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WO2025162459A1 - Nouveau composé ciblant un ligand, chélate, composition et utilisation associées - Google Patents

Nouveau composé ciblant un ligand, chélate, composition et utilisation associées

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Publication number
WO2025162459A1
WO2025162459A1 PCT/CN2025/075553 CN2025075553W WO2025162459A1 WO 2025162459 A1 WO2025162459 A1 WO 2025162459A1 CN 2025075553 W CN2025075553 W CN 2025075553W WO 2025162459 A1 WO2025162459 A1 WO 2025162459A1
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WIPO (PCT)
Prior art keywords
cancer
group
compound
pharmaceutically acceptable
formula
Prior art date
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Pending
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PCT/CN2025/075553
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English (en)
Chinese (zh)
Inventor
刘志博
文子豪
崔希洋
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Peking University
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Peking University
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Publication of WO2025162459A1 publication Critical patent/WO2025162459A1/fr
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Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Definitions

  • 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.
  • 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.
  • 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.
  • linkers are primarily classified into two categories: chemically cleavable linkers and enzymatically cleavable linkers.
  • 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).
  • GSH reduced glutathione
  • 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.
  • 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.
  • 9 out of 15 drugs utilize enzymatically cleavable linkers.
  • current controlled-release strategies lack specificity, resulting in significant off-target toxicity during the long-term circulation of ADCs in vivo.
  • 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.
  • One aspect of the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, isomer or solvate thereof,
  • W is oxygen or sulfur, preferably oxygen
  • X 1 is -L 1 -R 1 ;
  • Y 1 is -L 1 -R 2 ;
  • Z 1 is -L 2 -R 3 -L 1 -R 4 ;
  • L1 is independently a bond or a linker at each occurrence
  • L 2 is O, S or NH, preferably oxygen
  • R 3 is an optionally substituted arylene, heteroarylene, cycloalkylene or heterocyclylene, such as phenylene; the substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, cyano;
  • R 1 , R 2 and R 4 is a targeting group, and the other two are independently a targeting group, a drug molecule group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group or a capping group.
  • one of R 1 , R 2 , and R 4 is an isotope chelator or a labeling precursor group.
  • 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.
  • composition comprising or consisting of:
  • 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.
  • 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 the preparation of a compound of formula (I).
  • 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.
  • 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.
  • FIG3 shows photographs of the distribution of 68 Ga-LDP-FAP-MMA in HT1080-FAP tumor-bearing mice.
  • FIG4 shows the MMAE release of LDP-FAP-MMAE in different tissues of HT1080-FAP tumor-bearing mice.
  • FIG5 shows the tumor volume of HT1080-FAP tumor-bearing mice after treatment with LDP-FAP-MMAE.
  • FIG6 shows the SDS-PAGE and autoradiography results of the co-incubation of 177 Lu-labeled LDP-FAPI-DOTA and FAP protein.
  • FIG7 shows the PET-CT imaging results of mice administered with 68 Ga-FAPI-04 and 68 Ga-LDP-FAPI-DOTA.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG12 shows the results of autoradiography in SDS-PAGE experiments after co-incubation of LDP-FAP-S0456-DOTA and FAP protein.
  • FIG13 shows PET-CT imaging of 68 Ga radiolabeled LDP-FAP-S0456-DOTA in HT1080-FAP tumor-bearing mice.
  • FIG14 shows near-infrared fluorescence imaging of LDP-FAP-S0456-DOTA in HT1080-FAP tumor-bearing mice.
  • FIG15 shows that FAP-Cy5-Quencher and FAP-Cy5-Quencher-DOTA release quenching groups after adding FAP protein, and the fluorescence signal increases significantly.
  • 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.
  • FIG17 shows near-infrared fluorescence imaging of FAP-Cy5-Quencher and FAP-Cy5-Quencher-DOTA in HT1080-FAP tumor-bearing mice.
  • FIG18 shows the percentage of drug molecules released by LDP-Dox, LDP-Exatecan, and LDP-Dxd in the presence of FAP protein.
  • 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.
  • 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.”
  • pharmaceutically acceptable 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.
  • subject or “patient” as used in this application includes humans and mammals.
  • treatment may also include prophylaxis, unless specifically stated to the contrary.
  • solvate 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).
  • 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.
  • 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.).
  • pharmaceutically acceptable salt refers to relatively non-toxic addition salts of the disclosed compounds. See, for example, S. M. Berge et al., "Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the term “optionally” is used herein to describe a situation that may or may not occur.
  • 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.
  • 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.
  • 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.
  • substitution may be any position unless otherwise specified.
  • alkyl refers to a straight or branched alkane chain containing 1 to 14 carbon atoms.
  • representative examples of C1 - C14 alkyl groups 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 ).
  • C5 - C14 alkyl groups include, but are not limited to, n-pentyl ( C5 ), 3-pentyl ( C5 ), neopentyl ( C5 ), 3-methyl-2-butane ( C5 ), tert-pentyl ( C5 ), and n-hexyl ( C6 ).
  • the term "lower alkyl” refers to a straight or branched 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.
  • 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 .
  • optionally substituted alkyl means that the alkyl group may be unsubstituted or substituted.
  • Substituted alkyl groups include, but are not limited to, C 1-5 alkyl groups substituted with one or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, hydroxy, amino, mercapto, halogen, nitro, and -CN.
  • alkylene refers to a divalent hydrocarbon group as described above for "alkyl,” but having two points of attachment.
  • a methylene group is a -CH2- group and an ethylene group is a -CH2 - CH2- group.
  • halogen refers to fluorine, chlorine, iodine, or bromine.
  • cycloalkyl refers to a saturated cycloalkyl derived from a single carbon atom of a parent cycloalkane by removing a hydrogen atom.
  • Typical C3-14 cycloalkyls include, but are not limited to, groups of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.
  • Cycloalkyls can be described by the number of carbon atoms in the ring. For example, a cycloalkyl with 5-7 ring atoms can be referred to as a ( C5 - C7 )cycloalkyl.
  • a cycloalkyl can be a ( C5 - C14 )cycloalkyl, a ( C5 - C8 )cycloalkyl, a ( C5 - C7 )cycloalkyl, a ( C5 - C6 )cycloalkyl, and these can be referred to as C5 - C14cycloalkyl , C5 - C8cycloalkyl , C5 - C7cycloalkyl , C5 -C6cycloalkyl, or C5 - C7cycloalkyl using alternative language.
  • cycloalkylene 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.
  • 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.
  • 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.
  • arylene 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.
  • optionally substituted arylene includes unsubstituted arylene, as well as substituted arylene, for example, arylene substituted with one or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, hydroxy, amino, mercapto, halogen, nitro, and -CN.
  • 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.
  • 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.
  • heteroaryl includes optionally substituted monovalent fused or non-fused heteroaryls having at least one heteroatom.
  • 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.
  • 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).
  • 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.
  • monocyclic heteroaryls include pyridyl; fused ring heteroaryls include benzimidazolyl, quinolinyl, acridinyl, and non-fused biheteroaryls include bipyridinyl.
  • 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, quinazoliny
  • heteroarylene 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.
  • optionally substituted heteroarylene includes unsubstituted heteroarylene and substituted heteroarylene, such as heteroarylene substituted with one or more substituents selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, hydroxy, amino, thiol, halogen, nitro, and -CN.
  • any atom not specifically limited to a particular isotope represents any stable isotope of that atom.
  • Isotopic substitution such as deuterium substitution
  • Partial deuterium substitution means that at least one hydrogen is replaced by deuterium.
  • isotopes of hydrogen such as deuterium ( 2 H) and tritium ( 3 H) can be used anywhere in the structure to achieve the desired result.
  • isotopes of carbon such as 13 C and 14 C, can also be used.
  • the isotope is at least about 90, 95, or 99% or more isotopically enriched at any of the positions involved.
  • deuterium is at least about 90, 95, or 99% enriched at the desired position.
  • the substitution of a deuterium atom for a hydrogen atom occurs in a group selected from R 1 , R 2 , R 3 , R 4 , Ra , R b , R c , or any other substituent group defined herein.
  • at least one of R 1 , R 2 , R 3 , R 4 , Ra , R b , and R c is deuterium-enriched.
  • the alkyl residue may be deuterated (e.g., CDH 2 , CD 2 H, CD 3 , CH 2 CD 3 , CD 2 CD 3 , CHDCH 2 D, CH 2 CD 3 , CHDCHD 2 , OCDH 2 , OCD 2 H, or OCD 3 , etc.).
  • the unsubstituted carbon may be deuterated when two substituents are combined to form a ring.
  • 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.
  • reagents and starting materials used in the present disclosure are commercially available or can be prepared by conventional chemical synthesis methods.
  • targeting group refers to a ligand group that specifically binds to a targeting protein.
  • a targeting group is a ligand group that has a high affinity for a tumor or tissue-specific biomarker.
  • drug molecule group refers to a group derived from a drug molecule.
  • the drug molecule has one or more of cytotoxicity, immunomodulatory function, protein degradation function, and antimicrobial function.
  • the drug molecule is a cytotoxic drug, an immunomodulator, an antibiotic, a protein degrader, or a molecular glue.
  • the drug molecule is a DNA crosslinker, a microtubule inhibitor, a DNA alkylating agent, a topoisomerase inhibitor, or a combination thereof.
  • 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, ⁇ -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
  • 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.
  • fluorescent or molecular tag group refers to a group derived from a fluorescent or molecular tag.
  • the fluorescent or molecular label can be, for example, a fluorescent dye, a quantum dot, 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 Er, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 197 Hg, 211 At, 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 P
  • capping group 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.
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof,
  • W is oxygen or sulfur, preferably oxygen
  • X 1 is -L 1 -R 1 ;
  • Y 1 is -L 1 -R 2 ;
  • Z 1 is -L 2 -R 3 -L 1 -R 4 ;
  • L1 is independently a bond or a linker at each occurrence
  • L 2 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
  • R 1 , R 2 and R 4 is a targeting group, and the other two are independently a targeting group, a drug molecule group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group or a capping group.
  • R 3 is optionally substituted C 5-14 arylene, C 5-14 heteroarylene, C 5-14 cycloalkylene, or C 5-14 heterocyclylene.
  • R 3 is selected from:
  • the substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.
  • 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, dioxanylene, piperazinylene, 1,4-piperazinylene, pyrazinylene, morpholinylene, dioxanylene; and
  • R 3 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.
  • L1 being a bond means that the groups on both sides of L1 are directly connected.
  • L1 being a bond means that X1 is -R1 .
  • a linker refers to a divalent group that connects two groups. 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 substituted by one or more substituents selected from C 1-4 alkyl, C 1-4 alkoxy, hydroxy, amino, mercapto, halogen, nitro and -CN.
  • one of R 1 , R 2 , and R 4 is a targeting group for a targeting protein, and the other two are independently a drug molecule group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group, or a capping group.
  • R 4 is a targeting group for a targeting protein
  • R 1 is a drug molecule group, an isotope chelator or a labeling precursor group, or a fluorescent or molecular tag group
  • R 2 is a capping group
  • R 4 is a targeting group for a targeting protein
  • R 2 is a drug molecule group, an isotope chelator or a labeling precursor group, or a fluorescent or molecular tag group
  • R 1 is a capping group.
  • two of R 1 , R 2 , and R 4 are independently targeting groups of a targeting protein, 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.
  • R 1 and R 2 are independently targeting groups of a targeting protein, and R 4 is a drug molecule group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group, or a capping group; or R 1 and R 4 are independently targeting groups of a targeting protein, and R 2 is a drug molecule group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group, or a capping group; or R 2 and R 4 are independently targeting groups of a targeting protein, and R 1 is molecule group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group, or a capping group.
  • R 4 is a targeting group or a drug molecule group
  • R 1 and R 2 are each independently a targeting group, an isotope chelator or a labeling precursor group, a fluorescent or molecular tag group, or a capping group.
  • R 4 is a targeting group
  • R 1 and R 2 are each independently a drug molecule group, an isotope chelator or labeling precursor group, a fluorescent or molecular tag group, or a capping group.
  • R 4 is a targeting group
  • one of R 1 and R 2 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.
  • 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.
  • R4 is a targeting group of a targeted protein
  • the adjacent nucleophilic amino acid residues lysine, cysteine, tyrosine, etc.
  • the functional molecule will be covalently modified to the target protein while the targeting ligand will leave, achieving "traceless" labeling of the target protein.
  • R4 is a targeting group that targets a protein, R1 and R2, one of which 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 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 , rapidly and specifically releasing the drug molecule, isotope chelator or labeling precursor, or fluorescent or molecular tag, thereby achieving the diagnosis and treatment of diseases such as tumors.
  • the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof satisfies one or more of the following conditions:
  • the drug molecule group is derived from a cytotoxic drug, an immunomodulator, an antibiotic, a protein degrader, or a molecular glue;
  • isotope chelators or labeling precursor groups are selected from or
  • 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;
  • the targeting group is selected from a ligand group having high affinity for FAP, FOLR1, integrin, folate hydrolase, carbonic anhydrase or Nectin4.
  • the end-capping group is selected from methyl, methoxy, or
  • the subscript n is an integer from 1 to 4.
  • L 1 in X 1 or Y 1 is selected from or wherein subscripts m and n are integers of 0-4, respectively, and subscript c is an integer of 1-10.
  • the drug molecule group is selected from: or
  • the isotope chelator or label precursor group or fluorescent or molecular tag group is selected from:
  • the targeting group of the targeting protein is selected from or
  • the targeting group of the targeting protein is
  • one of R 1 , R 2 , and R 4 is an isotope chelator or a labeling precursor group, preferably R 1 or R 2 is an isotope chelator or a labeling precursor group.
  • the small molecule conjugate drug LDP-FAP-MMAE targeting FAP protein can specifically bind to FAP protein and then release the drug molecule MMAE.
  • the compound of formula (I) can be prepared by the reaction shown below or a similar reaction.
  • the present disclosure also provides a chelate or radionuclide label, comprising:
  • the isotope chelator or label precursor unit in the chelate or radionuclide label, is directly chelated with the radionuclide (e.g., 68 Ga is chelated with the isotope chelator or label precursor unit derived from DOTA), or the radionuclide is indirectly introduced by chelation with other metals (e.g., Al 3+ , Sc 3+ are chelated with the isotope chelator unit derived from DOTA, and the radionuclide 18 F is introduced into the chelate in a coordinated form with the metal ion).
  • the radionuclide e.g., 68 Ga is chelated with the isotope chelator or label precursor unit derived from DOTA
  • the radionuclide is indirectly introduced by chelation with other metals (e.g., Al 3+ , Sc 3+ are chelated with the isotope chelator unit derived from DOTA, and the radionuclide 18 F is introduced into the
  • the radionuclide is selected from the group consisting of: 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 Er, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 197 Hg, 211 At, 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 Pb, 212 Pb, 64 Cu, 67 Cu, 188 Re, 186 Re, 198 Au, 225 Ac, 227 Th and 199 Ag.
  • the radionuclide is 68 Ga.
  • the present disclosure also provides a pharmaceutical composition comprising or consisting of:
  • 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.
  • 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.
  • 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.
  • the present invention provides a kit comprising or consisting of:
  • 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.
  • the disease is characterized by overexpression of fibroblast activation protein.
  • 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.
  • 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.
  • the diseases targeted by the targeted therapy are malignant proliferative diseases, immune diseases, and infectious diseases.
  • 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.
  • 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.
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • JIA juvenile idiopathic arthritis
  • nr-AxSpA non-radiographic axial spondyloarthritis
  • PsA psoriatic arthritis
  • CD Crohn's disease
  • UC ulcerative colitis
  • SLE systemic lupus erythemato
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a disease characterized by overexpression of fibroblast activation protein 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.
  • CUP thymic cancer
  • glioma glioma
  • astrocytoma cervical cancer and prostate cancer.
  • 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).
  • the compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof has the following structure:
  • W is oxygen or sulfur, preferably oxygen
  • X 1 is -L 1 -R 1 ;
  • Y 1 is -L 1 -R 2 ;
  • Z 1 is -L 2 -R 3 -L 1 -R 4 ;
  • L1 at each occurrence, is independently a bond, a linker, or absent;
  • L 2 is O, S or NH, preferably oxygen
  • R 1 , R 2 , and R 4 are end-capping groups
  • each group or fragment of the structure of compound (II) are the same as the corresponding group or fragment in compound (I).
  • R 3 in the compound structure of (II) is selected from:
  • the substituent is selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.
  • R 3 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, morph
  • R 3 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 X is selected from F, Br, Cl, methoxy, trifluoromethyl, and cyano.
  • 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).
  • LDP-FAP-MMAE can be prepared by the aforementioned reaction scheme (1), and the specific reaction is shown below.
  • the method was 90% H 2 O (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% H 2 O (0.1% FA) + 10% MeCN from 4 to 4.5 min, and linearly changing to 90% H 2 O (0.1% FA) + 10% MeCN from 4.5 to 5 min.
  • LDP-FAP-MMAE specifically releases MMAE through FAP protein
  • 5 ⁇ M FAP protein, 250nM LDP-FAP-MMAE, human serum albumin (HSA) (45g/L), 5 ⁇ M DPP IV (FAP homologous protein), and 5 ⁇ M alkaline phosphatase (ALP) were co-incubated in PBS (pH 7.4) at 37°C.
  • LDP-FAP-MMAE releases MMAE in FAP-positive cells to kill cells
  • 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.
  • 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.
  • LDP-FAP-MMAE specifically releases MMAE in vivo
  • the gallium-germanium generator was eluted with 5 mL of 0.6 M high-purity hydrochloric acid to produce a Ga-68 hydrochloric acid solution.
  • 1 mL of the eluted Ga-68 solution was added to 100 ⁇ L of 3 M sodium hydroxide and 130 ⁇ L of 3 M sodium acetate to adjust the acidity to a final pH of 4.0.
  • 50 ⁇ g of TEFAPI-06 precursor was added, and the reaction mixture was heated to 90°C for 10 minutes.
  • the reaction solution was passed through a C18 cartridge to remove free ions, and then eluted from the C18 cartridge with ethanol. This yielded the labeled Ga-LDP-FAP-MMAE.
  • 37 MBq of the labeled product was diluted with 200 ⁇ L of normal saline and withdrawn with an insulin syringe for later use.
  • the ethanol content of the drug should not exceed 5%.
  • a healthy mouse was anesthetized and placed on the PET/CT acquisition bed.
  • a catheter was placed in the tail vein.
  • a syringe was connected to the catheter, 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 the test results.
  • LDP-FAP-MMAE 0.2 mg/kg
  • Plasma, liver, and tumor samples were ground and extracted with methanol.
  • MMAE content in the tissues was determined by UPLC-MS. The results showed that LDP-FAP-MMAE released significant amounts of MMAE only in the tumors.
  • the liver took up a high amount of LDP-FAP-MMAE but did not release MMAE, demonstrating specific MMAE release. See Figure 4 for the test results.
  • 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.
  • 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.
  • LDP-FAPI-DOTA can be covalently linked to FAP protein
  • FAP protein and Lu-labeled LDP-FAPI-DOTA were incubated in a 5:1 ratio 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 in the protein bands (see Figure 6), demonstrating covalent attachment to the FAP protein. The covalent site was identified by MS/MS.
  • LDP-FAPI-DOTA molecules can enhance tumor uptake
  • 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
  • LDP-FAP-H-FITC was prepared by the following reaction scheme.
  • 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%.
  • LDP-FAP-H-FITC and LDP-B-FAP-F-NIR-DOTA 1 ⁇ M were co-incubated with HT1080 cells and HT080-FAP-expressing cells for 6, 12, and 24 h, respectively. Fluorescence confocal microscopy was used to image 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.
  • Example 4 LDP-FAP-PEG0-S0456, LDP-FAP-PEG2-S0456, LDP-FAP-PEG5-S0456, LDP-FAP-F-PEG5-S0456
  • the synthetic route was the same as that of LDP-FAPI-DOTA, except that DOTA was replaced with S0456.
  • DOTA was replaced with S0456.
  • HPLC and UPLC-MS were used for synthesis, separation, and analysis, except that H 2 O (0.1%) was replaced with H 2 O (10 mM ammonium acetate).
  • 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%.
  • 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 product with a yield of 65%.
  • 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%.
  • 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%.
  • the synthetic route was the same as that of LDP-FAP-S0456-DOTA.
  • the FAP target head was replaced by NFmoc-PEG2 ethylenediamine-QSY-21
  • DOTA was replaced by NFmoc-PEG2 ethylenediamine-Cy5
  • NFmoc ethylenediamine was replaced by NFmoc-PEG2 ethylenediamine.

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Abstract

L'invention concerne un composé de formule (I) ou un sel, stéréoisomère ou solvate pharmaceutiquement acceptable de celui-ci, W étant de l'oxygène ou du soufre ; X1 est -L1-R1 ; Y1 est -L1-R2 ; Z1 est L2-R3-L1-R4 ; L1 est indépendamment une liaison ou un groupe de liaison à chaque occurrence ; L2 est O, S ou NH ; R3 est de l'arylène, de l'hétéroarylène, du cycloalkylène ou de l'hétérocyclylène éventuellement substitué ; l'un de R1, R2 et R4 est un groupe de ciblage, et les deux restants sont indépendamment un groupe de ciblage, un groupe de molécules de médicament, un agent de chélation d'isotopes ou un groupe de précurseurs de marquage, un groupe d'étiquettes fluorescentes ou moléculaires ou un groupe de coiffage. La présente divulgation concerne en outre un chélate, une composition pharmaceutique et son utilisation en tant qu'agents de diagnostic ou agents thérapeutiques pour le diagnostic et le traitement de maladies.
PCT/CN2025/075553 2024-02-02 2025-01-27 Nouveau composé ciblant un ligand, chélate, composition et utilisation associées Pending WO2025162459A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1809557A (zh) * 2003-04-16 2006-07-26 阿斯利康(瑞典)有限公司 化合物
CN115724838A (zh) * 2021-08-26 2023-03-03 成都先导药物开发股份有限公司 一种适合作为抗体偶联药物效应分子的sting激动剂

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1809557A (zh) * 2003-04-16 2006-07-26 阿斯利康(瑞典)有限公司 化合物
CN115724838A (zh) * 2021-08-26 2023-03-03 成都先导药物开发股份有限公司 一种适合作为抗体偶联药物效应分子的sting激动剂

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SILVANO SANCHINI ET AL.: "Rational Design, Synthesis and Biological Evaluation of Modular Fluorogenic Substrates with High Affinity and Selectivity for PTP1B", CHEMBIOCHEM, vol. 15, no. 7, 9 April 2014 (2014-04-09), XP072155452, DOI: 10.1002/cbic.201400033 *

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