein were co-incubated in PBS at pH 7.4 at 37°C. Fluorescence intensity was measured at corresponding time points (Ex = 620 nm, Em = 670 nm). A PBS group without FAP protein served as a control group. The results showed a significant increase in fluorescence signal after the addition of FAP protein. Figure 15 shows the experimental results for FAP-Cy5-Quencher and FAP-Cy5-Quencher-DOTA, respectively.

[0299] (2) The above molecules were co-incubated with HT1080 cells and HT080-FAP expressing cells at 1 μM / 1 μM, respectively, and imaging was performed using a fluorescence confocal microscope at the corresponding time points. The imaging channel was the Cy5 fluorescence channel. The test results are summarized in Figure 16. Figure 16 shows the generation of fluorescence signals in FAP expressing cells, while FAP negative cells have almost no fluorescence signals. The following figures show the experimental results of FAP-Cy5-Quencher co-incubation for 12 hours and FAP-Cy5-Quencher-DOTA co-incubation for 6-24 hours.

[0300] (3) Near-infrared fluorescence imaging was performed on HT1080-FAP tumor-bearing mice. Each mouse was administered 10 nmol via the tail vein, and imaging was performed. It was found that the molecule was specifically enriched in the tumor site and had a long tumor retention period. The test results are summarized in Figure 17. The upper and lower figures of Figure 17 show the imaging results of FAP-Cy5-Quencher after 3-50 hours of administration and FAP-Cy5-Quencher-DOTA after 0.5-60 hours of administration, respectively.

[0301] Example 7: LDP-Dox, LDP-Exatecan, LDP-Dxd

[0302] LDP-Dox

[0303] Synthesis and characterization:

[0304] The synthetic route is the same as that of LDP-FAP-MMAE, except that MMAE is replaced by Dox. UPLC-MS characterization of the final product [M+H] + =1784.65,t R =2.23min.

[0305] LDP-Exatecan

[0306] Synthesis and characterization:

[0307] The synthetic route is the same as that of LDP-FAP-MMAE, except that MMAE is replaced by Exatecan. UPLC-MS characterization of the final product [M+H] + =1676.64,t R =2.12min.

[0308] LDP-Dxd

[0309] Synthesis and characterization:

[0310] The synthetic route is the same as that of LDP-FAP-MMAE, except that MMAE is replaced by Dxd. UPLC-MS characterization of the final product [M+H] + =1734.64,t R =2.15min.

[0311] Biological test data

[0312] (1) 5 μM FAP protein was co-incubated with 250 nM of the above molecules in PBS at pH 7.4 at 37°C, and the release of drug molecules was detected by UPLC-MS at different time points. The test results are summarized in Figure 18

[0313] Example 8: CA-P-1, CA-P-2

[0314] CA-P-1

[0315] Synthesis and characterization:

[0316] The synthetic route is the same as that of LDP-FAP-H-FITC, except that FITC is replaced by coumarin and the FAP target is replaced by CA target (benzenesulfonamide). UPLC-MS characterization of the final product [M+H] +=745.19,t R =2.23min.

[0317] CA-P-2

[0318] Synthesis and characterization:

[0319] The synthetic route is the same as that of LDP-FAP-H-FITC, except that FITC is replaced by coumarin, the FAP target is replaced by CA target (benzenesulfonamide), and NFmoc-ethylenediamine is replaced by NFmoc-PEG2-ethylenediamine. UPLC-MS characterization of the final product [M+H] + =789.21,t R =2.22min.

[0320] Biological test data:

[0321] 5 μM carbonic anhydrase 1 protein was co-incubated with 250 nM of the above molecules in PBS at pH 7.4 at 37°C for 24 hours, and the increase in fluorescence signal was measured by fluorescence instrumentation. A control group without protein was used. The test results are summarized in Figure 19.

[0322] The above description is merely an exemplary embodiment of the present invention and is not intended to limit the scope of protection of the present invention. The scope of protection of the present invention is determined by the appended claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, in W is oxygen or sulfur, preferably oxygen; X1 is -L1-R1; Y1 is -L1-R2; Z1 is -L2-R3-L1-R4; L1 is independently a bond or a linker at each occurrence; L2 is O, S or NH, preferably oxygen; R3 is an optionally substituted arylene, heteroarylene, cycloalkylene or heterocyclylene; the substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, cyano; One of R1, R2, and R4 is a targeting group, and the other two are independently targeting groups, drug molecule groups, isotope chelators or labeling precursor groups, fluorescent or molecular tag groups, or capping groups.

2. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R3 is selected from Optionally substituted C 5-14 arylene; The optionally substituted C 5-14 heteroarylene; An optionally substituted divalent saturated or partially unsaturated fused, bridged or spirocyclic C 5- 14 cycloalkylene; or An optionally substituted divalent saturated or partially unsaturated fused, bridged or spirocyclic C 5- 14 Heterocycloalkylene containing 1 to 3 heteroatoms independently selected from N, O or S; The substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.

3. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R3 is selected from optionally substituted 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 2,6-naphthylene, furylene, thienylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrazinylene, pyrimidinylene, pyridazinylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene, tetrahydropyrrolylene, tetrahydrothienylene, tetrahydropyranylene, piperidylene, tetrahydrothiopyranylene, dioxanylene, piperazinylene, 1,4-piperazinylene, pyrazinylene, morpholinylene, dioxanylene; and the substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, cyano; or The R3 is preferably 3-X-1,4-phenylene, 2-X-1,4-phenylene, 2-X-1,5-phenylene, 3-X-1,5-phenylene, 3-X-1-phenylene, 2-X-1-phenylene, 4-X-1-phenylene, and the X is selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.

4. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R4 is a targeting group or a drug molecule group, and R1 and R2 are each independently a targeting group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group or a capping group.

5. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R4 is a targeting group, and R1 and R2 are each independently a drug molecule group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group or a capping group.

6. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R4 is a targeting group, one of R1 and R2 is a drug molecule group, an isotope chelator or a labeling precursor group or a fluorescent or molecular tag group, and the other is a capping group.

7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, which satisfies one or more of the following conditions: (a) Each occurrence of L1 is independently a bond or -L a -(L b ) m -L c -(L d ) n -L e -L f -, where L a 、L b 、L c 、L d 、L e 、L f Each occurrence is independently selected from a bond, -O-, -S-, -SS-, -S(=O)2-, -NH-, -N(CH3)-, -C(R a )(R b )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NH-, -NHC(=O)-, -C(=O)-N(CH3)-, -N(CH3)-C(=O)-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2NH-, -NHCH2-, -CH2O-, -OCH2-, -CH=NO-, -C(CH3)=N-NH-, -C(CH3)=N-NH-C(=O)-, -NH-CH2-C(=CH-COOH)-, a divalent peptide group comprising 1, 2, 3 or 4 amino acids, a cyclohexylene group, a phenylene group, a heterocyclylene group (e.g., piperazine-1,4-diyl) or R a and R b Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, phenyl, -OH, -SH, -NH2, -NH(CH3)2, and the subscripts m and n are 0, 1, 2, 3 or 4, respectively; (b) the end-capping group is selected from -L g -(L h ) n -L i -R c , where L g , L h , L i Each occurrence is independently selected from a bond, -O-, -S-, -C(R a )(R b )-, -NH-, -N(CH3)-, -C(=O)-, -CH2O- or -OCH2-, subscript n is an integer from 0 to 4, R a and R b Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, phenyl, -OH, -SH, -NH2, -NH(CH3) or -NH(CH3)2, R c Selected from methyl, ethyl, hydroxyl or mercapto; (c) the drug molecule group is derived from a cytotoxic drug, an immunomodulator, an antibiotic, a protein degrader, or a molecular glue; (d) isotope chelators or labeling precursor groups are selected from or (e) the fluorescent or molecular tag group is selected from a fluorescent labeling molecular group, an affinity purification labeling group, or a click chemistry labeling group; (f) The targeting group is selected from a ligand group having high affinity for FAP, FOLR1, integrin, carbonic anhydrase or nectin4.

8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein L1 is selected from -NH-, -CH2-, -N(CH3)-, -C(=O)-, -C(=O)-PEP-, -NH-PEP-, wherein subscripts m and n are 0, 1, 2, 3, or 4, respectively; PEP represents a divalent peptide group containing 1, 2, 3, or 4 amino acids; and subscript c is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the blocking group is selected from methyl, methoxy, or The subscript n is 1, 2, 3 or 4.

10. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein L1 in Z1 is selected from -NH-, -CH2-, -N(CH3)-, -C(=O)-, -C(=O)-PEP-, -NH-PEP-, wherein the subscript n is an integer of 1-4, and PEP represents a divalent peptide group containing 1, 2, 3 or 4 amino acids.

11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein L1 in X1 or Y1 is selected from or Wherein the subscripts m and n are 0, 1, 2, 3 or 4 respectively, and the subscript c is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

12. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the drug molecule group is selected from:

13. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof according to any one of claims 1 to 12, wherein the isotope chelator or labeling precursor group and the fluorescent or molecular tag group are selected from:

14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the targeting group is selected from or 15. The compound of formula (I) according to claim 14 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the targeting group is selected from 16. The compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein one of R1, R2 and R4 is an isotope chelator or a labeling precursor group.

17. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound of formula (I) is selected from or 18. A chelate or radionuclide label comprising (i) a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; and (ii) Radionuclides.

19. The chelate or radionuclide label according to claim 18, wherein the radionuclide is selected from: 18 F. 51 Cr, 67 Ga, 68 Ga, 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, 165 Dy, 169 Second, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As、 72 Se, 97 Such as 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, 67 Cu, 188 Re、 186 Re、 198 Au, 225 Ac, 227 Th and 199 Ag.

20. The chelate or radionuclide label according to claim 18, wherein the radionuclide is 68 Ga or 86 Y.

21. A pharmaceutical composition comprising or consisting of: A compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; or a chelate or radionuclide label according to any one of claims 18 to 20, Optionally, and pharmaceutically acceptable excipients.

22. A kit comprising or consisting of: (i) a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; or a chelate or radionuclide label according to any one of claims 18 to 20; or a pharmaceutical composition according to claim 21, and (ii) instructions for use in diagnosing or treating a disease.

23. Use of a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a chelate or radionuclide label according to any one of claims 18 to 20, or a pharmaceutical composition according to claim 21 in the preparation of a medicament for achieving targeted therapy or diagnosis.

24. The use according to claim 23, wherein the disease targeted by the targeted therapy is a malignant proliferative disease, an immune disease, and an infectious disease.

25. The method of claim 24, wherein the malignant proliferative disease is selected from the group consisting of breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, bile duct cell carcinoma, clear cell renal carcinoma, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, cancer of unknown primary, thymic carcinoma, glioma, glioma, astrocytoma, cervical cancer, prostate cancer, thyroid cancer, gastric cancer, bone cancer, lung cancer, lymphoma, uterine corpus cancer, gallbladder cancer, oral cancer, and testicular cancer.

26. The method of claim 24, wherein the immune disease is selected from the group consisting of rheumatoid arthritis (RA), ankylosing spondylitis (AS), juvenile idiopathic arthritis (JIA), non-radiographic axial spondyloarthritis (nr-AxSpA), psoriasis, psoriatic arthritis (PsA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), lupus nephritis (LN), multiple sclerosis (MS), bronchial asthma, etc.

27. A compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a chelate or radionuclide label according to any one of claims 18 to 20, or a pharmaceutical composition according to claim 21, for use in achieving targeted therapy or diagnosis.

28. A method for achieving targeted therapy or diagnosis, comprising using a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a chelate or radionuclide label according to any one of claims 18 to 20, or a pharmaceutical composition according to claim 21.

29. A method for inhibiting overexpression of fibroblast activation protein in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a chelate or radionuclide label according to any one of claims 18 to 20, or a pharmaceutical composition according to claim 21.

30. A method for diagnosing or treating a disease characterized by overexpression of fibroblast activation protein, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a chelate or radionuclide label according to any one of claims 18 to 20, or a pharmaceutical composition according to claim 21.

31. The method of claim 29 or 30, wherein the disease characterized by overexpression of fibroblast activation protein is selected from cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and scar disease; preferably, the cancer is selected from breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, bile duct cell carcinoma, clear cell renal carcinoma, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, primary unknown cancer, thymic cancer, glioma, glioma, astrocytoma, cervical cancer and prostate cancer.

32. Use of a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a chelate or radionuclide label according to any one of claims 18 to 20, or a pharmaceutical composition according to claim 21, for the preparation of a medicament for inhibiting overexpression of fibroblast activation protein in a subject in need thereof.

33. Use of a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a chelate or radionuclide label according to any one of claims 18 to 20, or a pharmaceutical composition according to claim 21, for the preparation of a medicament for diagnosing or treating a disease characterized by overexpression of fibroblast activation protein.

34. The use according to claim 32 or 33, wherein the disease characterized by overexpression of fibroblast activation protein is selected from cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and scar disease; preferably, the cancer is selected from breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, bile duct cell carcinoma, clear cell renal carcinoma, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, primary unknown cancer, thymic cancer, glioma, glioma, astrocytoma, cervical cancer and prostate cancer.

35. A compound of formula (II), in W is oxygen or sulfur, preferably oxygen; X1 is -L1-R1; Y1 is -L1-R2; Z1 is -L2-R3-L1-R4; L1, at each occurrence, is independently a bond, a linker, or absent; L2 is O, S or NH, preferably oxygen; R3 is an optionally substituted arylene, heteroarylene, cycloalkylene or heterocyclylene, wherein the substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, cyano; R1, R2, and R4 are end-capping groups; The end-capping group is selected from -L g -(L h ) n -L i -R c , where L g 、L h 、L i Each occurrence is independently selected from a bond, -O-, -S-, -C(R a )(R b )-, -NH-, -N(CH3)-, -C(=O)-, -CH2O- or -OCH2-, subscript n is an integer from 0 to 4, R a and R b Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, phenyl, -OH, -SH, -NH2, -NH(CH3) or -NH(CH3)2, R c Selected from methyl, ethyl, hydroxyl or mercapto; or a pharmaceutically acceptable salt, stereoisomer or solvate thereof.

36. The compound of formula (II) according to claim 35, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R3 is selected from Optionally substituted C 5-14 arylene; The optionally substituted C 5-14 heteroarylene; An optionally substituted divalent saturated or partially unsaturated fused, bridged or spirocyclic C 5- 14 cycloalkylene; or An optionally substituted divalent saturated or partially unsaturated fused, bridged or spirocyclic C 5- 14 Heterocycloalkylene containing 1 to 3 heteroatoms independently selected from N, O or S; The substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.

37. The compound of formula (I) according to claim 35, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R3 is selected from optionally substituted 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 2,6-naphthylene, furylene, thienylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrazinylene, pyrimidinylene, pyridazinylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene, tetrahydropyrrolylene, tetrahydrothienylene, tetrahydropyranylene, piperidylene, tetrahydrothiopyranylene, dioxanylene, piperazinylene, 1,4-piperazinylene, pyrazinylene, morpholinylene, dioxanylene, and the substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, or cyano; or The R3 is preferably 3-X-1,4-phenylene, 2-X-1,4-phenylene, 2-X-1,5-phenylene, 3-X-1,5-phenylene, 3-X-1-phenylene, 2-X-1-phenylene, 4-X-1-phenylene, and the X is selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.

38. Use of the compound of claim 36 or 37 in the preparation of the compound of claim 1.

39. A method for preparing the compound of claim 1, comprising using the compound of claim 36 or 37 as an intermediate.

40. Use of the compound according to claim 36 or 37 in the preparation of a medicament for achieving targeted therapy or diagnosis.

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