Fibroblast activation protein-targeted radiopharmaceutical

Abstract

A fibroblast activation protein-targeted radiopharmaceutical. The present invention specifically relates to a compound of formula (I), which can effectively target a fibroblast activation protein, exhibit a high metabolic rate in vivo, high specificity, low uptake in non-target organs and few toxic and side effects on non-target organs, is convenient for imaging and exhibits high safety. Therefore, said radiopharmaceutical can be used for diagnosing and / or treating diseases in which the fibroblast activation protein is over-expressed.

Description

Radiopharmaceuticals targeting fibroblast activation proteins

[0001] This application claims priority to Chinese Patent Application No. 202411545761.5, filed on October 31, 2024, which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention relates to the field of medicine, specifically to radiopharmaceuticals that target fibroblast activation proteins. Background Technology

[0003] Fibroblast activation protein (FAP) is highly overexpressed on cancer-associated fibroblasts (CAFs), the main stromal component of solid tumors, but generally not expressed in normal tissues and benign tumors. Tumor stromal CAFs can promote tumor cell growth and invasion, and have become important targets for tumor intervention. Overexpression of the tumor biomarker FAP is a significant characteristic of CAFs, and FAP is an important potential target for CAF-targeted tumor diagnosis and treatment. FAP is a type II transmembrane serine protease on tumor fibroblasts, existing on the cell surface in the form of homodimers. It belongs to the proline oligopeptidase family, and its enzymatic activity plays an important role in tumor growth and tissue remodeling. CAF surface-specific FAPα can promote tumor progression by promoting matrix remodeling, participating in VEGF / AKT / ERK signal transduction pathways to enhance the directional invasion of tumor cells along fibers, participating in tumor angiogenesis to form a tumor biological barrier and inhibit the function of effector T cells. The inducible high expression of FAP in the tumor stroma also depends on the malignant transformation of the tumor tissue. The degree of FAP high expression is positively correlated with poor tumor prognosis. FAP is expressed to varying degrees in various sarcomas, melanomas, esophageal cancers, breast cancers, bile duct cancers, lung cancers (FAP positive rate 97.3%), liver cancers, colorectal cancers, head and neck cancers, ovarian cancers, pancreatic cancers, neuroendocrine tumors, prostate cancers, kidney cancers, thyroid cancers, adenoid cystic cancers, and gastric cancers. FAP is not expressed or is expressed at low levels in normal tissues, but is highly expressed, particularly in ovarian cancers and pancreatic cancers.

[0004] Antibody-carrier antibody-drug conjugates (ADCs) are hampered by poor permeability, long half-life, prolonged uptake and retention in non-target organs, and significant toxicity, hindering their clinical development. FAP-targeting antibody-drug conjugates, such as 131I-mAbF19, also face disadvantages in tumor diagnosis and treatment due to poor permeability and long circulating half-life. However, FAP-targeting small molecule and peptide inhibitors, after structural modification and optimization screening, possess significant developmental value for cancer diagnosis and treatment if the challenges of rapid clearance and insufficient tumor uptake and retention can be overcome. In the preclinical stage, significant progress has been made in the structural development of tumor-targeting FAP small molecule inhibitors (FAPIs) (in terms of target specificity, affinity, and druggability), and novel molecules that can serve as lead compounds are constantly emerging, providing new possibilities for FAPI-based radiotherapy and treatment of tumors.

[0005] Currently, FAP-targeted diagnostic small molecule conjugates, such as […], are in the preclinical and clinical stages. 68 Ga]-FAPI-46、[ 177 Lu]-FAPI-46 and [ 225 Ac]-FAPI-46, etc., can be used for imaging diagnosis and targeted therapy of squamous cell carcinoma of the tongue, ovarian cancer, pancreatic cancer, and other malignant tumors. Small molecule peptide targeted conjugates, such as [ 68 [Ga]-FAP-2286, etc., have entered preclinical and early clinical research, and have achieved similar results in more than ten clinical malignant tumors. 68 Ga]-FAPI-46 is comparable to, and superior to [ 18 The ability of F-FDG to detect lesions in imaging diagnosis. 18 F] Labeled small molecule tracers, for example [ 18 F]AIF-FAPI-74 and [ 18 F]AIF-NOTA-FAPI-04 and others also exhibit good advantages in specific targeted binding and clinical lesion detection.

[0006] For tumor diagnosis and treatment, the use of structurally optimized and screened FAPIs as small molecule carriers for tumor targeting has become a superior choice in the field of anti-tumor diagnosis and treatment. Developing diagnostic drugs with better tumor selectivity and higher imaging efficacy has strong feasibility and great potential application value for the precision diagnosis and treatment of FAPI-positive malignant solid tumors. Summary of the Invention

[0007] This invention provides a radiopharmaceutical that targets fibroblast activation protein, which can be used to diagnose and / or treat diseases characterized by overexpression of fibroblast activation protein (FAP).

[0008] The radiopharmaceutical targeting fibroblast activation proteins described in this invention has the following advantages:

[0009] (1) It has a strong affinity for fibroblast activating protein (FAP);

[0010] (2) It has a strong specific binding to fibroblast activation protein (FAP);

[0011] (3) It has good specific targeting and clinical lesion detection for tumors, especially for diseases that overexpress fibroblast activation protein (FAP);

[0012] (4) It can diagnose primary tumors and their metastatic lesions, and the imaging is clear, thus effectively distinguishing tumors from normal tissues.

[0013] In one aspect, the present invention relates to compounds of formula (I), or isotopic variants, hydrates, esters or solvates thereof, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0014] The variables are as defined in this invention.

[0015] In another aspect, the present invention relates to a compound comprising a compound of formula (I), or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and an M complexed therewith, wherein,

[0016] Compounds of formula (I) are as defined in this invention;

[0017] M is selected from at least one of radioactive nuclides or non-radioactive elements.

[0018] In another respect, the present invention relates to compounds of formula (X), or isotopic variants, hydrates, esters or solvates thereof, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0019] in,

[0020] Wherein, Ab, L1 and L2 are as defined in this invention;

[0021] Z' is a coordinating group formed by the complexation of the chelating group Z derived from the chelating agent and M, where Z is as defined in this invention;

[0022] M is selected from at least one of radioactive nuclides or non-radioactive elements.

[0023] In another aspect, the present invention relates to pharmaceutical compositions comprising the compounds of the present invention, or isotopic variants thereof, hydrates, esters or solvates thereof, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0024] Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0025] In another aspect, the present invention relates to the compounds of the present invention, or pharmaceutically acceptable salts, isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers thereof, or the use of the pharmaceutical compositions of the present invention in the preparation of a medicament for inhibiting FAP expression.

[0026] In another respect, the present invention relates to the compounds of the present invention, or pharmaceutically acceptable salts, isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers thereof, or pharmaceutical compositions of the present invention for inhibiting FAP expression.

[0027] In another aspect, the present invention relates to a method for inhibiting FAP expression, wherein the method comprises administering to a subject a compound of the present invention, or a pharmaceutically acceptable salt, isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer, or a pharmaceutical composition of the present invention.

[0028] In another aspect, the present invention relates to the use of the compounds of the present invention, or pharmaceutically acceptable salts, isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers thereof, or the pharmaceutical compositions of the present invention in the preparation of reagents and / or medicaments for the diagnosis and / or treatment of one or more tumors, cancers or cells expressing FAP.

[0029] In another aspect, the present invention relates to compounds of the present invention, or pharmaceutically acceptable salts, isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers thereof, or pharmaceutical compositions of the present invention for the diagnosis and / or treatment of one or more tumors, cancers or cells expressing FAP.

[0030] In another aspect, the present invention relates to a method for diagnosing and / or treating one or more tumors or cancers expressing FAP, wherein the method comprises administering to a subject a compound of the present invention, or a pharmaceutically acceptable salt, isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer, or pharmaceutical composition of the present invention.

[0031] In another aspect, the diagnostic method is selected from optical imaging and / or radionuclide imaging; preferably, the radionuclide imaging is selected from PET imaging and / or SPECT imaging.

[0032] On the other hand, the treatment is selected from radiotherapy and / or fluorescent surgical navigation as an adjunct to surgery.

[0033] On the other hand, the tumors and cancers expressing FAP are selected from melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, head and neck cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, and neuroendocrine tumors.

[0034] Chemical definition

[0035] The definitions of specific functional groups and chemical terms are described in more detail below.

[0036] When listing a range of values, it is assumed that each value and a subrange within that range will be included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0037] “C 1-10 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms. In some embodiments, C 1-8 Alkyl, C 1-6 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl and C 1-2 Alkyl groups are preferred. C 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6"Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2). In some embodiments, straight-chain alkyl groups are preferred.

[0038] “C 2-10 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-8 alkenyl, C 2-6 alkenyl, C 2-4 alkenyl and C 2-3 Alkenyl groups are preferred. C 2-6 Examples of alkenyl groups include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, straight-chain alkenyl groups are preferred.

[0039] “C 2-10 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-8 alkynyl group, C 2-6 alkynyl group, C 2-4 alkynyl group and C 2-3 Alkyne groups are preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6"Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, a straight-chain alkynyl group is preferred.

[0040] “C 1-10 "Alkylene" refers to the removal of C 1-10 The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 1-8 Alkylene, C 1-6 Alkylene, C 1-4 Alkylene, C 1-3 Alkylene, C 1-2 Alkylenes and methylene groups are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc. In some embodiments, straight-chain alkylene groups are preferred.

[0041] “C 2-10 "Alkenyl" refers to the group that has been de-carbonied. 2-10 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 2-8 imidene group, C 2-6 imidene group, C 2-4 imide and C 2-3Alkenyl groups are particularly preferred. Exemplary unsubstituted alkenyl groups include, but are not limited to: vinylidene (-CH=CH-), propenylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-), butenylidene (e.g., -CH=CHCH2CH2-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-), and so on. Exemplary substituted alkenyl groups, such as those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted vinylenes (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylenes (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc. In some embodiments, linear alkenyl groups are preferred.

[0042] “C 2-10 "Iso-ynyl" refers to the group that has the C group removed. 2-10 The other hydrogen atom of the alkynyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 2-8 Ethyne group, C 2-6 Ethyne group, C 2-4 etyne and C 2-3 Alynyl groups are particularly preferred. Exemplary unsubstituted alynyl groups include, but are not limited to: ethynyl (-C≡C-), propynyl (e.g., -C≡CCH2-, -CH2-C≡C-), butynyl (e.g., -C≡CCH2CH2-, -CH2-C≡C-CH2-, -CH2-CH2-C≡C-), etc. Exemplary substituted alynyl groups, such as alynyl groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted propynyl (-C≡CCH(CH3)-, -C≡CC(CH3)2-, -CH(CH3)-C≡C-, -C(CH3)2-C≡C-), etc. In some embodiments, straight-chain alynyl groups are preferred.

[0043] “C 0-6 "alkylene" refers to chemical bonds and the aforementioned "C" 1-6 Alkylene", "C" 0-4 "alkylene" refers to chemical bonds and the aforementioned "C" 1-4 "Alkylene". The same logic applies to other similar cases.

[0044] When one of the variables is a single bond, it means that the two groups connected by that single bond are directly linked, such as AC. 0-6 C in alkylene-B0-6 When alkylene represents a single bond, AC 0-6 The structure of alkylene-B is actually AB.

[0045] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0046] Therefore, "C" 1-10 "Halogenated alkyl" refers to the above "C 1-10 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1- 8-Hydroalkyl groups are particularly preferred. In some embodiments, C 1-6 Halogenated alkyl groups are particularly preferred. In some embodiments, C 1-4 Haloalkyl groups are particularly preferred, and C4 groups are more preferred. 1-3 Halogenated alkyl, more preferably C 1-2 The haloalkyl group, more preferably halomethyl, is used. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CH2CF3, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The haloalkyl group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0047] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 cyclic carbon atoms and zero heteroatoms, optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, C 5-10 cycloalkyl, C 3-7 cycloalkyl and C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-7 cycloalkyl and C 5-6Cycloalkyl groups. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the bonding point is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Cycloalkyl groups also include the aforementioned cycloalkyl ring in which substituents on any non-adjacent carbon atoms are linked to form a bridged ring, together forming a polycyclic alkane sharing two or more carbon atoms. Cycloalkyl groups also include the aforementioned cycloalkyl ring in which substituents on the same carbon atom are linked to form a ring, together forming a polycyclic alkane sharing one carbon atom. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. The cycloalkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0048] “C 3-10 "Cycloalkylene" refers to the alkylene oxide that has had C removed. 3-10 The cycloalkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 3-7 Cycloalkylene, C 5-7 Cycloalkylene, C 3-6 Cycloalkylene and C 3-4 Cycloalkylene compounds are particularly preferred, such as cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene, with cyclopropylene being especially preferred. 3-10 Examples of cycloalkylene compounds include, but are not limited to, those mentioned above. wait.

[0049] "3-10 membered heterocyclic groups" refer to saturated or unsaturated groups of 3- to 10 membered non-aromatic ring systems having a ring carbon atom and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally contains 1, 2, or 3 double or triple bonds. In heterocyclic groups containing one or more nitrogen atoms, the linkage may be a carbon or nitrogen atom, provided the valence allows. In some embodiments, a 5-10 membered heterocyclic group is preferred, which is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3-7 membered heterocyclic group is preferred, which is a 3-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; a 5-7 membered heterocyclic group is preferred, which is a 5-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 3-6 membered heterocyclic group is preferred, which is a 3-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 4-6 membered heterocyclic group is preferred, which is a 4-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; and a 5-6 membered heterocyclic group is preferred, which is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the heterocyclic ring; or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on any non-adjacent carbon or nitrogen atom are linked to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on the same carbon atom are linked to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolylyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: pyrazolylyl, dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiohexane, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Heterocyclic groups also include those that share one or two atoms with a cycloalkyl, heterocyclic, aryl, or heteroaryl group to form a bridged or spirocyclic ring, wherein the shared atom may be a carbon or nitrogen atom, provided the valence allows. Heterocyclic groups also include those that can be optionally substituted with one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0050] "3-10 membered heterocyclic group" refers to a divalent group formed by removing another hydrogen atom from a 3-10 membered heterocyclic group, and can be substituted or unsubstituted. In some embodiments, 3-7 membered heterocyclic groups, 5-7 membered heterocyclic groups, 3-6 membered heterocyclic groups, and 3-4 membered heterocyclic groups are particularly preferred, such as cyclopropylidene, tetrahydrofuranide, and pyranide. Examples of 3-10 membered heterocyclic groups include, but are not limited to, those listed below. wait.

[0051] “C 6-14 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, C 6-10 Aryl groups are preferred. In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C14”). 14"Aryl"; for example, anthracene and phenanthrene (e.g., 1-anthrayl, 2-anthrayl, 1-phenanthrene, and 2-phenanthrene). Aryl groups also include ring systems in which the aforementioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0052] "5-14 membered heteroaryl" refers to a 4n+2 aromatic ring system of a 5-14 membered monocyclic or bicyclic ring (e.g., having 6, 10, or 14 shared π electrons arranged in a ring) having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 4n+2 aromatic ring system of a 5-10 membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5-6 membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. In other embodiments, 5 membered heteroaryl groups are particularly preferred. Exemplary 5 membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5 membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, imidazolidenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5 membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiazolyl. Exemplary 5 membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6 membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl or pyridinoneyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azirmonoheptatrienyl, oxazirmonoheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazoleyl, benzotriazolyl, benzothiopheneyl, isobenzothiopheneyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0053] “C 6-14 "Asyl" refers to the absence of C 6-14The aryl group is a divalent group formed by the other hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 6-10 Aryl groups are preferred. In some embodiments, phenylene groups (e.g.) ) is preferred. In some embodiments, naphthylene (e.g. ) is the preferred option.

[0054] "5-14-membered heteroaryl" refers to a divalent group formed by removing another hydrogen atom from a 5-14-membered heteroaryl group, and can be substituted or unsubstituted. In some embodiments, 5-10-membered heteroaryl groups are preferred. In some embodiments, 5-6-membered heteroaryl groups are preferred. Some exemplary 5-14-membered heteroaryl groups include, but are not limited to: wait.

[0055] The divalent groups formed by removing one hydrogen atom from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined above are collectively referred to as "subunits". Cyclic groups such as cycloalkyl, heterocyclic, aryl, and heteroaryl are collectively referred to as "cyclogroups".

[0056] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0057] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NRbb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(Rcc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0058] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0059] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0060] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc)2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0061] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0062] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR)ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee )3、-OSi(R ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0063] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0064] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. ggGroup substitution;

[0065] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1- 6-alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6-alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1- 6-alkyl, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0066] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2Rcc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0067] The term "substitution" refers to the replacement of one or more hydrogen atoms on a specific atom by a substituent, including deuterium and hydrogen variants, provided that the valence of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Positions on the aromatic ring cannot be oxo-substituted. The term "optional substitution" means that an atom may or may not be substituted by a substituent; unless otherwise stated, the type and number of substituents can be arbitrary, as long as it is chemically feasible.

[0068] When any variable (e.g., R) appears more than once in the composition or structure of a compound, the definition of that variable is independent each time it appears. Therefore, for example, if a group is substituted by 0-2 Rs, that group can optionally be substituted by up to two Rs, where the definition of R is independent each time it appears. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations yield a stable compound.

[0069] When the linking group (i.e., the divalent structure) listed does not specify its connection direction, the connection direction is arbitrary. For example, when the linking group L in ALB is -CH2O-, -CH2O- can connect A and B in the same direction according to the reading order from left to right, forming A-CH2O-B, or it can connect A and B in the opposite direction according to the reading order from left to right, forming A-OCH2-B. Combinations of linking groups, substituents, and / or their variants are only permitted if a stable compound can be obtained.

[0070] Unless otherwise stated, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the connection sites of chemical bonds are variable and there are hydrogen atoms at the connectable sites, when a connectable site with a hydrogen atom is connected to a chemical bond, as the number of connected chemical bonds increases, the number of hydrogen atoms at that site decreases accordingly, and the group becomes a group with the corresponding valence.

[0071] Other definitions

[0072] As used herein, the term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. The noun “treatment” as used herein also refers to the action of the verb “to treat,” as defined above.

[0073] The term "amino acid residue" refers to any natural or synthetic amino acid residue, not limited to the group consisting of 20 naturally occurring amino acids, where a residue refers to the portion remaining after the amino acid linked by a peptide bond has lost water. The 20 naturally occurring amino acid residues are selected from the group consisting of the following amino acid residues: alanine (Ala or A), cysteine ​​(Cys or C), aspartic acid (Asp or D), glutamic acid (Glu or E), phenylalanine (Phe or F), glycine (Gly or G), histidine (His or H), isoleucine (Ile or I), lysine (Lys or K), leucine (Leu or L), methionine (Met or M), asparagine (Asn or N), proline (Pro or P), glutamine (Gln or Q), arginine (Arg or R), serine (Ser or S), threonine (Thr or T), valine (Val or V), tryptophan (Trp or W), and tyrosine (Tyr or Y).

[0074] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0075] Pharmaceutically acceptable base addition salts are those formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0076] The base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form a salt. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then separating the free acid. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents; however, for the purposes of this invention, the salts are equivalent to their respective free acids.

[0077] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Salts of amino acids are also included, such as arginine salts, gluconates, and galacturonic acids (see, for example, Berge S. et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19, incorporated herein by reference).

[0078] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0079] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0080] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0081] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0082] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0083] Unless otherwise stated, the “preventively effective amount” of a compound as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventively effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0084] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Attached Figure Description

[0085] Figure 1 shows 68 Radiometric thin-layer chromatography results of Ga-compound 1.

[0086] Figure 2 shows 177 Radiometric thin-layer chromatography results of Lu-compound 2.

[0087] Figure 3 shows 68 Radiometric thin-layer chromatography results of Ga-compound 3.

[0088] Figure 4 shows 177 Radiometric thin-layer chromatography results of Lu-compound 3.

[0089] Figure 5 shows 68 Radiometric thin-layer chromatography results of Ga-compound 4.

[0090] Figure 6 shows 177 Radiometric thin-layer chromatography results of Lu-compound 4.

[0091] Figure 7 shows 68 Radiometric thin-layer chromatography results of Ga-compound 5.

[0092] Figure 8 shows 68 Radiometric thin-layer chromatography results of Ga-compound 6.

[0093] Figure 9 shows 68 Radiometric thin-layer chromatography results of Ga-compound 7.

[0094] Figure 10 shows 177 Radiometric thin-layer chromatography results of Lu-compound 7.

[0095] Figure 11 shows 68 Radiometric thin-layer chromatography results of Ga-compound 8.

[0096] Figure 12 shows 177 Radiometric thin-layer chromatography results of Lu-compound 8.

[0097] Figure 13 shows 68 Radiometric thin-layer chromatography results of Ga-compound 9.

[0098] Figure 14 shows177 Radiometric thin-layer chromatography results of Lu-compound 9.

[0099] Figure 15 shows 68 Radiometric thin-layer chromatography (TLC) results of Ga-compound 10.

[0100] Figure 16 shows 68 Radiometric thin-layer chromatography results of Ga-compound 12.

[0101] Figure 17 shows 18 Radiochemical purity spectrum of F-compound 11.

[0102] Figure 18 shows 68 Ga-compound 1, 68 PET / CT imaging results of Ga-FAPI46 on the B-hFAP MC38 mouse model.

[0103] Figure 19 shows 68 Ga-compound 1, 68 Uptake results of Ga-FAPI46 in different tissues of the B-hFAP MC38 mouse model.

[0104] Figure 20 shows 68 PET / CT imaging results of Ga-compound 2 in the B-hFAP MC38 mouse model.

[0105] Figure 21 shows 68 Ga-compound 2 and 68 Uptake results of Ga-FAPI46 in different tissues of the B-hFAP MC38 mouse model.

[0106] Figure 22 shows 68 Ga-compound 2 and 68 PET / CT imaging results of Ga-FAPI46 on the B-hFAP MC38 model.

[0107] Figure 23 shows 68 Ga-compound 2 and 68 Uptake results of Ga-FAPI46 in different tissues of the B-hFAP MC38 mouse model.

[0108] Figure 24 shows 177 SPECT / CT imaging results of Lu-compound 2 in two B-hFAP MC38 mouse models.

[0109] Figure 25 shows the drug administration in ICR mice. 68 Blood drug concentration change curve after Ga-compound 2.

[0110] Figure 26 shows 68 Ga-compound 3, 68 Ga-compound 4 and 68 PET / CT imaging results of Ga-FAPI46 on the A549 mouse model.

[0111] Figure 27 shows 68 Ga-compound 3, 68 Ga-compound 4 and 68 Uptake results of Ga-FAPI46 in different tissues of the A549 mouse model.

[0112] Figure 28 shows 68 Ga-compound 3, 68 PET / CT imaging results of Ga-compound 4 and 18F-FDG in the B-hFAP MC38 mouse model.

[0113] Figure 29 shows 68 Ga-compound 3, 68 The uptake of Ga-compounds 4 and 18F-FDG in different tissues of the B-hFAP MC38 mouse model.

[0114] Figure 30 shows the drug administration in ICR mice. 68 Blood drug concentration change curve after Ga-compound 3.

[0115] Figure 31 shows 177 The uptake of Lu-compound 3 in different tissues of A549 mouse model and B-hFAP MC38 mouse model.

[0116] Figure 32 shows 68 PET / CT imaging results of Ga-compound 6 in the B-hFAP MC38 mouse model.

[0117] Figure 33 shows 68 Uptake of Ga-compound 6 in different tissues of the B-hFAP MC38 mouse model.

[0118] Figure 34 shows 68 Uptake of Ga-compound 6 in different tissues of the B-hFAP MC38 mouse model.

[0119] Figure 35 shows the drug administration in ICR mice. 68 Blood drug concentration change curve after Ga-compound 3.

[0120] Figure 36 shows 68 PET / CT imaging results of Ga-compound 5 in the B-hFAP MC38 mouse model.

[0121] Figure 37 shows 68 The uptake of Ga-compound 5 in different tissues of the B-hFAP MC38 mouse model.

[0122] Figure 38 shows 68 The uptake of Ga-compound 5 in different tissues of the B-hFAP MC38 mouse model.

[0123] Figure 39 shows the drug administration in ICR mice. 68 Blood drug concentration change curve after Ga-compound 5.

[0124] Figure 40 shows 68 PET / CT imaging results of Ga-compound 7 in the B-hFAP MC38 mouse model.

[0125] Figure 41 shows 68 Uptake of Ga-compound 7 in different tissues of the B-hFAP MC38 mouse model.

[0126] Figure 42 shows 68 PET / CT imaging results of Ga-compound 8 in the B-hFAP MC38 mouse model.

[0127] Figure 43 shows 68 Uptake of Ga-compound 8 in different tissues of the B-hFAP MC38 mouse model.

[0128] Figure 44 shows 177 Lu-compound 3, 177 Lu-compound 7, 177 Uptake of Lu-compound 8 in different tissues of the B-hFAP MC38 mouse model.

[0129] Figure 45 shows 177 Uptake of Lu-compound 9 in different tissues of the B-hFAP MC38 mouse model.

[0130] Figure 46 illustrates the drug administration. 177 (a) Relative tumor volume change and (b) body weight change in OS-RC-2 model mice of Lu-compound 8.

[0131] Figure 47 illustrates the drug administration. 177 (a) Relative tumor volume change and (b) body weight change in OS-RC-2 model mice of Lu-compound 9.

[0132] Figure 48 shows 68 Uptake of Ga-compound 9 in different tissues of the B-hFAP MC38 mouse model.

[0133] Figure 49 shows 68 Uptake values ​​of Ga-compound 9 in different tissues of the B-hFAP MC38 mouse model.

[0134] Figure 50 shows 68 The ratio of tumor uptake to muscle or heart uptake of Ga-compound 9 in the B-hFAP MC38 mouse model.

[0135] Figure 51 shows 68 PET / CT imaging results of Ga-compound 10 in the B-hFAP MC38 mouse model.

[0136] Figure 52 shows 68 Uptake of Ga-compound 10 in different tissues of the B-hFAP MC38 mouse model.

[0137] Figure 53 shows 68 PET / CT imaging results of Ga-compound 12 in the B-hFAP MC38 mouse model.

[0138] Figure 54 shows 68 Uptake of Ga-compound 12 in different tissues of the B-hFAP MC38 mouse model.

[0139] Figure 55 shows 18 PET / CT imaging results of compound F11 in the B-hFAP MC38 mouse model.

[0140] Figure 56 shows 18 Uptake of F-compound 11 in different tissues of the B-hFAP MC38 mouse model.

[0141] Figure 57 shows 18 PET / CT imaging results of F-compound 12 in the B-hFAP MC38 mouse model.

[0142] Figure 58 shows 18 Uptake of F-compound 12 in different tissues of the B-hFAP MC38 mouse model.

[0143] Figure 59 shows a PET / CT cross-sectional view of patient 1.

[0144] Figure 60 shows a whole-body PET / CT MIP image of patient 1 (SUV = 0-8).

[0145] Figure 61 shows a PET / CT cross-sectional view of patient 2.

[0146] Figure 62 shows the whole-body PET / CT MIP image of patient 2 (SUV = 0-8).

[0147] Figure 63 shows a PET / CT cross-sectional view of patient 3.

[0148] Figure 64 shows the MIP image of patient 3.

[0149] Figure 65 shows the radioactive uptake values ​​of multiple tissues in patient 3.

[0150] Figure 66 shows a PET / CT cross-sectional view of patient 4.

[0151] Figure 67 shows the MIP image of patient 4.

[0152] Figure 68 shows the radioactive uptake values ​​of multiple tissues in patient 4. Detailed Implementation Plan

[0153] In this document, “compound of the present invention” refers to a compound of formula (I) (including its sub-formulas, such as (I-1), (I-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2), (VIII), (VIII-1), (VIII-2), (IX-1), (IX-2), (IX-3), (IX-4), (IX-5), (IX-6), (IX-7), (IX-8), (IX-9), (IX-10) etc.), its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof.

[0154] In this document, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood (unless otherwise stated) that all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomers included in this invention may have carbon-carbon double bonds in the forms of Z and E. Regarding compounds existing in different tautomeric forms, a single compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

[0155] In one embodiment, the present invention provides a compound of formula (I), or an isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0156] in,

[0157] Ab is a ligand that binds to fibroblast activation proteins, for example

[0158] R1 and R2 are independently selected from H, D, halogens, OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups;

[0159] Rm is independently selected from chemical bonds, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 alkynyl group, C 6-14 Areneyl or 5-14 heteroaryl, for example

[0160] Rn is independently selected from CN, OH, NH2 or B(OH)2;

[0161] m is independently selected from 1, 2, 3, 4, or 5;

[0162] L1 is the linker base;

[0163] L2 is an amino acid chain consisting of 2-8 amino acid residues linked together, wherein each amino acid residue may optionally be further replaced by one or more amino acid residues.

[0164] Z is a chelating group derived from the chelating agent.

[0165] In another embodiment, the present invention provides the above-described compound, or its isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, having the following structure:

[0166] in,

[0167] A1, A2, and A3 are amino acid residues;

[0168] A4 is an H or an amino acid residue;

[0169] W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6 -、-C(O)O-(CR c R d ) 1-6 -、-NR-(CR c R d ) 1-6 -、-C(O)-C 3-7 Cycloalkylene-(CR)c R d ) 0- 6-,-C(O)-3-7-membered heterocyclic group-(CR) c R d ) 0-6 -、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -、-C(O)-5-10-membered heteroaryl-(CR c R d ) 0-6 -;

[0170] W1 is selected from chemical bonds, -O-, -NR-, -C(O)-, -OC(O)-, -C(O)-NR-, or -NR-C(O)-;

[0171] W2 is selected from C 1-10 Alkylene, C 2-10 imide or C 2-10 Ethyne group;

[0172] V1 is selected from chemical bonds or -(CR) a R b ) 1-10 -;

[0173] V2 is selected from chemical bonds, -O-, -NR-, C(O)-, -NR-C(O)-, or -C(O)-NR-;

[0174] R a and R b Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-C 6-14 Aryl or -C 1-6 alkylene-5-14-membered heteroaryl;

[0175] R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0176] R is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0177] Other variables are as defined in this paper.

[0178] In another embodiment, the present invention provides a compound comprising a compound of formula (I), or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and an M complexed therewith.

[0179] in,

[0180] Compounds of formula (I) are as defined herein;

[0181] M is selected from at least one of radioactive nuclides or non-radioactive elements.

[0182] In another embodiment, the present invention provides a compound of formula (X), or an isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0183] in,

[0184] Ab, L1, and L2 are as defined in this paper;

[0185] Z' is the coordination group formed by the complexation of the chelating group Z derived from the chelating agent and M, where Z is as defined in this article;

[0186] M is selected from at least one of radioactive nuclides or non-radioactive elements.

[0187] In the compounds of this invention, the variables can be defined as follows.

[0188] Ab

[0189] In one implementation, Ab is a ligand that binds to fibroblast activation proteins, for example...

[0190] In one implementation, Ab is... In another implementation, Ab is In another implementation, Ab is In another implementation, Ab is In another implementation, Ab is In another implementation, Ab is In another implementation, Ab is In another implementation, Ab is In another implementation, Ab is

[0191] In a more specific implementation, Ab is... In another, more specific implementation, Ab is In another, more specific implementation, Ab is

[0192] In a more specific implementation, Ab is... In another, more specific implementation, Ab is In another, more specific implementation, Ab is In another, more specific implementation, Ab is In another, more specific implementation, Ab is

[0193] Rm and Rn

[0194] In one embodiment, Rm is a chemical bond; in another embodiment, Rm is a C bond. 1-6 Alkylene; in another embodiment, Rm is C 2-6 Idemenyl; in another embodiment, Rm is C 2-6 Alkyne group; in another embodiment, Rm is C 6-14 aryl; in another embodiment, Rm is a 5-14 member heteroaryl, for example

[0195] In one embodiment, Rn is CN; in another embodiment, Rn is OH; in yet another embodiment, Rn is NH2; and in yet another embodiment, Rn is B(OH)2.

[0196] R1 and R2

[0197] In one embodiment, R1 is H; in another embodiment, R1 is D; in yet another embodiment, R1 is a halogen; in yet another embodiment, R1 is C. 1-6 Alkyl; in another embodiment, R1 is C 1-6 alkoxy group; in another embodiment, R1 is C 1-6 Halogenated alkyl; in another embodiment, R1 is C 1-6 Halogenated alkoxy groups.

[0198] In one embodiment, R2 is H; in another embodiment, R2 is D; in yet another embodiment, R2 is a halogen; in yet another embodiment, R2 is C. 1-6 Alkyl; in another embodiment, R2 is C 1-6 alkoxy group; in another embodiment, R2 is C 1-6 Halogenated alkyl; in another embodiment, R2 is C 1-6 Halogenated alkoxy groups.

[0199] m

[0200] In one implementation, m is 1; in another implementation, m is 2; in another implementation, m is 3; in another implementation, m is 4; in another implementation, m is 5.

[0201] L1

[0202] In one embodiment, L1 is a linker; in another embodiment, L1 is -W0-W1-V1-V2-W2-W3-; in another embodiment, L1 is -W0-W1-V1-V2-W2-C(O)-; in another embodiment, L1 is -W0-W1-V1-V2-W2-OC(O)-; in another embodiment, L1 is -W0-W1-V1-V2-W2-NR-C(O)-.

[0203] In one embodiment, L1 is -W1-W2-C(O)-; in another embodiment, L1 is -W1-W2-OC(O)-; in yet another embodiment, L1 is -W1-W2-NR-C(O)-; in yet another embodiment, L1 is -W0-W1-V1-V2-W2-C(O)-; in yet another embodiment, L1 is -W1-V1-V2-W2-C(O)-.

[0204] In one implementation, L1 is -C 1-6 Alkylene -C(O)-, for example -(CH2) 1-6 -C(O)-; In another embodiment, L1 is -C 2-6 Imenoyl-C(O)-, for example -CH=CH-(CH2) 1-4 -C(O)-; In another embodiment, L1 is -C 2-6 Alkyne-C(O)-, for example -C≡C-(CH2). 1- 4-C(O)-; In another embodiment, L1 is -NR-C 1-6 Alkylene -C(O)-, for example -NR-(CH2) 1-6 -C(O)-; In another embodiment, L1 is -NR-C(O)-C 1-6 Alkylene -C(O)-, for example -NR-C(O)-(CH2) 1-6 -C(O)-; In another embodiment, L1 is In another implementation, L1 is In another implementation, L1 is In another implementation, L1 is In another implementation, L1 is In another implementation, L1 is In another implementation, L1 is In another implementation, L1 is

[0205] In one implementation, L1 is not replaced; in another implementation, L1 is replaced by one, two, three, four, or five R*. In a specific implementation, L1 is selected from:

[0206] R

[0207] In one implementation, R is H; in another implementation, R is C. 1-6 alkyl.

[0208] Ar

[0209] In one embodiment, Ar is phenyl; in another embodiment, Ar is naphthyl; in yet another embodiment, Ar is anthraceneyl; and in yet another embodiment, Ar is phenanthryl.

[0210] n

[0211] In one implementation, n is 1; in another implementation, n is 2; in another implementation, n is 3; in another implementation, n is 4; in another implementation, n is 5; in another implementation, n is 6; in another implementation, n is 7; in another implementation, n is 8; in another implementation, n is 9; in another implementation, n is 10.

[0212] R*

[0213] In one embodiment, R* is H; in another embodiment, R* is D; in another embodiment, R* is a halogen; in another embodiment, R* is OH; in another embodiment, R* is CN; in another embodiment, R* is NH2; in another embodiment, R* is C. 1-6 Alkyl; in another embodiment, R* is C 1-6 Halogenated alkyl groups.

[0214] W0

[0215] In one embodiment, W0 is a chemical bond; in another embodiment, W0 is -C(O)-(CR) c R d ) 1-6 -; In another embodiment, W0 is -C(O)O-(CR)c R d ) 1-6 -; In another embodiment, W0 is -NR-(CR c R d ) 1-6 -; In another embodiment, W0 is -C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -; In another embodiment, W0 is a -C(O)-3-7 membered heterocyclic group -(CR c R d ) 0-6 -; In another embodiment, W0 is -C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -; In another embodiment, W0 is -C(O)-5-10-membered heteroaryl-(CR c R d ) 0-6 -

[0216] R c and R d

[0217] In one implementation, R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-4 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, C 3-5 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0218] W1

[0219] In one embodiment, W1 is a chemical bond; in another embodiment, W1 is -O-; in another embodiment, W1 is -NR-; in another embodiment, W1 is -C(O)-; in another embodiment, W1 is -OC(O)-; in another embodiment, W1 is -C(O)-NR-; in another embodiment, W1 is -NR-C(O)-.

[0220] V1

[0221] In one embodiment, V1 is a chemical bond; in another embodiment, V1 is -(CR) a R b ) 1-10-; In another implementation, V1 is -(CR a R b ) 1-6 -, for example -(CR) a R b ) 1-4 -

[0222] R a and R b

[0223] In one implementation, R a H; in another embodiment, R a For D; in another implementation, R a It is a halogen; in another embodiment, R a C 1-6 Alkyl; in another embodiment, R a C 1-6 Halogenated alkyl; in another embodiment, R a -C 1-6 Alkylene-C 6-14 Aryl, for example -C 1-4 Alkylene-C 6-14 aryl; in another embodiment, R a -C 1-6 Alkylene-5-14-membered heteroaryl.

[0224] In one implementation, R b H; in another embodiment, R b For D; in another implementation, R b It is a halogen; in another embodiment, R b C 1-6 Alkyl; in another embodiment, R b C 1-6 Halogenated alkyl; in another embodiment, R b -C 1-6 Alkylene-C 6-14 Aryl groups, such as -C 1-4 Alkylene-C 6-14 aryl; in another embodiment, R b -C 1-6 Alkylene-5-14-membered heteroaryl.

[0225] V2

[0226] In one embodiment, V2 is a chemical bond; in another embodiment, V2 is -O-; in another embodiment, V2 is -NR-; in another embodiment, V2 is C(O)-; in another embodiment, V2 is -NR-C(O)-; in another embodiment, V2 is -C(O)-NR-.

[0227] W2

[0228] In one implementation, W2 is C 1-10 Alkylene, such as C 1-6 Alkylene; in another embodiment, W2 is C 2-10 imide groups, such as C 2-6 alkenyl; in another embodiment, W2 is C 2-10 alkyne groups, such as C 2-6 Alynyl group.

[0229] W3

[0230] In one embodiment, W3 is -O-; in another embodiment, W3 is -NR-; in another embodiment, W3 is C(O)-; in another embodiment, W3 is -OC(O)-; in another embodiment, W3 is -C(O)NR-; in another embodiment, W3 is -NR-C(O)-.

[0231] L2

[0232] In one embodiment, L2 is an amino acid chain consisting of 2-8 (preferably 2-5) amino acid residues linked together; in another embodiment, each amino acid residue in L2 is optionally further substituted by one or more (preferably 1, 2, or 3, preferably 1) amino acid residues; in another embodiment, each amino acid residue in L2 is not substituted; in yet another embodiment, L2 is... In another implementation, L2 is In another implementation, L2 is In another implementation, L2 is In another implementation, L2 is In another implementation, L2 is In another implementation, L2 is

[0233] L2 is selected from:

[0234] A1, A2, A3 and A4

[0235] In one embodiment, A1 is an amino acid residue; in another embodiment, A1 is a glycine residue; in another embodiment, A1 is an alanine residue; in another embodiment, A1 is a phenylalanine residue; in another embodiment, A1 is a lysine residue; in another embodiment, A1 is a tyrosine residue; in another embodiment, A1 is an aspartic acid residue; in another embodiment, A1 is a serine residue; in another embodiment, A1 is a glutamic acid residue; in another embodiment, A1 is a pyroglutamic acid residue; in another embodiment, A1 is a citrulline residue; in another embodiment, A1 is... Preferred

[0236] In one embodiment, A2 is an amino acid residue; in another embodiment, A2 is a glycine residue; in another embodiment, A2 is an alanine residue; in another embodiment, A2 is a phenylalanine residue; in another embodiment, A2 is a lysine residue; in another embodiment, A2 is a tyrosine residue; in another embodiment, A2 is an aspartic acid residue; in another embodiment, A2 is a serine residue; in another embodiment, A2 is a glutamic acid residue; in another embodiment, A2 is a pyroglutamic acid residue; in another embodiment, A2 is a citrulline residue; in another embodiment, A2 is... Preferred In another implementation, A2 is In another implementation, A2 is

[0237] In one embodiment, A3 is an amino acid residue; in another embodiment, A3 is a glycine residue; in another embodiment, A3 is an alanine residue; in another embodiment, A3 is a phenylalanine residue; in another embodiment, A3 is a lysine residue; in another embodiment, A3 is a tyrosine residue; in another embodiment, A3 is an aspartic acid residue; in another embodiment, A3 is a serine residue; in another embodiment, A3 is a glutamic acid residue; in another embodiment, A3 is a pyroglutamic acid residue; in another embodiment, A3 is a citrulline residue; in another embodiment, A3 is...

[0238] In one embodiment, A4 is H; in another embodiment, A4 is an amino acid residue; in another embodiment, A4 is a glycine residue; in another embodiment, A4 is an alanine residue; in another embodiment, A4 is a phenylalanine residue; in another embodiment, A4 is a lysine residue; in another embodiment, A4 is a tyrosine residue; in another embodiment, A4 is an aspartic acid residue; in another embodiment, A4 is a serine residue; in another embodiment, A4 is a glutamic acid residue; in another embodiment, A4 is a pyroglutamic acid residue; in another embodiment, A4 is a citrulline residue.

[0239] In one more specific embodiment, A1 is selected from glycine residues, alanine residues, phenylalanine residues, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues; in another more specific embodiment, A1 is selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues; in yet another more specific embodiment, A1 is a lysine residue, preferably. Preferred

[0240] In one more specific embodiment, A2 is selected from glycine residues, alanine residues, phenylalanine residues, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues; in another more specific embodiment, A2 is selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues; in yet another more specific embodiment, A2 is selected from tyrosine residues, aspartic acid residues, and serine residues; in yet another more specific embodiment, A2 is selected from... (Preferred) ),

[0241] In one more specific embodiment, A3 is selected from glycine residues, alanine residues, phenylalanine residues, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues; in another more specific embodiment, A3 is selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues; in yet another more specific embodiment, A3 is a lysine residue, preferably. Preferred

[0242] In one more specific embodiment, A4 is H or an amino acid residue; in another more specific embodiment, A4 is an amino acid residue; in yet another more specific embodiment, A4 is selected from glycine residue, alanine residue, phenylalanine residue, lysine residue, tyrosine residue, aspartic acid residue, serine residue, glutamic acid residue, pyroglutamic acid residue, or citrulline residue; in yet another more specific embodiment, A4 is selected from lysine residue, tyrosine residue, aspartic acid residue, serine residue, glutamic acid residue, pyroglutamic acid residue, or citrulline residue; in yet another more specific embodiment, A4 is selected from glutamic acid residue, pyroglutamic acid residue, citrulline residue, and aspartic acid residue.

[0243] Z

[0244] In one embodiment, Z is a chelating group derived from a chelating agent; in another embodiment, Z is 1,4,7,10-tetraazacyclododecane-N,N',N",N”'-tetraacetic acid (DOTA); in another embodiment, Z is N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC); in another embodiment, Z is 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA); in another embodiment, Z is 2-(4,7-bis(carboxymethyl)-1,4,7-triazononane-1- In another embodiment, Z is 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA); in another embodiment, Z is 1,4,7-triazacyclononanephosphonic acid (TRAP); in another embodiment, Z is 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO); in another embodiment, Z is 3,6,9,15-tetraazabicyclo[9.3.1].]15-1(15),11,13-triene-3,6,9-triacetic acid (PCTA); in another embodiment, Z is N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO); in another embodiment, Z is diethylenetriaminepentaacetic acid (DTPA); in another embodiment, Z is trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA); in another embodiment, Z is 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxy-Do3A); in another embodiment, Z is p-isocyanothiobenzyl-DTPA (SCN-Bz-DTPA); in another embodiment, Z is 1-(p-isocyanothiobenzyl)-3-methyl-DTPA (1B3M); in another embodiment, Z In another embodiment, Z is 2-(p-isocyanothiobenzyl)-4-methyl-DTPA (1M3B); in another embodiment, Z is 1-(2)-methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA); in another embodiment, Z is (R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA); in another embodiment In one embodiment, Z is 6-hydrazinopyridine-3-carboxylic acid (HYNIC); in another embodiment, Z is 2-(4-isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA); in yet another embodiment, Z is 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA).

[0245] In one implementation, Z is DOTA; in another implementation, Z is NOTA; in another implementation, Z is NODAGA; in another implementation, Z is DOTAGA; in another implementation, Z is HBED-CC; in another embodiment, Z is p-SCN-Bn-CHX-A"-DTPA; in another embodiment, Z is p-SCN-Bn-NOTA; in another implementation, Z is p-SCN-Bn-DOTA.

[0246] In a more specific embodiment, Z is a chelating group derived from a chelating agent selected from the following: 1,4,7,10-tetraazacyclododecane-N,N',N",N”'-tetraacetic acid (DOTA).

[0247] N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC)

[0248] 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA)

[0249] 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA),

[0250] 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA),

[0251] 1,4,7-Triazacyclononanephosphonic acid (TRAP)

[0252] 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO),

[0253] 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA),

[0254] N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO)

[0255] Diethyltriaminepentaacetic acid (DTPA)

[0256] trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA)

[0257] 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A)

[0258] p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA),

[0259] 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M),

[0260] 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B),

[0261] 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA),

[0262] [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA),

[0263] 6-Hydroxypyridine-3-carboxylic acid (HYNIC)

[0264] 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or

[0265] 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA).

[0266] In another, more specific implementation, Z is selected from DOTA NOTA、 NODAGA、 DOTAGA, HBED-CC, p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA and p-SCN-Bn-DOTA; in another more specific implementation, Z is selected from... DOTA NOTA、 NODAGA、 DOTAGA, p-SCN-Bn-NOTA and p-SCN-Bn-DOTA; in another, more specific implementation, Z is... DOTA.

[0267] Chiral centers *1, *2, *3, *4, *5, *6, *7 and *8

[0268] In one embodiment, *1 is an (S) configuration; in another embodiment, *1 is an (R) configuration; in yet another embodiment, *1 is a racemic form.

[0269] In one embodiment, *2 is an (S) configuration; in another embodiment, *2 is an (R) configuration; in yet another embodiment, *2 is a racemic form.

[0270] In one embodiment, *3 is an (S) configuration; in another embodiment, *3 is an (R) configuration; in yet another embodiment, *3 is a racemic form.

[0271] In one embodiment, *4 is an (S) configuration; in another embodiment, *4 is an (R) configuration; in yet another embodiment, *4 is a racemic form.

[0272] In one embodiment, *5 is an (S) configuration; in another embodiment, *5 is an (R) configuration; in yet another embodiment, *5 is a racemic form.

[0273] In one embodiment, *6 is an (S) configuration; in another embodiment, *6 is an (R) configuration; in yet another embodiment, *6 is a racemic form.

[0274] In one embodiment, *7 is an (S) configuration; in another embodiment, *7 is an (R) configuration; in yet another embodiment, *7 is a racemic form.

[0275] In one embodiment, *8 is in (S) configuration; in another embodiment, *8 is in (R) configuration; in yet another embodiment, *8 is in runaway form.

[0276] *1, *2, *3, *4, *5, *6, *7 and *8 are independently selected from (S) or (R) configurations, or are racemic forms.

[0277] M

[0278] In one embodiment, M is a radionuclide; in another embodiment, M is a non-radioactive element; in another embodiment, M is a diagnostic nuclide; in another embodiment, M is a therapeutic nuclide; in yet another embodiment, M is... 68 Ga; in another implementation, M is 18 F; in another implementation, M is 99 mTc; in another embodiment, M is 89 Zr; in another implementation, M is 124 I; In another implementation, M is 76 Br; in another embodiment, M is 43 Sc; In another implementation, M is 111 In another implementation, M is... 45 Ti; in another implementation, M is 52 Mn; in another embodiment, M is 59 Fe; in another embodiment, M is 64Cu; in another embodiment, M is 94 mTc; in another embodiment, M is 67 Ga; in another implementation, M is 71 / 72 / 74 As; in another implementation, M is 82m Rb; in another implementation, M is 86 Y; in another implementation, M is 177 Lu; in another implementation, M is 90 Y; in another implementation, M is 131 I; In another implementation, M is 153 Sm; in another implementation, M is 67 Cu; in another embodiment, M is 89 Sr; In another embodiment, M is 166 Ho; in another implementation, M is 177 Yb; In another embodiment, M is 47 Sc; In another implementation, M is 186 / 188 Re; In another implementation, M is 212 / 213 Bi; in another implementation, M is 149 Pm; in another implementation, M is 212 Pb; in another embodiment, M is 211 At; in another implementation, M is 223 Ra; in another implementation, M is 161 Tb; In another implementation, M is 225 Ac; in another implementation, M is 227 Th.

[0279] In one more specific embodiment, M is selected from at least one of a radionuclide or a non-radioactive element; in another more specific embodiment, the radionuclide is selected from at least one of a diagnostic nuclide or a therapeutic nuclide; in yet another more specific embodiment, the diagnostic nuclide is selected from... 68 Ga、 18 F, 99 mTc, 89 Zr、 124 I, 76 Br、 43 Sc、 111 In、 45 Ti、 52 Mn, 59 Fe、 64 Cu、 94 mTc, 67 Ga、 71 / 72 / 74As、 82m Rb or 86 Y; In another, more specific embodiment, the therapeutic radionuclide is selected from... 177 Lu、 90 Y、 131 I, 153 Sm、 67 Cu、 89 Sr、 166 Ho、 177 Yb、 47 Sc、 186 / 188 Re、 212 / 213 Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 161 Tb, 225 Ac or 227 Th; In another, more specific embodiment, the radionuclide is selected from... 68 Ga、 18 F, 89 Zr、 99 mTc or 177 Lu; In another, more specific embodiment, the radionuclide 18 F is through 18 FAl is formed by complexing with a compound of formula (I); in another more specific embodiment, M is selected from... 68 Ga、 18 F or 177 Lu; in another, more specific implementation, M is selected from... 68 Ga or 177 Lu.

[0280] Z'

[0281] In one embodiment, Z' is a coordinating group formed by the complexation of a chelating group Z derived from a chelating agent and M.

[0282] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of Ab can be combined with rings R1, R2, m, Rm, Rn, L1, R, Ar, n, R*, W0, W1, V1, V2, W2, W3, L2, A1, A2, A3, A4, Z, R a R b R c R dThis invention relates to any combination of technical solutions such as M, Z', *1, *2, *3, *4, *5, *6, *7, and *8. The present invention aims to include combinations of all these technical solutions; due to space limitations, they are not listed individually.

[0283] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0284] L1 is -W0-W1-V1-V2-W2-W3-, preferably -W0-W1-V1-V2-W2-C(O)-, -W0-W1-V1-V2-W2-OC(O)- or -W0-W1-V1-V2-W2-NR-C(O)-;

[0285] W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6 -、-C(O)O-(CR c R d ) 1-6 -、-NR-(CR c R d ) 1-6 -、-C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0- 6-,-C(O)-3-7-membered heterocyclic group-(CR) c R d ) 0-6 -、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -、-C(O)-5-10-membered heteroaryl-(CR c R d ) 0-6 -;

[0286] W1 is selected from chemical bonds, -O-, -NR-, C(O)-, -OC(O)-, -C(O)-NR-, or -NR-C(O)-;

[0287] W2 is selected from C 1-10 Alkylene, C 2-10 imide or C 2-10 Ethyne group;

[0288] W3 is selected from -O-, -NR-, C(O)-, -OC(O)-, -C(O)NR- or -NR-C(O)-;

[0289] V1 is selected from chemical bonds or -(CR) a R b ) 1-10 -;

[0290] V2 is selected from chemical bonds, -O-, -NR-, C(O)-, -NR-C(O)-, or -C(O)-NR-;

[0291] R a and R b Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-C 6-14 Aryl or -C 1-6 alkylene-5-14-membered heteroaryl;

[0292] R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0293] R is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0294] L1 can be optionally replaced by 1, 2, 3, 4 or 5 R*;

[0295] R* is selected from H, D, halogens, OH, CN, NH2, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0296] Preferably,

[0297] L1 is selected from -W1-W2-C(O)-, -W1-W2-OC(O)-, -W1-W2-NR-C(O)-, -W0-W1-V1-V2-W2-C(O)- or -W1-V1-V2-W2-C(O)-;

[0298] W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6 -、-C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -、-C(O)-3-7 membered heterocyclic group-(CR c Rd ) 0-6 -、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -、-C(O)-5-10-membered heteroaryl-(CR c R d ) 0-6 -, preferably a chemical bond or -C(O)-(CR c R d ) 1-6 -;

[0299] W1 is selected from chemical bonds, -NR-, C(O)-, -C(O)-NR-, or -NR-C(O)-;

[0300] W2 is selected from C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0301] V1 is -(CR) a R b ) 1-4 -;

[0302] V2 is selected from -NR-, -C(O)-, or -NR-C(O)-;

[0303] R a and R b Independently selected from H or -C 1-4 Alkylene-C 6-14 Aryl;

[0304] R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0305] R is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0306] L1 can be optionally replaced by one, two, or three R*s;

[0307] R* is selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0308] Preferably,

[0309] L1 is selected from -C 1-6 Alkylene -C(O)-, -C2-6 alkenyl-C(O)-, -C 2-6 Ethyne-C(O)-, -NR-C 1-6 Alkylene-C(O)-, -NR-C(O)-C 1-6 Alkylene-C(O)-, Wherein, R is selected from H or C. 1-6 Alkyl, Ar is selected from phenyl, naphthyl, anthraceneyl or phenanthryl, and each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0310] L W Selected from -(CR) c R d ) 1-6 -、C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -, 3-7 member heterocyclic-(CR) c R d ) 0-6 -、C 6-10 Aspartic-(CR) c R d ) 0-6 -or 5-10% heteroaryl-(CR) c R d ) 0-6 -, preferably -(CR) c R d ) 1-6 -;

[0311] R c and R d Independently selected from H and C 1-6 Alkyl or C 3-7 cycloalkyl;

[0312] L1 can be optionally replaced by one, two, or three R*s;

[0313] R* is selected from H and C. 1-4 Alkyl or C 3-5 cycloalkyl;

[0314] More preferably,

[0315] L1 is selected from -(CH2) 1-6 -C(O)-, -CH=CH-(CH2) 1-4 -C(O)-, -C≡C-(CH2) 1-4 -C(O)-, -NR-(CH2) 1-6 -C(O)-, -NR-C(O)-(CH2)1-6 -C(O)-、

[0316] R is independently selected from H or C. 1-4 Alkyl, Ar is independently selected from phenyl, naphthyl, anthraceneyl or phenanthryl, and each n is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8;

[0317] L W Independently selected from -(CR c R d ) 1-4 -、C 3-7 Cycloalkylene-(CR) c R d ) 0-4 -, 3-7 member heterocyclic-(CR) c R d ) 0-4 -、C 6-10 Aspartic-(CR) c R d ) 0- 4- or 5-10-membered heteroaryl-(CR) c R d ) 0-4 -, preferably -(CR) c R d ) 1-4 -;

[0318] R c and R d Independently selected from H and C 1-4 Alkyl or C 3-5 cycloalkyl;

[0319] For example,

[0320] L1 is selected from:

[0321] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0322] L2 is an amino acid chain consisting of 2-5 amino acid residues linked together, wherein each amino acid residue may optionally be further replaced by one or more amino acid residues.

[0323] Each amino acid is independently selected from glycine residues, alanine residues, phenylalanine, naphthylalanine, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues.

[0324] Preferably,

[0325] L2 is

[0326] A1, A2, A3, and A4 are amino acid residues;

[0327] Preferably,

[0328] L2 is

[0329] A1, A2, A3, and A4 are independently selected from glycine residues, alanine residues, phenylalanine, naphthylalanine, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues.

[0330] More preferably,

[0331] L2 is

[0332] A1 is a lysine residue;

[0333] A2 is selected from tyrosine residues, aspartic acid residues, or serine residues;

[0334] A3 is a lysine residue;

[0335] A4 is selected from glutamic acid residues, pyroglutamic acid residues, citrulline residues, or aspartic acid residues;

[0336] For example,

[0337] L2 is selected from:

[0338] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0339] Z is a chelating group derived from a chelating agent, which is selected from the following:

[0340] 1,4,7,10-Tetraazacyclododecane-N,N',N",N”'-Tetraacetic acid (DOTA)

[0341] N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC)

[0342] 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA)

[0343] 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA),

[0344] 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA),

[0345] 1,4,7-Triazacyclononanephosphonic acid (TRAP)

[0346] 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO),

[0347] 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA),

[0348] N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO)

[0349] Diethyltriaminepentaacetic acid (DTPA)

[0350] trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA)

[0351] 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A)

[0352] p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA),

[0353] 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M),

[0354] 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B),

[0355] 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA),

[0356] [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA),

[0357] 6-Hydroxypyridine-3-carboxylic acid (HYNIC)

[0358] 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or

[0359] 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA);

[0360] Preferably,

[0361] Z is selected from DOTAGA, NOTA、 NODAGA、 DOTA HBED-CC, p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA p-SCN-Bn-DOTA.

[0362] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0363] Ab is selected from:

[0364] R1 and R2 are independently selected from H, D, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups;

[0365] m is selected from 1, 2, 3, 4, or 5;

[0366] Preferably,

[0367] Ab is selected from:

[0368] R1 is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0369] R2 is selected from H, halogen, or C. 1-6 alkyl;

[0370] m is selected from 1, 2, or 3;

[0371] Preferably,

[0372] Ab is Preferred

[0373] R1 is selected from H or C. 1-6 alkyl;

[0374] R2 is selected from H or halogen;

[0375] m is selected from 1, 2, or 3;

[0376] More preferably,

[0377] Ab is selected from

[0378] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0379] Ab is selected from:

[0380] R1 and R2 are independently selected from H, D, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups;

[0381] m is selected from 1, 2, 3, 4, or 5;

[0382] L1 is -W0-W1-V1-V2-W2-W3-, preferably -W0-W1-V1-V2-W2-C(O)-, -W0-W1-V1-V2-W2-OC(O)- or -W0-W1-V1-V2-W2-NR-C(O)-;

[0383] W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6 -、-C(O)O-(CR c R d )1-6 -、-NR-(CR c R d ) 1-6 -、-C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0- 6-,-C(O)-3-7-membered heterocyclic group-(CR) c R d ) 0-6 -、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -、-C(O)-5-10-membered heteroaryl-(CR c R d ) 0-6 -;

[0384] W1 is selected from chemical bonds, -O-, -NR-, C(O)-, -OC(O)-, -C(O)-NR-, or -NR-C(O)-;

[0385] W2 is selected from C 1-10 Alkylene, C 2-10 imide or C 2-10 Ethyne group;

[0386] W3 is selected from -O-, -NR-, C(O)-, -OC(O)-, -C(O)NR- or -NR-C(O)-;

[0387] V1 is selected from chemical bonds or -(CR) a R b ) 1-10 -;

[0388] V2 is selected from chemical bonds, -O-, -NR-, C(O)-, -NR-C(O)-, or -C(O)-NR-;

[0389] R a and R b Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-C 6-14 Aryl or -C 1-6 alkylene-5-14-membered heteroaryl;

[0390] R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0391] R is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0392] L1 can be optionally replaced by 1, 2, 3, 4 or 5 R*;

[0393] R* is selected from H, D, halogens, OH, CN, NH2, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0394] L2 is an amino acid chain consisting of 2-5 amino acid residues linked together, wherein each amino acid residue may optionally be further replaced by one or more amino acid residues.

[0395] Z is a chelating group derived from the chelating agent.

[0396] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0397] Ab is selected from:

[0398] R1 is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0399] R2 is selected from H, halogen, or C. 1-6 alkyl;

[0400] m is selected from 1, 2, or 3;

[0401] L1 is selected from -W1-W2-C(O)-, -W1-W2-OC(O)-, -W1-W2-NR-C(O)-, -W0-W1-V1-V2-W2-C(O)- or -W1-V1-V2-W2-C(O)-;

[0402] W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6 -、-C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -、-C(O)-3-7 membered heterocyclic group-(CR c R d ) 0-6-、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -、-C(O)-5-10-membered heteroaryl-(CR c R d ) 0-6 -, preferably a chemical bond or -C(O)-C 1-6 alkylene-;

[0403] W1 is selected from chemical bonds, -NR-, C(O)-, -C(O)-NR-, or -NR-C(O)-;

[0404] W2 is selected from C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0405] V1 is -(CR) a R b ) 1-4 -;

[0406] V2 is selected from -NR-, C(O)-, or -NR-C(O)-;

[0407] R a and R b Independently selected from H or -C 1-4 Alkylene-C 6-14 Aryl;

[0408] R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0409] R is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0410] L1 can be optionally replaced by one, two, or three R*s;

[0411] R* is selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0412] L2 is

[0413] A1, A2, A3, and A4 are amino acid residues;

[0414] Z is a chelating group derived from a chelating agent, which is selected from the following:

[0415] 1,4,7,10-Tetraazacyclododecane-N,N',N",N”'-Tetraacetic acid (DOTA)

[0416] N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC)

[0417] 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA)

[0418] 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA),

[0419] 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA),

[0420] 1,4,7-Triazacyclononanephosphonic acid (TRAP)

[0421] 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO),

[0422] 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA),

[0423] N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO)

[0424] Diethyltriaminepentaacetic acid (DTPA)

[0425] trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA)

[0426] 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A)

[0427] p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA),

[0428] 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M),

[0429] 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B),

[0430] 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA),

[0431] [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA),

[0432] 6-Hydroxypyridine-3-carboxylic acid (HYNIC)

[0433] 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or

[0434] 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA).

[0435] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0436] Ab is selected from Preferred selection

[0437] R1 is selected from H or C. 1-6 alkyl;

[0438] R2 is selected from H or halogen;

[0439] m is selected from 1, 2, or 3;

[0440] L1 is selected from -C 1-6 Alkylene -C(O)-, -C 2-6 alkenyl-C(O)-, -C 2-6 Ethyne-C(O)-, -NR-C 1-6 Alkylene-C(O)-, -NR-C(O)-C 1-6 Alkylene-C(O)-, Wherein, R is independently selected from H or C. 1-6 Alkyl, Ar is independently selected from phenyl, naphthyl, anthraceneyl or phenanthryl, and each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0441] L W Selected from -(CR) c R d ) 1-6-、C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -, 3-7 member heterocyclic-(CR) c R d ) 0-6 -、C 6-10 Aspartic-(CR) c R d ) 0-6 -or 5-10% heteroaryl-(CR) c R d ) 0-6 -, preferably -(CR) c R d ) 1-6 -;

[0442] R c and R d Independently selected from H and C 1-6 Alkyl or C 3-7 cycloalkyl;

[0443] L1 can be optionally replaced by one, two, or three R*s;

[0444] R* is selected from H or C 1-4 alkyl;

[0445] L2 is

[0446] A1, A2, A3, and A4 are independently selected from glycine residues, alanine residues, phenylalanine, naphthylalanine, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues.

[0447] Z is selected from DOTAGA, NOTA、 NODAGA、 DOTA HBED-CC, p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA p-SCN-Bn-DOTA.

[0448] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0449] Ab is selected from:

[0450] L1 is selected from -(CH2) 1-6 -C(O)-, -CH=CH-(CH2) 1-4 -C(O)-, -C≡C-(CH2) 1-4 -C(O)-, -NR-(CH2) 1-6 -C(O)-, -NR-C(O)-(CH2) 1-6 -C(O)-、 Wherein, R is independently selected from H or C. 1-4 Alkyl, Ar is independently selected from phenyl, naphthyl, anthraceneyl or phenanthryl, and each n is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8;

[0451] L W Selected from -(CR) c R d ) 1-4 -、C 3-7 Cycloalkylene-(CR) c R d ) 0-4 -, 3-7 member heterocyclic-(CR) c R d ) 0-4 -、C 6-10 Aspartic-(CR) c R d ) 0-4 -or 5-10% heteroaryl-(CR) c R d ) 0-4 -, preferably -(CR) c R d ) 1-4 -;

[0452] R c and R d Independently selected from H and C 1-4 Alkyl or C 3-5 cycloalkyl;

[0453] Preferably, L1 is selected from:

[0454] L2 is

[0455] A1 is a lysine residue;

[0456] A2 is selected from tyrosine residues, aspartic acid residues, or serine residues;

[0457] A3 is a lysine residue;

[0458] A4 is selected from glutamic acid residues, pyroglutamic acid residues, citrulline residues, or aspartic acid residues;

[0459] Z is selected from DOTAGA, NOTA、 NODAGA、 DOTA HBED-CC, p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA; 2-(4-isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid p-SCN-Bn-DOTA;2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

[0460] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0461] L2 is selected from:

[0462] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0463] in,

[0464] R1 and R2 are independently selected from H, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0465] m is selected from 0, 1, 2, 3, 4 or 5;

[0466] L1 is selected from -W1-W2-C(O)- or -W1-V1-V2-W2-C(O)-;

[0467] W1 is selected from chemical bonds, -NR-, C(O)-, or -NR-C(O)-;

[0468] W2 is selected from C 1-6 Alkylene, C2-6 imide or C 2-6 Ethyne group;

[0469] V1 is -(CR) a R b ) 1-6 -;

[0470] V2 is selected from -NR-, C(O)-, or -NR-C(O)-;

[0471] R a and R b Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-C 6-14 Aryl or -C 1-6 alkylene-5-14-membered heteroaryl;

[0472] R is selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0473] L1 can be optionally replaced by one, two, or three R*s;

[0474] R* is selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0475] L2 is

[0476] A1, A2, A3, and A4 are amino acid residues;

[0477] Z is a chelating group derived from the chelating agent;

[0478] Preferably,

[0479] R1 is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, preferably H or C 1-6 alkyl;

[0480] R2 is selected from H, halogen, or C. 1-6 Alkyl groups, preferably H or halogens;

[0481] m is selected from 0, 1, 2, or 3;

[0482] L1 is selected from -C 1-6 Alkylene -C(O)-, -C 2-6 alkenyl-C(O)-, -C 2-6 Ethyne-C(O)-, -NR-C 1-6 Alkylene-C(O)-, -NR-C(O)-C1-6 Alkylene-C(O)-, Wherein, R is independently selected from H or C. 1-6 Alkyl group, Ar is independently selected from phenyl, naphthyl, anthraceneyl or phenanthryl, and n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0483] L1 can be optionally replaced by one, two, or three R*s;

[0484] R* is selected from H or C 1-4 alkyl;

[0485] L2 is

[0486] A1 is a lysine residue;

[0487] A2 is selected from tyrosine residues, aspartic acid residues, or serine residues;

[0488] A3 is a lysine residue;

[0489] A4 is selected from glutamic acid residues, pyroglutamic acid residues, citrulline residues, or aspartic acid residues;

[0490] Z is a chelating group derived from a chelating agent, which is selected from the following:

[0491] 1,4,7,10-Tetraazacyclododecane-N,N',N",N”'-Tetraacetic acid (DOTA)

[0492] N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC)

[0493] 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA)

[0494] 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA),

[0495] 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA),

[0496] 1,4,7-Triazacyclononanephosphonic acid (TRAP)

[0497] 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO),

[0498] 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA),

[0499] N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO)

[0500] Diethyltriaminepentaacetic acid (DTPA)

[0501] trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA)

[0502] 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A)

[0503] p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA),

[0504] 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M),

[0505] 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B),

[0506] 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA),

[0507] [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA),

[0508] 6-Hydroxypyridine-3-carboxylic acid (HYNIC)

[0509] 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or

[0510] 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA);

[0511] Preferably,

[0512] R1 is selected from H or C. 1-6 Alkyl groups, such as H or CH3;

[0513] R2 is selected from H or halogens, such as H or F;

[0514] m is selected from 1 or 2;

[0515] L1 is selected from -C 1-6 alkylene-C(O)- or Wherein, R is selected from H or C. 1-6 Alkyl, Ar is selected from phenyl, naphthyl, anthraceneyl or phenanthryl, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0516] L1 can be optionally replaced by one, two, or three R*s;

[0517] R* is selected from H or C 1-4 alkyl;

[0518] For example, L1 is selected from:

[0519] L2 is selected from:

[0520] Z is selected from DOTAGA, NOTA、 NODAGA、 DOTA HBED-CC, p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA p-SCN-Bn-DOTA.

[0521] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, hydrate, ester or solvate, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (VII), (VII-1) or (VII-2):

[0522] in,

[0523] R1 and R2 are independently selected from H, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0524] Rn is selected from CN, OH, or NH2;

[0525] m is selected from 0, 1, 2, 3, 4 or 5;

[0526] W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6-、-C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -、-C(O)-3-7 membered heterocyclic group-(CR c R d ) 0-6 -、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -or-C(O)-5-10 heteroaryl-(CR c R d ) 0-6 -;

[0527] W1 is selected from -C(O)-, -OC(O)-, -C(O)-NR-, or -NR-C(O)-;

[0528] W2 is selected from C 1-10 Alkylene, C 2-10 imide or C 2-10 Ethyne group;

[0529] V1 is selected from chemical bonds or -(CR) a R b ) 1-10 -;

[0530] V2 is selected from chemical bonds, -O-, -NR-, C(O)-, or -NR-C(O)-;

[0531] R a and R b Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-C 6-14 Aryl or -C 1-6 alkylene-5-14-membered heteroaryl;

[0532] R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0533] A1, A2, A3, and A4 are amino acid residues;

[0534] Z is a chelating group derived from the chelating agent;

[0535] Preferably,

[0536] R1 is selected from H and C.1-6 Alkyl or C 1-6 Halogenated alkyl groups, preferably H or C 1-6 alkyl;

[0537] R2 is selected from H, halogen, or C. 1-6 Alkyl groups, preferably H or halogens;

[0538] Rn is selected from CN, OH, or NH2;

[0539] m is selected from 0, 1, 2, or 3;

[0540] -W0-W1-V1-V2-W2-C(O)- is for

[0541] R is selected from H or C. 1-6 alkyl;

[0542] Ar is selected from phenyl, naphthyl, anthraceneyl, or phenanthrene;

[0543] n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0544] L W Selected from -(CR) c R d ) 1-6 -、-C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -, 3-7 member heterocyclic-(CR) c R d ) 0-6 -、C 6-10 Aspartic-(CR) c R d ) 0-6 -or 5-10% heteroaryl-(CR) c R d ) 0-6 -, preferably -(CR) c R d ) 1-6 -;

[0545] R c and R d Independently selected from H and C 1-6 Alkyl or C 3-5 cycloalkyl;

[0546] L1 can be optionally replaced by one, two, or three R*s;

[0547] R* is selected from H and C. 1-4 Alkyl or C 3-5 cycloalkyl;

[0548] A1 is a lysine residue;

[0549] A2 is selected from tyrosine residues, aspartic acid residues, or serine residues;

[0550] A3 is a lysine residue;

[0551] A4 is selected from glutamic acid residues, pyroglutamic acid residues, citrulline residues, or aspartic acid residues;

[0552] Z is a chelating group derived from a chelating agent, which is selected from the following:

[0553] 1,4,7,10-Tetraazacyclododecane-N,N',N",N”'-Tetraacetic acid (DOTA)

[0554] N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC)

[0555] 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA)

[0556] 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA),

[0557] 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA),

[0558] 1,4,7-Triazacyclononanephosphonic acid (TRAP)

[0559] 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO),

[0560] 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA),

[0561] N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO)

[0562] Diethyltriaminepentaacetic acid (DTPA)

[0563] trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA)

[0564] 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A)

[0565] p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA),

[0566] 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M),

[0567] 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B),

[0568] 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA),

[0569] [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA),

[0570] 6-Hydroxypyridine-3-carboxylic acid (HYNIC)

[0571] 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or

[0572] 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA);

[0573] Preferably,

[0574] R1 is selected from H or C. 1-6 Alkyl groups, such as H or CH3;

[0575] R2 is selected from H or halogens, such as H or F;

[0576] Rn is selected from CN, OH or NH2, preferably CN;

[0577] m is selected from 1 or 2;

[0578] -W0-W1-V1-V2-W2-C(O)- is selected from the following structures: Preferred

[0579] Selected from: Z is selected from DOTAGA, NOTA、 NODAGA、 DOTA HBED-CC, p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA p-SCN-Bn-DOTA.

[0580] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, hydrate, ester or solvate, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (VII), (VII-1) or (VII-2):

[0581] in,

[0582] R1 and R2 are independently selected from H, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0583] Rn is selected from CN, OH, or NH2;

[0584] m is selected from 0, 1, 2, 3, 4 or 5;

[0585] W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6 -、-C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -、-C(O)-3-7 membered heterocyclic group-(CR c R d ) 0-6 -、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -or-C(O)-5-10 heteroaryl-(CR c R d ) 0-6 -;

[0586] W1 is selected from -C(O)-, -OC(O)-, -C(O)-NR-, or -NR-C(O)-;

[0587] W2 is selected from C 1-10 Alkylene, C 2-10 imide or C 2-10 Ethyne group;

[0588] V1 is selected from chemical bonds or -(CR) a R b ) 1-10 -;

[0589] V2 is selected from chemical bonds, -O-, -NR-, C(O)-, or -NR-C(O)-;

[0590] R a and R b Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-C 6-14 Aryl or -C 1-6 alkylene-5-14-membered heteroaryl;

[0591] R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups;

[0592] A1, A2, A3, and A4 are amino acid residues;

[0593] Z is a chelating group derived from the chelating agent;

[0594] Preferably,

[0595] R1 is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, preferably H or C 1-6 alkyl;

[0596] R2 is selected from H, halogen, or C. 1-6 Alkyl groups, preferably H or halogens;

[0597] Rn is selected from CN, OH, or NH2;

[0598] m is selected from 0, 1, 2, or 3;

[0599] -W0-W1-V1-V2-W2-C(O)- is for

[0600] R is selected from H or C. 1-6 alkyl;

[0601] Ar is selected from phenyl, naphthyl, anthraceneyl, or phenanthrene;

[0602] n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0603] L W Selected from -(CR) c R d ) 1-6 -、-C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -, 3-7 member heterocyclic-(CR) c R d ) 0-6 -、C 6-10 Aspartic-(CR) c R d ) 0-6 -or 5-10% heteroaryl-(CR) c R d ) 0-6 -, preferably -(CR) c R d ) 1-6 -, for example -CH2-;

[0604] R c and R d Independently selected from H and C 1-6 Alkyl or C 3-5 Cycloalkyl, preferably H;

[0605] L1 can be optionally replaced by one, two, or three R*s;

[0606] R* is selected from H and C. 1-4 Alkyl or C 3-5 cycloalkyl;

[0607] A1 is a lysine residue;

[0608] A2 is selected from tyrosine residues, aspartic acid residues, or serine residues;

[0609] A3 is a lysine residue;

[0610] A4 is selected from glutamic acid residues, pyroglutamic acid residues, citrulline residues, or aspartic acid residues;

[0611] Z is a chelating group derived from a chelating agent, which is selected from the following:

[0612] 1,4,7,10-Tetraazacyclododecane-N,N',N",N”'-Tetraacetic acid (DOTA)

[0613] N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC)

[0614] 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA)

[0615] 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA),

[0616] 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA),

[0617] 1,4,7-Triazacyclononanephosphonic acid (TRAP)

[0618] 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO),

[0619] 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA),

[0620] N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO)

[0621] Diethyltriaminepentaacetic acid (DTPA)

[0622] trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA)

[0623] 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A)

[0624] p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA),

[0625] 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M),

[0626] 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B),

[0627] 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA),

[0628] [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA),

[0629] 6-Hydroxypyridine-3-carboxylic acid (HYNIC)

[0630] 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or

[0631] 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA);

[0632] Preferably,

[0633] R1 is selected from H or C. 1-6 Alkyl groups, such as H or CH3;

[0634] R2 is selected from H or halogens, such as H or F;

[0635] Rn is selected from CN, OH or NH2, preferably CN;

[0636] m is selected from 1 or 2;

[0637] -W0-W1-V1-V2-W2-C(O)- is selected from the following structures: Preferred

[0638] Selected from:

[0639] Z is selected from DOTAGA, NOTA、 NODAGA、 DOTA HBED-CC, p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA p-SCN-Bn-DOTA.

[0640] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0641] *1, *2, *3, *4, *5, *6, *7 and *8 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms;

[0642] R1 is selected from H or C. 1-4 Alkyl groups, such as H or methyl groups;

[0643] W1 is selected from chemical bonds, -O-, or -NR-;

[0644] R is selected from H or C. 1-4 Alkyl groups, such as H or methyl groups;

[0645] Ar is selected from phenyl, naphthyl, or anthracene, preferably phenyl or naphthyl;

[0646] n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0647] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0648] *1, *2, *3, *4, *5, *6, *7 and *8 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms;

[0649] R1 is selected from H or C. 1-4 Alkyl groups, such as H or methyl groups;

[0650] W1 is selected from chemical bonds, -O-, or -NR-;

[0651] R is selected from H or C. 1-4 Alkyl groups, such as H or methyl groups;

[0652] Ar is selected from phenyl, naphthyl, or anthracene, preferably phenyl or naphthyl;

[0653] n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0654] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0655] In a more specific embodiment, the present invention provides a compound comprising a compound of formula (I), or an isotopic variant thereof, a hydrate, an ester or solvate thereof, a tautomer, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and an M complexed therewith.

[0656] in,

[0657] Compounds of formula (I) are as defined herein;

[0658] M is selected from at least one of a radioactive nuclide or a non-radioactive element;

[0659] Preferably, the radionuclide is selected from at least one of diagnostic or therapeutic radionuclides;

[0660] Preferably, the diagnostic radionuclide is selected from... 68 Ga、 18 F, 99 mTc, 89 Zr、 124 I, 76 Br、 43 Sc、 111 In、 45 Ti、 52 Mn, 59 Fe、 64 Cu、 94 mTc, 67 Ga、 71 / 72 / 74 As、 82m Rb or 86 Y;

[0661] Preferably, the therapeutic radionuclide is selected from... 177 Lu、 161 Tb, 90 Y、 131 I, 153 Sm、 67 Cu、 89 Sr、 166 Ho、 177 Yb、 47 Sc、 186 / 188 Re、 212 / 213 Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 225 Ac or 227 Th;

[0662] Preferably, the radionuclide is selected from... 68 Ga、 18 F, 89 Zr、 99mTc or 177 Lu;

[0663] Preferably, M is selected from... 68 Ga、 18 F or 177 Lu;

[0664] Preferably, the radionuclide 18 F is through 18 Formed by FAl complexation.

[0665] In a more specific embodiment, the present invention provides a compound of formula (X), or an isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0666] in,

[0667] Ab, L1, and L2 are as defined in this paper;

[0668] Z' is the coordination group formed after Z and M complex, and Z is as defined in this article;

[0669] M is selected from at least one of a radioactive nuclide or a non-radioactive element;

[0670] Preferably, the radionuclide is selected from at least one of diagnostic or therapeutic radionuclides;

[0671] Preferably, the diagnostic radionuclide is selected from... 68 Ga、 18 F, 99 mTc, 89 Zr、 124 I, 76 Br、 43 Sc、 111 In、 45 Ti、 52 Mn, 59 Fe、 64 Cu、 94 mTc, 67 Ga、 71 / 72 / 74 As、 82m Rb or 86 Y;

[0672] Preferably, the therapeutic radionuclide is selected from... 177 Lu、 161 Tb, 90 Y、 131 I, 153 Sm、 67 Cu、 89 Sr、 166 Ho、 177 Yb、47 Sc、 186 / 188 Re、 212 / 213 Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 225 Ac or 227 Th;

[0673] Preferably, the radionuclide is selected from... 68 Ga、 18 F, 89 Zr、 99 mTc or 177 Lu;

[0674] Preferably, M is selected from... 68 Ga、 18 F or 177 Lu;

[0675] Preferably, the radionuclide 18 F is through 18 Formed by FAl complexation.

[0676] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0677] The compounds of this invention can exist as tautomers. Tautomers are functional group isomers that arise from the rapid movement of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can interconvert, but usually the more stable isomer is the dominant form. The most important examples are enol and keto tautomers.

[0678] Those skilled in the art will understand that organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are called "solvates." When the solvent is water, the complex is called a "hydrate." This invention covers all solvates of the compounds of this invention.

[0679] The term "solvent" refers to a compound or its salt that is bound to a solvent and formed typically by a solvent decomposition reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0680] The term "hydrate" refers to a compound that is bound to water. Typically, it is determined by the ratio of the number of water molecules contained in the hydrate to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0681] The compounds of this invention can be in amorphous or crystalline forms (polymorphs). Furthermore, the compounds of this invention can exist in one or more crystalline forms. Therefore, this invention encompasses all amorphous or crystalline forms of the compounds of this invention within its scope. The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates) with a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

[0682] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0683] Furthermore, prodrugs are also included in the context of this invention. As used herein, the term "prodrug" refers to a compound which is converted in vivo, for example, by hydrolysis in the blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series, Vol. 14; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and D. Fleisher, S. Ramon, and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs," Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

[0684] A prodrug is any covalently bonded compound of the present invention that, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in a manner that allows the modification to produce the parent compound through conventional operation or in vivo cleavage. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or thiol group is bonded to any group, which, when administered to a patient, can cleave to form a hydroxyl, amino, or thiol group. Thus, representative examples of prodrugs include (but are not limited to) acetate / amide, formate / amide, and benzoate / amide derivatives of formula (I) with hydroxyl, thiol, and amino functional groups. Additionally, in the case of carboxylic acids (-COOH), esters, such as methyl esters, ethyl esters, etc., can be used. The ester itself may be active and / or hydrolyzable under in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that readily decompose in the body to release the parent acid or its salt.

[0685] The present invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient thereof. All such forms are subject to the present invention.

[0686] Pharmaceutical Compositions and Kits

[0687] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as the "active component") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the compound of the present invention.

[0688] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0689] Suitable formulations for administering the compounds of the present invention will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, sugar lozenges, solutions (particularly for injection (subcutaneous, intravenous, intramuscular) and infusion), elixirs, syrups, capsules, emulsions, inhalers, or dispersible powders. The content of one or more pharmaceutically active compounds should range from 0.1 to 90 wt%, preferably 0.5 to 50 wt%, of the composition as a whole, i.e., an amount sufficient to achieve the dosage range specified below. If necessary, the specified dosage may be administered several times daily.

[0690] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0691] Dosage

[0692] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0693] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0694] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0695] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0696] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0697] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dose form for the purpose of precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0698] For oral dosage, a typical regimen is one to five oral doses daily, particularly two to four oral doses, typically three oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the compound of the invention, with preferred doses each providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0699] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0700] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0701] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0702] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0703] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[0704] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs or porous membrane types, or patches with various solid matrices.

[0705] The above-described components for oral, injectable, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0706] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0707] This invention also relates to pharmaceutically acceptable formulations of the compounds of this invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0708] Indications

[0709] For tumors that overexpress FAP, the development of FAP inhibitors could provide therapeutic benefits to a large number of cancer patients. The compounds in this invention exert their therapeutic effect by negatively regulating the activity of FAP within tumor cells, and after labeling with therapeutic radionuclides, they can be used for molecular imaging diagnosis and treatment of tumors.

[0710] In some embodiments, the compounds or complexes of the present invention can diagnose and treat a variety of cancers, including but not limited to tumor types such as kidney cancer, lung cancer, colorectal cancer, gastric cancer (e.g., poorly differentiated adenocarcinoma (lesser curvature mucosa of the gastric body)), follicular dendritic cell sarcoma (FDCS), pancreatic cancer, melanoma, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head and neck cancer, astrocytoma, and oral cancer.

[0711] Example

[0712] The compounds and preparation methods of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technical solutions implemented based on the content of the present invention are covered within the scope of protection intended by the present invention.

[0713] Unless otherwise specified, the experimental methods used in the following examples are conventional methods in the art; the reagents, raw materials, instruments, equipment, etc. used in the following examples are all commercially available.

[0714] FAPI46 and FAPI04 were purchased from Jiangxi Tanzhen Biotechnology Co., Ltd., and can also be synthesized by referring to existing technical synthesis methods. 68 Ga-FAPI46, 68 Ga-FAPI04 can be marked using existing technical methods, or it can be marked independently.

[0715] Table 1

[0716] The structures of Fmoc-D-Lys(Dde)-OH, Fmoc-D-Tyr(tBu)-OH, Fmoc-D-Lys(Alloc)-OH, Fmoc-D-Glu(tBu)-OH, Fmoc-2Nal-OH, Fmoc-D-Ala-OH, and Fmoc-Gly-OH are as follows:

[0717] Example 1: Synthesis of Compound 1

[0718] Step 1:

[0719] Compound 1a (3.00 g) was added to an HBr / AcOH (89.4 g) solution at 20 °C. The reaction mixture was stirred at 60 °C for 12 hours. NaHCO3 was added to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate. The extracted organic phase was washed with saturated brine and dried over anhydrous Na2SO4. After drying, the phase was filtered, concentrated, and purified to obtain compound 2a (1.00 g).

[0720] Step Two:

[0721] Compound 2a (500 mg) and compound 2a-1 (1.46 g) were dissolved in pyridine (5.00 mL), and POCl3 (709 mg) was added at 0 °C. The reaction was stirred at 0 °C for 1 hour. NaHCO3 was added to the reaction solution and extracted with DCM. The extracted organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified to obtain compound 3a (390 mg).

[0722] Step 3:

[0723] An aqueous solution of LiOH·H₂O (0.50 M, 4.00 mL) was slowly added to a methanol (3.00 mL) solution containing compound 3a (390 mg). The reaction mixture was stirred at 20 °C for 1 hour. HCl (1.00 M) was added to the reaction mixture to adjust the pH to 7, and compound 4a (350 mg) was prepared by reverse phase reaction.

[0724] Step Four:

[0725] Compound 4a (500 mg) was dissolved in DMF (2.50 mL), and then DMF (2.50 mL) containing 4a-1 (2.17 g), HATU (456 mg), and DIEA (2.23 g) were added sequentially. The reaction was stirred at 35 °C for 1 hour. Compound 5a (500 mg) was directly prepared from the reaction solution using a reverse-phase reaction.

[0726] Step 5:

[0727] Compound 5a (500 mg) was dissolved in DCM (5.00 mL), and TFA (7.67 g) was added. The reaction was stirred at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and compound Int A (173 mg) was prepared by reverse-phase reaction (TFA).

[0728] Step Six:

[0729] Compound 6a (2.00 g) was dissolved in DMF (20.0 mL), and K2CO3 (3.60 g) and allyl bromide (1.58 g) were added. The reaction was stirred at 20 °C for 12 hours. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate, and evaporated to dryness. After purification, compound 7a (2.30 g) was obtained.

[0730] Step Seven:

[0731] TFA (17.6 g) was slowly added to a DCM (11.5 mL) solution containing compound 7a (2.30 g). The reaction solution was stirred at 20 °C for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain compound 8a (1.50 g).

[0732] Step 8:

[0733] Peptide synthesis

[0734] The peptide was synthesized using standard Fmoc chemical methods.

[0735] 1) Weigh 0.20 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-D-Lys(Dde)-OH (0.20 mmol, 1.00 eq) into a reaction column. Add 20.0 mL of DCM, then add 0.80 mmol of DIEA dropwise. Adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20°C for 2 hours, add MeOH dropwise into the reaction column. After a nitrogen atmosphere of 30 minutes, purge the column until no liquid flows out. Add DMF to wash the column, then purge again until no liquid flows out.

[0736] 2) Deprotection: Add 20% piperidine / DMF (V:V) (40.0 mL) to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry it under vacuum to obtain the final resin.

[0737] 3) Coupling: Weigh Fmoc-D-Tyr(tBu)-OH (0.60 mmol, 3.00 eq) and HBTU (0.57 mmol, 2.85 eq) into the resin obtained in the previous step. Add 30.0 mL of DMF and then add DIEA (1.20 mmol) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20°C for 30 minutes, then remove the reaction solution, add DMF to wash, and drain the waste until no liquid flows out.

[0738] Repeat steps 2)-3) above to couple the following materials that require coupling in sequence:

[0739] Note:

[0740] Shrink the resin with MeOH (30.0 mL), drain the waste until no liquid flows out, and then dry the resin.

[0741] Note: Alloc removal conditions were: PhSiH3 (2.00 mmol), Pd(PPh3)4 (0.02 mmol).

[0742] Peptide cleavage:

[0743] At room temperature, the dried resin was added to the prepared cutting solution (90% TFA / 2.5% H2O / 5% TIS / 2.5% 3-Mpr) and cut for 2 hours. The solution was filtered, and the filtrate was added to ice-cold isopropyl ether for sedimentation and centrifugation, followed by washing with isopropyl ether. The solution was dried under vacuum for 2 hours to obtain the unpurified crude peptide.

[0744] Peptide purification:

[0745] The crude peptide was purified by preparative high performance liquid chromatography to obtain the final product compound 1 (15.8 mg, purity 98.7%).

[0746] LCMS: MS observed: [M+H] + =1560.7

[0747] HPLC: Purity: 98.7%

[0748] Example 2: Synthesis of Compound 2

[0749] Step 1:

[0750] At 0°C, thionyl chloride (17.2 mL) was slowly added dropwise to a solution of compound B-1a (10.0 g) in anhydrous methanol (200 mL). The reaction solution was heated to 65°C and reacted for 2 h. The methanol in the reaction solution was first removed by rotary evaporation. The concentrated crude product was washed with saturated sodium bicarbonate, then extracted with ethyl acetate. The combined organic phases were washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain solid compound B-2a (10.0 g).

[0751] Compound B-2a (3.00 g), compound B-3a (2.09 g), tetrakis(triphenylphosphine)palladium (651 mg), and cuprous iodide (107 mg) were dissolved in DMF (10.0 mL). DIEA (14.5 g) was added dropwise to the reaction mixture under nitrogen protection. The reaction mixture was then reacted at 80 °C for 2 hours under nitrogen protection. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography to obtain compound B-4a (2.70 g).

[0752] Step Two:

[0753] A wet palladium on carbon (500 mg) was added to an anhydrous methanol (100 mL) solution containing compound B-4a (2.30 g) under inert gas protection. Hydrogen was then displaced at 15 psi and the reaction mixture was reacted at 20 °C for 12 h under a hydrogen atmosphere. The reaction mixture was slowly filtered through diatomaceous earth, and the filtrate was concentrated to obtain compound B-5a (1.90 g).

[0754] Step 3:

[0755] Lithium hydroxide (397 mg) was added to a 1:1 mixture of tetrahydrofuran (4.00 mL) and water (4.00 mL) containing compound B-5a (380 mg). The reaction mixture was reacted at 20 °C for 1 h. The reaction mixture was poured into water (10.0 mL), the pH was adjusted to 6 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative column chromatography in a 0.05% TFA system to obtain compound B-6a (700 mg).

[0756] Step Four:

[0757] N,N-diisopropylethylamine (1.11 mL) was added to a solution of N,N-dimethylformamide (10.0 mL) containing compounds B-6a (700 mg), B-7a (700 mg), and HATU (1.21 g). The reaction solution was reacted at 20 °C for 1 h. The reaction solution was concentrated under vacuum and purified by preparative column chromatography in a 0.1% TFA system to obtain compound B-8a (1.00 g).

[0758] Step 5:

[0759] A 1:1 mixture of trifluoroacetic acid (4 mL) and dichloromethane (4 mL) was added to compound B-8a (1.00 g), and the reaction solution was reacted at 20 °C for 1 h. The reaction solution was concentrated under vacuum and purified by preparative column chromatography in a 0.05% TFA system to obtain Int B (828 mg, TFA).

[0760] Peptide synthesis: This peptide was synthesized using standard Fmoc chemical methods.

[0761] 1) Weigh 0.30 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and 0.30 mmol of Fmoc-D-Lys(Dde)-OH into a reaction column. Add 20.0 mL of DCM, then add 1.20 mmol of DIEA dropwise. Adjust the nitrogen atmosphere to ensure the resin bubbles evenly. After reacting at 20°C for 2 hours, add 0.60 mL of MeOH dropwise into the reaction column. After bubbling with nitrogen for 30 minutes, purge the column until no liquid flows out. Add DMF to wash the column, then purge again until no liquid flows out.

[0762] 2) Deprotection: Add 20% piperidine / DMF (V:V) (40.0 mL) to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry it under vacuum to obtain the final resin.

[0763] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.90 mmol) and HBTU (0.85 mmol) into the resin obtained in the previous step, add 30.0 mL of DMF, and then add DIEA (1.80 mmol) dropwise into the reaction column. Adjust the nitrogen atmosphere to make the resin bulge evenly. After reacting at 20 °C for 30 minutes, remove the reaction solution, add DMF to wash, and discharge the waste until no liquid flows out.

[0764] 4) Deprotection: Add 20% piperidine / DMF (V:V) (40.0 mL) to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry it under vacuum to obtain the final resin.

[0765] 5) Coupling of amino acids: Weigh 0.90 mmol of Fmoc-D-Lys(Alloc)-OH and 0.85 mmol of HBTU into the resin obtained in the previous step. Add 30.0 mL of DMF and then add 1.80 mmol of DIEA dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20 °C for 30 minutes, remove the reaction solution, add DMF to wash, and drain the waste until no liquid flows out.

[0766] 6) Deprotection: Add 20% piperidine / DMF (V:V) (40.0 mL) to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry it under vacuum to obtain the final resin.

[0767] 7) Coupling: Weigh Fmoc-D-Glu(tBu)-OH (0.90 mmol) and HBTU (0.85 mmol) into the resin obtained in the previous step. Add 30.0 mL of DMF and then add DIEA (1.80 mmol) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure the resin bulges evenly. After reacting at 20°C for 30 minutes, remove the reaction solution, add DMF to wash, and drain the waste until no liquid flows out.

[0768] 8) Deprotection: Add 20% piperidine / DMF (V:V) (40.0 mL) to the resin and agitate under nitrogen for 15 minutes. Wash the resin five times with DMF (40.0 mL) and dry under vacuum to obtain the resin.

[0769] 9) Boc Protection: Prepare the capping solution with a Boc anhydride:DIEA:DMF (V:V:V) ratio of 10:5:85 (volume ratio). Add 30.0 mL of the capping solution to the reaction column and adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20°C for 30 minutes, remove the reaction solution, add DMF to wash, and discharge waste until no liquid flows out.

[0770] 10) Alloc removal: Wash the resin three times with DMF (40.0 mL) and three times with DCM (40.0 mL). Add an appropriate amount of DCM (40.0 mL) and purge with nitrogen gas. Add PhSiH3 (3.00 mmol) and Pd(PPh3)4 (0.03 mmol) sequentially, and react. Wash the resin with DMF and dry under vacuum to obtain the resin.

[0771] 11) Coupling of chelating groups: Weigh DOTAGA (0.45 mmol, 1.50 eq) and HATU (0.42 mmol, 1.42 eq) into the resin obtained in the previous step. Add 30.0 mL of DMF, then add DIEA (0.90 mmol, 3.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20°C for 1 hour, remove the reaction solution, add DMF to wash, and discharge waste until no liquid flows out.

[0772] 12) De-Dde removal: Prepare a 3% hydrazine hydrate / DMF solution, add 40.0 mL of the hydrazine hydrate solution to the resin and agitate with nitrogen gas to stimulate the reaction. Wash the resin with DMF and dry it under vacuum to obtain the final resin.

[0773] 13) Ligand coupling: Weigh Int B (0.45 mmol) and HOAt (0.45 mmol) into the resin obtained in the previous step, add 30.0 mL of DMF, and then add DIC (0.45 mmol) dropwise into the reaction column. Adjust the nitrogen atmosphere to make the resin bulge evenly. React at 20 °C, remove the reaction solution, add DMF to wash, and discharge the waste until no liquid flows out.

[0774] 14) Shrink the resin 5 times with MeOH (30.0 mL), 3 minutes each time, drain the waste until no liquid flows out, pour out the resin and dry it for later use.

[0775] Peptide cleavage:

[0776] At room temperature, the dried resin was added to the prepared cutting solution (90% TFA / 2.5% H2O / 5% TIS / 2.5% 3-Mpr, 20 mL), and ultrasonically cut for 3 h. The solution was filtered, and the filtrate was added to ice-cold isopropyl ether (100 mL) for sedimentation and centrifugation, followed by washing twice with isopropyl ether (100 mL). The solution was dried under vacuum for 2 h to obtain the unpurified crude compound 2. The unpurified crude compound was purified by preparative high-performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain the final product compound 2 (15.0 mg, purity 98.2%).

[0777] LCMS: MS observed: [M+H] + =1451.6

[0778] HPLC: Purity: 98.2%

[0779] Example 3: Synthesis of Compound 3

[0780] Steps one through three:

[0781] The intermediate B-6a was prepared according to steps one through three of Example 2:

[0782] Step Four:

[0783] Compound C-2 (1.00 g) was added to a DMF (10.0 mL) solution containing compound C-1 (1.12 g) and HATU (4.51 g). After stirring for 10 min, DIEA (3.10 mL) was added, and the reaction solution was reacted at 25 °C for 12 h. The reaction solution was concentrated by rotary evaporation and purified by preparative column chromatography in a 0.1% TFA system to obtain compound C-3 (1.50 g).

[0784] Step 5:

[0785] TFA (4.00 mL) and DCM (4.00 mL) were added to compound C-3 (1.50 g), and the reaction solution was reacted at 20 °C for 0.5 h. The reaction solution was concentrated under vacuum to obtain crude brown oily compound C (3.40 g).

[0786] Step Six:

[0787] DIEA (1.59 mL) was added to a DMF (10.0 mL) solution containing compound B-6a (1.00 g), compound C (2.47 g), and HATU (1.73 g). The reaction solution was reacted at 20 °C for 1 h. The reaction solution was concentrated under vacuum and purified by preparative column chromatography in a 0.1% TFA system to obtain compound C-8a (700 mg).

[0788] Step Seven:

[0789] A 1:1 mixture of TFA (4 mL) and DCM (4 mL) was added to compound 8a (700 mg), and the reaction solution was reacted at 20 °C for 1 h. The reaction solution was concentrated under vacuum and purified by preparative column chromatography in a 0.1% TFA system to obtain Int C (343 mg).

[0790] Step 8:

[0791] t-BuOH (6.27 g) and DMAP (3.76 g) were added dropwise to DCM (100 mL) containing compound 3-1 (10.0 g), followed by DCC (17.5 g). The reaction mixture was reacted at 20 °C for 12 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain the crude product. Compound 3-2 (10.0 g) was obtained by column chromatography.

[0792] Step Nine:

[0793] NaOH (2.36 g) was added to a solution of THF (50 mL) and H2O (50 mL) containing compound 3-2 (10.0 g), and the reaction was carried out at 20 °C for 2 hours. The reaction solution was evaporated to dryness to obtain unpurified compound 3-3 (10.0 g).

[0794] Step 10:

[0795] BnBr (8.38 g) was added dropwise to DMF (110 mL) containing compound 3-3 (10.0 g), and the reaction was carried out at 20 °C for 2 hours. The reaction solution was poured into H2O (300 mL), extracted with ethyl acetate, and the organic phase was washed with brine. After drying with Na2SO4, the solution was filtered and concentrated to obtain the crude product. Column chromatography was used to obtain a colorless oil compound 3-4 (8.40 g).

[0796] Step Eleven:

[0797] NMM (1.19 g) and Ms₂O (2.05 g) were added dropwise to THF (20 mL) containing compound 3-4 (2.00 g) at 0 °C, and the reaction was carried out at 20 °C for 1 hour. The reaction solution was poured into H₂O, extracted with ethyl acetate, and the organic phase was washed with brine. After drying with Na₂SO₄, the solution was filtered and concentrated to give compound 3-5 (2.41 g).

[0798] Step Twelve:

[0799] K₂CO₃ (1.77 g) was added to 50 mL of DMF containing compounds 3-6 (3.30 g) and 3-5 (2.41 g), and the reaction was carried out at 20 °C for 24 hs. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. After reverse-phase purification and lyophilization under TFA conditions, compound 3-7 (3.50 g) was obtained.

[0800] Step Thirteen:

[0801] Pd / C (0.20 g) was added to 20 mL of MeOH containing compound 3-7 (2.00 g) under nitrogen atmosphere, and the mixture was purged three times with hydrogen. The reaction was carried out at 25 °C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. After reverse-phase purification and lyophilization under TFA conditions, compound S-DotaGa (1.35 g) was obtained.

[0802] Step Fourteen:

[0803] Peptide synthesis:

[0804] This peptide was synthesized using standard Fmoc chemical methods.

[0805] 1) Weigh 0.20 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-D-Lys(Dde)-OH (0.20 mmol, 1.00 eq) into the reaction column. Add 20.0 mL of DCM, then add DIEA (0.80 mmol, 4.00 eq) dropwise. Adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20°C for 2 hours, add MeOH dropwise into the reaction column, agitate with nitrogen for 30 minutes, and then purge the waste. Wash with DMF and purge the waste again.

[0806] 2) Deprotection: Add 20% piperidine / DMF (V:V) (40.0 mL) to the resin and agitate with nitrogen. Wash the resin with DMF and dry it under vacuum to obtain the final resin.

[0807] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.60 mmol, 3.00 eq) and HBTU (0.57 mmol, 2.85 eq) into the resin obtained in the previous step. Add 30.0 mL of DMF and then add DIEA (1.20 mmol, 6.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20 °C for 30 minutes, then remove the reaction solution, add DMF to wash, and discharge waste until no liquid flows out.

[0808] Repeat steps 2)-3) above to couple the following amino acids:

[0809] Note:

[0810] Shrink the resin with MeOH for 3 minutes each time, drain the waste until no liquid flows out, pour out the resin and dry it for later use.

[0811] Note: Alloc removal conditions were: PhSiH3 (2.00 mmol, 10.0 eq), Pd(PPh3)4 (0.02 mmol, 0.10 eq).

[0812] The conditions for Dde removal are: 3% hydrazine hydrate / DMF (mass fraction).

[0813] Peptide cleavage:

[0814] At room temperature, the dried resin was added to the prepared cutting solution (90% TFA / 2.5% H2O / 5% TIS / 2.5% 3-Mpr), and ultrasonically cut for 3 hours. The solution was filtered, and the filtrate was added to ice-cold isopropyl ether for sedimentation and centrifugation, followed by washing with isopropyl ether. The solution was dried under vacuum for 2 hours to obtain the crude peptide, unpurified compound 3.

[0815] Peptide purification:

[0816] The crude peptide was purified by preparative high performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain the final product, compound 3 (16.0 mg, 10.23 μmol, purity: 97.3%, TFA).

[0817] LCMS: MS observed: [M+H] + =1465.7

[0818] HPLC: Purity: 97.3%

[0819] Example 4: Synthesis of Compound 4

[0820] Peptide synthesis:

[0821] This peptide was synthesized using standard Fmoc chemical methods.

[0822] 1) Weigh 0.20 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-D-Lys(Dde)-OH (0.20 mmol, 1.00 eq) into the reaction column. Add 20.0 mL of DCM, then add DIEA (0.80 mmol, 4.00 eq) dropwise. Adjust the nitrogen atmosphere to ensure the resin agitates evenly. After reacting at 20°C for 2 hours, add 0.40 mL of MeOH dropwise into the reaction column. After agitating with nitrogen for 30 minutes, purge the column until no liquid flows out. Add DMF to wash the column, then purge again until no liquid flows out.

[0823] 2) Deprotection: Add 20% piperidine / DMF (V:V) (40.0 mL) to the resin and agitate under nitrogen for 15 minutes. Wash the resin five times with DMF and dry it to obtain the final resin.

[0824] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.60 mmol, 3.00 eq) and HBTU (0.57 mmol, 2.85 eq) into the resin obtained in the previous step. Add 30.0 mL of DMF and then add DIEA (1.20 mmol, 6.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20 °C for 30 minutes, then remove the reaction solution, add DMF to wash, and discharge waste until no liquid flows out.

[0825] Repeat steps 2-3 above to couple the following amino acids:

[0826] Note:

[0827] Shrink the resin with MeOH for 3 minutes each time, drain the waste until no liquid flows out, pour out the resin and dry it for later use.

[0828] Note: Alloc removal conditions were: PhSiH3 (2.00 mmol, 10.0 eq), Pd(PPh3)4 (0.02 mmol, 0.10 eq).

[0829] The conditions for Dde removal are: 3% hydrazine hydrate / DMF (mass fraction).

[0830] Peptide cleavage:

[0831] At room temperature, the dried resin was added to the prepared cutting solution (90% TFA / 2.5% H2O / 5% TIS / 2.5% 3-Mpr), and ultrasonically cut for 3 hours. The solution was filtered, and the filtrate was added to ice-cold isopropyl ether for sedimentation and centrifugation, followed by washing twice with isopropyl ether. The solution was dried under vacuum for 2 hours to obtain the crude peptide, unpurified compound 4.

[0832] Peptide purification:

[0833] The crude peptide was purified by preparative high performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain the final product compound 4 (12.0 mg, purity 97.5%, TFA).

[0834] LCMS: MS observed: [M+H] + =1465.7

[0835] HPLC:R t =9.53 min, purity: 97.5%

[0836] Example 5: Synthesis of Compound 5

[0837] Step 1:

[0838] DIEA (8.15 g), HOBt (3.31 g), and EDCI (4.16 g) were added to compound 5-2 (3.97 g) dissolved in 20.0 mL of DMF. Then, compound 5-1 (2.00 g) was added at 0 °C. The reaction solution was stirred at 25 °C for 12 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified to obtain the oily compound 5-3 (1.23 g).

[0839] Step Two:

[0840] Compound 5-3 (1.95 g) was dissolved in HCl / dioxane (1.00 M, 20.0 mL), and the reaction solution was reacted at 20 °C for 0.5 h. The reaction solution was diluted with ACN (20.0 mL) and water (20.0 mL) and lyophilized to give unpurified oily compound 5-4 (1.65 g).

[0841] Step 3:

[0842] DIEA (3.59 g) and HBTU (3.68 g) were added to compound 5-5 (2.45 g) dissolved in 20.0 mL DMF. Then, compound 5-4 was added at 0 °C. The reaction solution was stirred at 25 °C for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by rotary evaporation to obtain oily compound 5-6 (830 mg).

[0843] Step Four:

[0844] Compounds 5-6 were dissolved in HCl / dioxane (1M, 8.00 mL) and stirred at 25°C for 3 hours. Triethylamine (6.54 g) and tetrahydrofuran-2,5-dione (153 mg) were then added, and the reaction mixture was stirred at 25°C for another 3 hours. 1M HCl (10.0 mL) was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by rotary evaporation to give solid compound 5-7 (483 mg).

[0845] Step 5:

[0846] Step Six:

[0847] Polypeptide synthesis

[0848] This peptide was synthesized using standard Fmoc chemical methods.

[0849] 1) Weigh 0.30 mmol of 2-CTC resin (degree of substitution Sub = 0.30 mmol / g) and 0.30 mmol of Fmoc-D-Lys(Dde)-OH into the reaction column. Add 20.0 mL of DCM, then add 1.20 mmol of DIEA dropwise. Adjust the nitrogen atmosphere to ensure the resin agitates evenly. After reacting at 20°C for 2 hours, add MeOH dropwise into the reaction column, agitate with nitrogen for 30 minutes, and then purge. Add DMF to wash, and purge again until no liquid flows out.

[0850] 2) Deprotection: Add 20% piperidine / DMF (V:V) (30.0 mL) to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry it to obtain the final resin.

[0851] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.90 mmol) and HBTU (0.85 mmol) into the resin obtained in the previous step. Add 30.0 mL of DMF, then add DIEA (1.80 mmol) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20°C for 30 minutes. Remove the reaction solution, add DMF, and drain the waste until no liquid flows out.

[0852] Repeat steps 2-3 above to couple the following amino acids:

[0853] Note:

[0854] 4) Coupling of amino acids: Compound 7 (280 mg) was dissolved in DCM (3.00 mL), and HOSu (56.8 mg) was added and stirred for 5 minutes. Then DCC (101 mg) was added dropwise. The reaction was stirred at 25 °C for half an hour, filtered, and the reaction solution was dried with nitrogen gas and then dissolved in DMF. The solution was poured into the resin obtained in the previous step, and DIEA was added dropwise into the reaction column. The nitrogen gas was adjusted to make the resin bulge evenly. The reaction was carried out at 20 °C for 1 hour. The reaction solution was removed, DMF was added for washing, and waste was discharged until no liquid flowed out.

[0855] Shrink the resin with MeOH, discharge the waste until no more liquid flows out, then pour out the resin and dry it.

[0856] Note: Alloc removal conditions were: PhSiH3 (5.00 mmol), Pd(PPh3)4 (0.05 mmol).

[0857] The conditions for Dde removal are: 3% hydrazine hydrate / DMF (mass fraction).

[0858] Peptide cleavage:

[0859] At room temperature, the dried resin was added to the prepared cutting solution (90% TFA / 2.5% H2O / 5% TIS / 2.5% 3-Mpr, 30.0 mL), and ultrasonically cut for 3 h. The solution was filtered, and the filtrate was added to ice-cold isopropyl ether for sedimentation and centrifugation, followed by washing twice with isopropyl ether. The solution was dried under vacuum for 2 h to obtain unpurified compound 5.

[0860] Polypeptide purification:

[0861] The crude peptide was purified by preparative high performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain the final product compound 5 (14.0 mg, 96.5% purity, TFA).

[0862] LCMS:MS cal.:1439.7,MS observed:[M-H2O+H] + =1422.7

[0863] HPLC: Purity: 96.5%.

[0864] Example 6: Synthesis of Compound 6

[0865] Peptide synthesis:

[0866] The peptide was synthesized using standard Fmoc chemical methods.

[0867] 1) Weigh 0.20 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and 0.20 mmol of Fmoc-D-Lys(Dde)-OH into a reaction column. Add 10.0 mL of DCM, then add 0.80 mmol of DIEA dropwise. Adjust the nitrogen atmosphere to ensure the resin bubbles evenly. After reacting at 20°C for 2 hours, add MeOH dropwise into the reaction column. After bubbling with nitrogen for 30 minutes, purge the column until no liquid flows out. Add DMF to wash the column, then purge again until no liquid flows out.

[0868] 2) Deprotection: Add 20% piperidine / DMF (V:V) (30.0 mL) to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry it under vacuum to obtain the final resin.

[0869] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.60 mmol) and HBTU (0.57 mmol) into the resin obtained in the previous step. Add 30.0 mL of DMF, then add DIEA (1.20 mmol) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20°C for 30 minutes. Remove the reaction solution, add DMF to wash, and drain the waste until no liquid flows out.

[0870] Repeat steps 2-3 above to couple the following amino acids:

[0871] Note:

[0872] Shrink the resin with MeOH, discharge the waste until no more liquid flows out, pour out the resin and dry it for later use.

[0873] Note: Alloc / Allyl removal conditions were: PhSiH3 (5.00 mmol, 10.0 eq), Pd(PPh3)4 (0.05 mmol, 0.10 eq);

[0874] The conditions for Dde removal are: 3% hydrazine hydrate / DMF by mass.

[0875] Peptide cleavage:

[0876] At room temperature, the dried resin was added to the prepared cutting solution (90% TFA / 2.5% H2O / 5% TIS / 2.5% 3-Mpr, 20.0 mL), and ultrasonically heated to 35°C for 3 h. The solution was filtered, and the filtrate was added to ice-cold isopropyl ether for sedimentation and centrifugation, followed by washing with isopropyl ether. The solution was dried under vacuum for 2 h to obtain unpurified compound 6.

[0877] Peptide purification:

[0878] The unpurified compound 6 was purified by preparative high performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain the final product, compound 6 (13.0 mg, 96.5% purity, TFA).

[0879] LCMS:MS cal.:1392.6,MS observed:[M+H] + =1393.6

[0880] HPLC:R t = 9.76 min, purity: 96.5%

[0881] Example 7: Synthesis of Compound 7

[0882] Steps one through five:

[0883] Prepare intermediate Int A, following steps one through five of Example 1.

[0884] Step Six:

[0885] Prepare intermediate 7a, following step six in Example 1.

[0886] Synthesis of compound 7:

[0887] The peptide was synthesized using standard Fmoc chemical methods.

[0888] 1) Weigh 0.30 mmol of 2-CTC resin (degree of substitution Sub = 0.30 mmol / g) and Fmoc-D-Lys(Dde)-OH (0.30 mmol, 1.00 eq) into a reaction column. Add 20.0 mL of DCM, then add DIEA (1.20 mmol, 4.00 eq) dropwise. Adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20°C for 2 hours, add MeOH (1.00 mL) dropwise into the reaction column. After agitating with nitrogen for 30 minutes, purge the column until no liquid flows out. Add DMF to wash the column, then purge again until no liquid flows out.

[0889] 2) Deprotection: Add 30.0 mL of a 20% piperidine / DMF solution (V:V) to the resin and agitate under nitrogen for 15 minutes. Wash the resin five times with DMF and dry it under vacuum to obtain the final resin.

[0890] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.90 mmol, 3.00 eq) and HBTU (0.85 mmol, 2.85 eq) into the resin obtained in the previous step. Add 30.0 mL of DMF and then add DIEA (1.80 mmol, 6.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20 °C for 30 minutes, then remove the reaction solution, add DMF to wash, and drain the waste until no liquid flows out.

[0891] Repeat steps 2-3 above to couple the following amino acids:

[0892] Note:

[0893] Shrink the resin with MeOH (100mL) for 3 minutes each time, drain the waste until no liquid flows out, pour out the resin and dry it for later use.

[0894] Note: Alloc removal conditions were: PhSiH3 (5.00 mmol, 10.0 eq), Pd(PPh3)4 (0.05 mmol, 0.10 eq);

[0895] The conditions for removing Dde were: 3% hydrazine hydrate / DMF by mass.

[0896] Peptide cleavage and purification:

[0897] At room temperature, the dried resin was added to the prepared cutting solution (90% TFA / 2.5% H2O / 5% TIS / 2.5% 3-Mpr, 30.0 mL), and cutting was performed for 2 h. After filtration and purification, the final product compound 7 (6.2 mg, 95.0% purity, TFA) was obtained.

[0898] LCMS:R t =1.03min, MS cal.:1661.83, MS observed:[M+2H] 2+ =831.3

[0899] HPLC:R t =11.4 min, purity: 95.0%

[0900] Example 8: Synthesis of Compound 8

[0901] Steps one through three:

[0902] Prepare intermediate 4a, following steps one to three in Example 1.

[0903] Step Four:

[0904] Compound 4a (578 mg), HATU (659 mg), and DIEA (1.01 mL) were dissolved in DMF (6.00 mL), and compound C (367 mg) dissolved in DIEA (1.01 mL) was added to the solution. The reaction was stirred at 35 °C for 1 hour. Compound D (481 mg) was obtained after purification.

[0905] Step Two:

[0906] Compound D (481 mg) was dissolved in DCM (4.00 mL), and TFA (1.00 mL) was added. The reaction was stirred at 25 °C for 1 hour. Purification yielded Int D (168 mg, HCl).

[0907] Peptide synthesis:

[0908] The peptide was synthesized using standard Fmoc chemical methods.

[0909] 1) Weigh 0.30 mmol of 2-CTC resin (degree of substitution Sub = 0.30 mmol / g) and Fmoc-D-Lys(Dde)-OH (0.30 mmol, 1.00 eq) into the reaction column. Add 20.0 mL of DCM, then add DIEA (1.20 mmol, 4.00 eq) dropwise. Adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20°C for 2 hours, add MeOH (1.00 mL) dropwise into the reaction column. Agitate with nitrogen for 30 minutes, then purge until no liquid flows out. Wash with DMF and purge again.

[0910] 2) Deprotection: Add 20% piperidine / DMF (V:V) (30.0 mL) to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry it to obtain the final resin.

[0911] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.90 mmol, 3.00 eq) and HBTU (0.85 mmol, 2.85 eq) into the resin obtained in the previous step. Add 30.0 mL of DMF and then add DIEA (1.80 mmol, 6.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20 °C for 30 minutes, then remove the reaction solution, add DMF to wash, and drain the waste until no liquid flows out.

[0912] Repeat steps 2-3 above to couple the following amino acids:

[0913] Note:

[0914] Shrink the resin with MeOH (100mL) for 3 minutes each time, drain the waste until no liquid flows out, pour out the resin and dry it for later use.

[0915] Note: Alloc removal conditions were: PhSiH3 (5.00 mmol, 10.0 eq), Pd(PPh3)4 (0.05 mmol, 0.10 eq), 10 min * 3

[0916] The conditions for Dde removal are: 3% hydrazine hydrate / DMF, 15 min * 2

[0917] Peptide cleavage and purification:

[0918] At room temperature, the dried resin was added to the prepared cutting solution (90% TFA / 2.5% H2O / 5% TIS / 2.5% 3-Mpr, 30.0 mL), cut and filtered, and the filtrate was directly purified. The final product, compound 8 (5.2 mg, 95.1% purity, TFA), was obtained by preparative high-performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile).

[0919] LCMS:R t =1.03min,MS cal.:1675.85,MS observed:[M+2H] 2+ =838.4

[0920] HPLC:R t =11.4 min, purity: 95.1%.

[0921] Example 9: Synthesis of compound 9

[0922] Step 1:

[0923] Peptide synthesis

[0924] This peptide was synthesized using standard Fmoc chemical methods:

[0925] Weigh 3.00 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-D-Ala-OH (3.00 mmol, 1.00 eq) into a reaction column. Add 150.0 mL of DCM, then add DIEA (12.0 mmol, 4.00 eq) dropwise. Purge the resin with nitrogen to induce uniform bubbling. After reacting at 20 °C for 2 hours, add 6.00 mL of MeOH dropwise into the column. Purge with nitrogen for 30 minutes, then purge until no liquid flows out. Wash with DMF, then purge again until no liquid flows out.

[0926] Deprotection: Add 20% piperidine / DMF (150.0 mL) (V:V) to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF.

[0927] Amino acid coupling: Weigh Fmoc-Gly-OH (9.00 mmol, 3.00 eq) and HBTU (8.55 mmol, 2.85 eq) into the above resin, add 90.0 mL of DMF, and then add DIEA (18.0 mmol, 6.00 eq) dropwise into the reaction column. Nitrogen gas is used to uniformly bulge the resin. The reaction is carried out at 20 °C for 30 minutes. The reaction solution is then removed, and the column is washed with DMF. Waste is discharged until no liquid flows out.

[0928] Deprotection: Add 20% piperidine / DMF (150.0 mL) (V:V) to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry under vacuum to obtain the final resin.

[0929] Amino acid coupling: Weigh Fmoc-2Nal-OH (9.00 mmol, 3.00 eq) and HBTU (8.55 mmol, 2.85 eq) into the above resin, add 90.0 mL of DMF, and then add DIEA (18.0 mmol, 6.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20 °C for 30 minutes. Remove the reaction solution, wash with DMF, and drain the waste until no liquid flows out.

[0930] Deprotection: Add 20% piperidine / DMF (150.0 mL) (V:V) to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry under vacuum to obtain the final resin.

[0931] Amino acid coupling: Weigh 4.50 mmol (1.50 eq) of 8-(tert-butoxy)-8-oxomethyleneoctanoic acid into the above resin, add 90.0 mL of DMF, and then add DIEA (9.00 mmol (3.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20 °C for 30 minutes. Remove the reaction solution, wash with DMF, and drain the waste until no liquid flows out.

[0932] Shrink the resin with MeOH, discharge the waste until no more liquid flows out, pour out the resin and dry it for later use.

[0933] Peptide cleavage:

[0934] At room temperature, the prepared cutting fluid (20% HFIP in DCM, 30.0 mL) was added to the dried resin and agitated with nitrogen. The mixture was filtered, and the filtrate was concentrated to obtain crude product 9-1.

[0935] Peptide purification:

[0936] The crude peptide was purified by preparative high performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain compound 9-1 (1.15 g).

[0937] Step Two:

[0938] HATU (1.23 g, 2.00 eq) and compound 9-2 (273 mg, 1.00 eq) were added to a DMF (9.00 mL) solution, followed by compound 9-1 (900 mg, 1.00 eq). After stirring for 30 min, DIEA (628 mg, 4.86 mmol, 846 μL, 3.00 eq) was added, and the mixture was stirred at 20 °C for 2 h. The mixture was then purified directly by high performance liquid chromatography (0.075% TFA system) and lyophilized to obtain compound 9-3 (835 mg).

[0939] Step 3:

[0940] Compound 3a (0.35 g, 1.00 eq) and formic acid solution (14.3 mg, 4.00 mL) were added to DCM (1.00 mL). The mixture was then stirred at 20 °C for 2 hours. The reaction mixture was dried under nitrogen and concentrated. The purified lyophilized product was Int E (140 mg).

[0941] Step Four:

[0942] Int E (150 mg, 1.00 eq) was dissolved in DCM (2.00 mL), followed by the addition of DCC (54.3 μL, 1.10 eq) and pentafluorophenol (49.4 mg, 1.10 eq). The mixture was stirred at 20 °C for 1 hour. The mixture was purified and lyophilized to obtain Int E-1 (125 mg).

[0943] Step 5:

[0944] Peptide synthesis:

[0945] This peptide was synthesized using standard Fmoc chemical methods.

[0946] Weigh 1.00 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-D-Lys(Cbz)-OH (1.00 mmol, 1.00 eq) into the reaction column. Add 60.0 mL of DCM, then add DIEA (4.00 mmol, 4.00 eq) dropwise. Adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20°C for 2 hours, add 2.00 mL of MeOH dropwise into the reaction column. After agitating with nitrogen for 30 minutes, purge the column until no liquid flows out. Add DMF to wash the column, then purge again until no liquid flows out.

[0947] Deprotection: Add 20% piperidine / DMF (100.0 mL) (V:V) to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry under vacuum to obtain the final resin.

[0948] Amino acid coupling: Weigh Fmoc-D-Tyr(tBu)-OH (3.00 mmol, 3.00 eq) and HATU (2.85 mmol, 2.85 eq) into the above resin. Add 100.0 mL of DMF, then add DIEA (3.00 mmol, 3.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20°C for 30 minutes. Remove the reaction solution, add DMF to wash for 1 minute each time, and drain the waste until no liquid flows out.

[0949] Repeat steps 2-3 above to couple the following amino acids:

[0950] Note:

[0951] Shrink the resin with MeOH (300mL), drain the waste until no liquid flows out, pour out the resin and dry it for later use.

[0952] Note: The conditions for Dde removal are: 3% hydrazine hydrate / DMF, 15 min * 2

[0953] Peptide cleavage:

[0954] At room temperature, the dried resin was added to the prepared cutting solution (92.5% TFA / 2.5% H2O / 2.5% TIS / 2.5% 3-Mpr, 30.0 mL), and cutting was performed for 2 hours. The solution was then filtered and purified to obtain crude product 9-4.

[0955] Peptide purification:

[0956] The crude peptide was purified by preparative high performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain compound 9-4 (300 mg, TFA).

[0957] Step Six:

[0958] Compound 9-4 (102 mg, 1.05 eq) and Int E-1 (50.0 mg, 1.10 eq) were dissolved in DMF (2.00 mL) and added to DIEA (20.3 μL, 2.00 eq). The mixture was stirred at 25 °C for 12 hours. The mixture was then directly purified and lyophilized to give compound 9-5 (125 mg).

[0959] [Corrected according to Rule 91, December 17, 2025] Step Seven:

[0960] Compound 9-5 (95.0 mg, 1.00 eq) was dissolved in DMF (2.00 mL) and piperidine (0.20 mL, 7.55 eq) was added. The mixture was stirred at 20 °C for 1 hour. The mixture was then directly purified and lyophilized to give compound 9 (10.4 mg, purity 97.0%, TFA).

[0961] LCMS: Rt=1.06min, MS cal: 1547.7, MS observed: [M]+=1547.7

[0962] HPLC: Rt = 8.43 min, purity 97.0%

[0963] Example 10: Synthesis of compound 10

[0964] Step 1:

[0965] This peptide was prepared using the standard Fmoc solid-phase peptide synthesis method. Specifically, starting amino acids were immobilized on 2-CTC resin, and the Fmoc protecting groups were removed using a piperidine / dimethylformamide system. Subsequently, the desired amino acids were sequentially coupled, and the deprotection and coupling steps were repeated until the target polypeptide chain was synthesized. After synthesis, the peptide chain was cleaved using a fluoroisopropanol (HFIP) system, the filtrate was collected, and the solvent was removed by rotary evaporation to obtain the crude compound 10⁻¹.

[0966] Step Two:

[0967] Compound c and compound 10-1 were reacted in DMF solvent in the presence of condensing agent HATU and organic base DIEA at room temperature. The reaction solution was extracted, filtered, and concentrated to obtain compound 10-2.

[0968] Step 3:

[0969] Compound 10-2 was dissolved in dichloromethane, formic acid was added, and the mixture was stirred at room temperature. The reaction solution was concentrated, and the crude product was purified by reversed-phase column chromatography and lyophilized to obtain compound 10-3.

[0970] Step Four:

[0971] Compound 10⁻³ was dissolved in dichloromethane, and dicyclohexylcarbodiimide (DCC) and pentafluorophenol were added. The mixture was stirred at room temperature. The reaction solution was concentrated, and the crude product was purified by high-performance liquid chromatography and lyophilized to obtain compound 10⁻⁴.

[0972] Step 5:

[0973] This peptide was synthesized using standard Fmoc chemistry. Solid-phase synthesis was performed using 2-CTC resin as the immobilizer and the Fmoc strategy. First, Fmoc-D-Lys(Boc)-OH was coupled to the resin. After deprotection, Fmoc-D-Tyr(tBu)-OH, Dde-D-Lys(Fmoc)-OH, DOTA, and Fmoc-D-Glu(tBu)-OH amino acid monomers were sequentially coupled, all in the presence of conventional condensing agents (HATU / HBTU or DIC / DIEA). If necessary, the Dde protecting group was removed using a 3% hydrazine hydrate / DMF solution. After synthesis, the resin was washed and dried to obtain the resin-bound target peptide intermediate. The dried resin was then treated with a TFA-containing cleavage solution to cleave the peptide from the resin. After filtering to remove the resin, the filtrate was precipitated, centrifuged, and washed to obtain the crude peptide.

[0974] The crude peptide was purified by preparative high performance liquid chromatography (mobile phase: water / acetonitrile containing TFA), the target component was collected and lyophilized to obtain the final peptide 10⁻⁵ with a purity of approximately 100%.

[0975] LCMS:MS cal.:1174.55,MS observed:[M+H] + =1175.6)

[0976] HPLC:R t = 8.12min, purity: 100%

[0977] Step Six:

[0978] Compounds 10-5 and 10-4 were dissolved in dimethylformamide (DMF), and the base DIEA was added. The mixture was stirred at room temperature. The reaction solution was concentrated, and the crude product was purified by reversed-phase column chromatography and lyophilized to obtain compound 10-6.

[0979] Step Seven:

[0980] Compound 10-6 was deprotected under piperidine / dimethylformamide conditions. After the reaction was complete, the reaction solution was purified by high-performance liquid chromatography and lyophilized to obtain the target compound 10 (trifluoroacetate).

[0981] LCMS:MS cal:1623.8,MS observed:[M+H] 2+ =1624.8

[0982] HPLC:R t =7.65min, purity: 96.42%

[0983] Example 11: Synthesis of compound 11

[0984] Step 1:

[0985] Solid-phase synthesis was performed using 2-CTC resin as the support and employing the Fmoc strategy. Fmoc-D-Lys(Dde)-OH, Fmoc-D-Tyr(tBu)-OH, Alloc-D-Lys(Fmoc)-OH, DOTA(tBu)3, Fmoc-D-Glu(OtBu)-OH, and allyl octanoic acid amino acid / modification units were sequentially coupled to the solid-phase synthesis resin. The coupling reactions used HBTU, HATU, or DIC as condensing agents, in conjunction with DIEA. If necessary, Dde / Alloc deprotection was achieved using 3% hydrazine hydrate / DMF or PhSiH3 / Pd(PPh3)4 conditions. Finally, pentafluorophenol ester modification was introduced to obtain the modified peptide resin. The target peptide was cleaved from the resin by treatment with a TFA / water / TIS / 3-Mpr mixed cleavage solution. The crude product was precipitated with isopropyl ether, centrifuged, and dried to obtain the crude peptide compound. The crude peptide was purified by preparative high performance liquid chromatography (mobile phase: 0.075% TFA water / acetonitrile) and lyophilized to obtain compound 11-1.

[0986] Step Two:

[0987] Intermediate compound c was reacted with compound 11-2 in DMF solvent under HATU / DIEA conditions to generate compound 11-3. After the reaction was completed, the mixture was quenched with water and extracted. The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain compound 11-3.

[0988] Compound 11-3 was dissolved in acetonitrile, and TsOH·H2O was added. The mixture was stirred at 45°C until the starting material was completely converted. The reaction solution was then concentrated to obtain compound 11-4.

[0989] Compound 11-4 and compound 11-1 were subjected to a condensation reaction in DMF solution under DIEA conditions. After the reaction was completed, the target compound 11 (TFA salt) was obtained by purification by sedimentation, centrifugation and reversed-phase preparative high-performance liquid chromatography (TFA mobile phase system).

[0990] LCMS:MS cal.:1446.70,MS observed:1447.6

[0991] HPLC: R t=4.925min, purity=95.0%

[0992] Example 12: Synthesis of compound 12

[0993] Step 1:

[0994] Peptides were constructed using the standard Fmoc solid-phase synthesis method. Fmoc-D-Lys(Dde)-OH was loaded onto 2-CTC resin, followed by sequential coupling with Fmoc-D-Tyr(tBu)-OH, Alloc-D-Lys(Fmoc)-OH, DOTA(tBu)3, Fmoc-D-Glp-OH, allyl octanoic acid, and pentafluorophenol ester. HBTU, HATU, or DIC were used as condensation reagents during the coupling process, and Dde or Alloc deprotection was achieved, if necessary, under 3% hydrazine hydrate / DMF or PhSiH3 / Pd(PPh3)4 conditions. After coupling, the peptides were cleaved from the resin using a TFA / water / TIS / 3-Mpr mixture. The crude product was precipitated with isopropyl ether, centrifuged, and dried to obtain the crude peptide compound. The crude peptide compound was purified by preparative high-performance liquid chromatography (mobile phase: 0.075% TFA / water / acetonitrile) and lyophilized to obtain compound 12-1.

[0995] Step Two:

[0996] Compound 11-4 and compound 12-1 were subjected to a condensation reaction in DMF solution under alkaline conditions. After the reaction was completed, the target compound 12 was obtained by purification by sedimentation, centrifugation, and reversed-phase preparative high-performance liquid chromatography (TFA mobile phase system).

[0997] LCMS:MS cal.:1428.69,MS observed:[M+H] + =1429.79

[0998] HPLC: R t =7.77min, purity=98.4%

[0999] Example 13 Radiolabeling

[1000] 13.1 68 Labeling process of Ga-compound 1

[1001] Add 1 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL of aqueous solution of compound 1 (containing 60 μg of compound 1), mix thoroughly, and then add 1 mL of... 68The GaCl3 solution was reacted with 0.1M hydrochloric acid at 25°C for 15 min, then the reaction was terminated. The reaction solution was diluted with 5 mL of physiological saline, filtered, and a sample was taken for analysis. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >90%.

[1002] 68 The results of radiometric thin-layer chromatography of Ga-compound 1 are shown in Figure 1.

[1003] 13.2 177 Lu-compound 2 labeling process

[1004] Add 0.2 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to the reaction flask, then add 60 μL of aqueous solution of compound 2 (containing 60 μg of compound 2), mix thoroughly, and then add 0.2 mL of... 177 The reaction solution of LuCl3 in 0.05M hydrochloric acid was reacted at 80℃ for 15 min, then the reaction was terminated, and samples were taken for analysis. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >90%.

[1005] 177 The results of radiometric thin-layer chromatography of Lu-compound 2 are shown in Figure 2.

[1006] 13.3 68 Ga-compound 3 labeling process

[1007] Add 1.6 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL of aqueous solution of compound 3 (containing 60 μg of compound 3), mix thoroughly, and add 1 mL of... 68 The GaCl3 solution was reacted with 0.1M hydrochloric acid at 100°C for 10 min, then the reaction was terminated. The reaction solution was diluted with 5 mL of physiological saline, filtered, and a sample was taken for analysis. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >90%.

[1008] 68 The results of radiometric thin-layer chromatography of Ga-compound 3 are shown in Figure 3.

[1009] 13.4 177 Lu-compound 3 labeling process

[1010] Add 0.05 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to the reaction flask, then add 60 μL of aqueous solution of compound 3 (containing 60 μg of compound 3), mix thoroughly, and then add 0.05 mL of... 177The reaction solution of LuCl3 in 0.05M hydrochloric acid was reacted at 80℃ for 15 min, the reaction was terminated, and a sample was taken for analysis. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >90%.

[1011] 177 The results of radiometric thin-layer chromatography of Lu-compound 3 are shown in Figure 4.

[1012] 13.5 68 Ga-compound 4 labeling process

[1013] Add 1 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL of aqueous solution of compound 4 (containing 60 μg of compound 4), mix thoroughly, and add 1 mL of... 68 The GaCl3 solution was reacted with 0.1M hydrochloric acid at 100°C for 10 min. The reaction solution was then diluted with 5 mL of physiological saline, filtered, and a sample was taken for analysis. The radiochemical purity of the product was determined using Radio-iTLC, and the radiochemical purity was >90%.

[1014] 68 The results of radiometric thin-layer chromatography of Ga-compound 4 are shown in Figure 5.

[1015] 13.6 177 Lu-compound 4 labeling process

[1016] Add 0.05 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to the reaction flask, then add 60 μL of aqueous solution of compound 4 (containing 60 μg of compound 4), mix thoroughly, and then add 0.05 mL of... 177 The reaction solution of LuCl3 in 0.05M hydrochloric acid was reacted at 80℃ for 15 min, then the reaction was terminated, and samples were taken for analysis. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >90%.

[1017] 177 The results of radiometric thin-layer chromatography of Lu-compound 4 are shown in Figure 6.

[1018] 13.7 68 Ga-compound 5 labeling process

[1019] Add 1 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL of aqueous solution of compound 5 (containing 60 μg of compound 5), mix thoroughly, and add 1 mL of... 68The GaCl3 solution was reacted with 0.1M hydrochloric acid at 100°C for 10 min, then the reaction was terminated. The reaction solution was diluted with 5 mL of physiological saline, filtered, and a sample was taken for analysis. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >90%.

[1020] 68 The results of radiometric thin-layer chromatography of Ga-compound 5 are shown in Figure 7.

[1021] 13.8 68 Ga-compound 6 labeling process

[1022] Add 1 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL of aqueous solution of compound 6 (containing 60 μg of compound 6), mix thoroughly, and add 1 mL of... 68 The GaCl3 solution was reacted with 0.1M hydrochloric acid at 80°C for 10 min, then the reaction was terminated. The reaction solution was diluted with 5 mL of physiological saline, filtered, and a sample was taken for analysis. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >90%.

[1023] 68 The radiometric thin-layer chromatography results of Ga-compound 6 are shown in Figure 8.

[1024] 13.9 68 Ga-compound 7 labeling process

[1025] Add 1 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL of aqueous solution of compound 7 (containing 60 μg of compound 7), mix thoroughly, and add 1 mL of... 68 The GaCl3 solution was reacted with 0.1M hydrochloric acid at 80°C for 10 min, then the reaction was terminated. The reaction solution was diluted with 5 mL of physiological saline, filtered, and a sample was taken for analysis. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >90%.

[1026] 68 The results of radiometric thin-layer chromatography of Ga-compound 7 are shown in Figure 9.

[1027] 13.10 177 Lu-compound 7 labeling process

[1028] Add 1 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL of aqueous solution of the precursor of compound 7 (containing 60 μg of compound 7), mix thoroughly, and then add 1 mL of... 177The reaction solution of LuCl3 in 0.05M hydrochloric acid was reacted at 80℃ for 15 min. The reaction was then terminated, and a sample was taken for analysis. The radiochemical purity of the product was determined using Radio-iTLC; the radiochemical purity was >95%.

[1029] 177 The results of radiometric thin-layer chromatography of Lu-compound 7 are shown in Figure 10.

[1030] 13.11 68 Ga-compound 8 labeling process

[1031] Add 1 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL of aqueous solution of compound 8 (containing 60 μg of compound 8), mix thoroughly, and add 1 mL of... 68 The GaCl3 solution was reacted with 0.1M hydrochloric acid at 80°C for 10 min, the reaction was terminated, and the product was separated, purified, and sampled for analysis. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >90%.

[1032] 68 The results of radiometric thin-layer chromatography of Ga-compound 8 are shown in Figure 11.

[1033] 13.12 177 Lu-compound 8 labeling process

[1034] Add 1 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL of aqueous solution of compound 8 (containing 60 μg of compound 8), mix thoroughly, and then add 1 mL of... 177 The reaction solution of LuCl3 in 0.05M hydrochloric acid was reacted at 80℃ for 15 min. The reaction was then terminated, and a sample was taken for analysis. The radiochemical purity of the product was determined using Radio-iTLC; the radiochemical purity was >95%.

[1035] 177 The results of radiometric thin-layer chromatography of Lu-compound 8 are shown in Figure 12.

[1036] 13.13 68 Ga-compound 9 labeling process

[1037] Add 1 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL of aqueous solution of compound 9 (containing 60 μg of compound 9), mix thoroughly, and add 1 mL of... 68The GaCl3 solution was reacted with 0.1M hydrochloric acid at 80°C for 10 min, then the reaction was terminated. The reaction solution was diluted with 5 mL of physiological saline, filtered, and a sample was taken for analysis. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >90%.

[1038] 68 The radiometric thin-layer chromatography results of Ga-compound 9 are shown in Figure 13.

[1039] 13.14 177 Lu-compound 9 labeling process

[1040] Add 0.5 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL of aqueous solution of compound 9 (containing 60 μg of compound 9), mix thoroughly, and then add 0.5 mL of [the solution is missing from the original text]. 177 The reaction solution of LuCl3 in 0.05M hydrochloric acid was reacted at 80℃ for 15 min. The reaction was then terminated, and a sample was taken for analysis. The radiochemical purity of the product was determined using Radio-iTLC; the radiochemical purity was >95%.

[1041] 177 The results of radiometric thin-layer chromatography of Lu-compound 9 are shown in Figure 14.

[1042] 13.15 68 Ga-compound 10, 68 Ga-compound 12 labeling process

[1043] Add 1 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to a vial, then add 60 μL (containing 60 μg) of the aqueous solution of the precursor of compound 10 or compound 12, mix thoroughly, and then add 1 mL of... 68 The GaCl3 solution was reacted with 0.1M hydrochloric acid at 80°C for 10 minutes, then the reaction was terminated. The reaction solution was diluted with 5 mL of physiological saline, filtered, and sampled for analysis. This is the product solution 68Ga-compound 10. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >95%.

[1044] 68 The results of radiometric thin-layer chromatography of Ga-compound 10 are shown in Figure 15.

[1045] 68 The results of radiometric thin-layer chromatography of Ga-compound 12 are shown in Figure 16.

[1046] 13.16 18 Labeling process of F-compound 11

[1047] Add 2.5 mL of acetonitrile solution, 27 μL of AlCl3, 45 μL of acetic acid, and 40 μL of an aqueous solution of precursor compound 11 (containing 200 μg of precursor compound 11) to a vial and add to the reaction flask. Shake well. Take a certain amount of the generated fluorine [18F] aqueous solution and measure and record its radioactivity using an activity meter (the fluorine [18F] aqueous solution can be generated by a cyclotron). Add the fluorine [18F] aqueous solution to a pretreated QMA column, and then elute with 0.5 mL of physiological saline. The eluent flows directly into the reaction flask, which is then capped with a rubber stopper. Place the reaction flask at 80 °C for 15 min. Cool the reaction flask to room temperature, dilute the reaction solution with sterile water for injection, purify it using a C18 column, discard the eluent, slowly wash the C18 column with 1.5 mL of 70% ethanol solution, collect the eluent into a product bottle, dilute with 9 mL of physiological saline, and filter through a sterile filter membrane into a sterile vacuum bottle. The product was sampled and tested, and its radiochemical purity was determined by HPLC. The results are shown in Figure 17.

[1048] Experimental Example 1: Preclinical Experiment

[1049] Laboratory animals:

[1050] The B-hFAP MC38 model, provided by Biocytogen Jiangsu Gene Biotechnology Co., Ltd., is a transgenic model of MC38 mouse colon cancer cells, in which human FAP is highly expressed on the surface of B-hFAP MC38 cells. It is also used to establish a subcutaneous ectopic xenograft model based on C57BL / 6 mice.

[1051] The A549 mouse model was provided by Hengjia Biotechnology (Suzhou) Co., Ltd. This model is an A549 subcutaneous heterotopic xenograft (CDX) model established in BALB / c nude mice, constructed from human lung adenocarcinoma A549 cells.

[1052] Imaging equipment used in the experiment:

[1053] MicroPET / CT Imaging System (SNPC-303 Super Nova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.): The acquired PET / CT images are reconstructed by the equipment's built-in software and processed and analyzed using PMOD software to obtain the radioactive uptake distribution of different tissues (expressed as %ID / g).

[1054] The experiment used 68 Ga-FAPI46, 68 Ga-FAPI04 was purchased from Jiangxi Tanzhen Biotechnology Co., Ltd. 18 The F-FDG drug was provided by the Affiliated Hospital of Jiangnan University.

[1055] 1.1 Affinity Measurement

[1056] The affinity of analytes (compounds 1 to 8) for FAP was determined using the Biacore 8K protein interaction system. FAP protein (purchased from ACROBiosystems Inc.) was coupled to the surface of a CM5 chip. A series of analyte solutions of different concentrations were prepared with buffer, injected, and the affinity between the analytes and FAP was measured. The affinity between the analytes and FAP was determined by the equilibrium dissociation constant K. D (K d / K a The value represents K, where K is the number of K. d KD is the dissociation constant, and Ka is the binding constant. The smaller the KD value, the higher the affinity between the sample and the protein.

[1057] The test results are as follows: the equilibrium dissociation constants KD values ​​of compounds 1, 2, 3, 4, 5, 6, 7, 8, and 9 bound to FAP are (6.31±1.11)E-12M, (6.35±0.66)E-11M, (1.66±0.01)E-8M, (2.23±0.02)E-8M, (1.05±0.03)E-6M, (6.08±0.07)E-9M, (1.11±0.08)E-10M, (5.36±0.06)E-9M, and (1.27±0.05)E-7M, respectively. It can be seen that compounds 1, 2, 6, 7, and 8 have a strong affinity for CAIX protein.

[1058] 1.2 68 PET / CT scan tissue distribution and targeting experiments of Ga-compound 1B-hFAP MC38 model

[1059] Experimental steps:

[1060] Four B-hFAP MC38 animal models were selected and injected via tail vein. 68 Ga-FAPI46 (dose: 80 μCi / animal). Animals were placed in a MicroPET / CT imaging system and underwent dynamic 30 min and static 1 h, 2 h, and 3 h microPET / CT scans after administration.

[1061] Two days later, mice from the same batch were injected again via the tail vein. 68 Ga-compound 1 (dose: 80 μCi / animal) was administered and PET / CT scans were performed using the same imaging modality and time points.

[1062] The acquired image data was reconstructed using the equipment software, and then processed and analyzed using PMOD software to generate tissue distribution maps and quantitatively determine the radioactive uptake values ​​of each tissue and organ (expressed as %ID / g).

[1063] 68 Ga-compound 1, 68 Figure 18 shows the PET / CT imaging results of Ga-FAPI46 on the B-hFAP MC38 mouse model. 68 Ga-compound 1, 68 Figure 19 shows the uptake results of Ga-FAPI46 in different tissues of the B-hFAP MC38 mouse model.

[1064] The results showed that 68 Ga-compound 1 drugs rapidly accumulate at tumor sites (as indicated by the arrows in Figure 18) and maintain high uptake levels at the tumor site for up to 4 hours after administration. Simultaneously, they are rapidly excreted via the kidneys, with low uptake in other non-target organs, resulting in a high tumor / background ratio after 1 hour. This produces high-contrast images at the tumor site, providing excellent imaging results. 68 The uptake of Ga-FAPI46 at the tumor site gradually decreases over time, resulting in decreased tumor image contrast and poor imaging effect.

[1065] Table 2. 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 1

[1066] Table 3. 68 Radioactive uptake values ​​of various tissues and organs after Ga-FAPI46 administration

[1067] 1.3 68 PET / CT scan tissue distribution and targeting validation of Ga-compound 2B-hFAP MC38 model

[1068] Experimental steps:

[1069] Two B-hFAP MC38 animal models were selected and injected with the above-mentioned substance via the tail vein. 68 Ga-compound 2 drug (dose: 80 μCi / animal) was administered to animals placed in the imaging chamber of a MicroPET / CT imaging system. Static MicroPET / CT scans were performed at 1h, 2h, and 3h after drug administration. The scan images and the radioactive uptake values ​​of various tissues and organs were analyzed (expressed as %ID / g).

[1070] 68 Figure 20 shows the PET / CT imaging results of Ga-compound 2 in the B-hFAP MC38 mouse model, and Figure 21 shows the uptake results in different tissues of the B-hFAP MC38 mouse model.

[1071] The results showed that68 Ga-compound 2 can rapidly accumulate in tumor tissue (as indicated by the arrow in Figure 20). A high tumor / background ratio can be obtained 1 hour after administration. The uptake level is low in other non-target organs, thus forming a clear high-contrast image at the tumor site. Up to 4 hours after administration, the tumor uptake value does not decrease significantly and still maintains a high uptake level.

[1072] Table 4. 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 2

[1073] 1.4 68 PET / CT scan tissue distribution and targeting validation of Ga-compound 2B-hFAP MC38 model

[1074] Experimental steps:

[1075] Two B-hFAP MC38 mice (numbered 1 and 2) were selected. Mouse number 2 was injected via tail vein. 68 Ga-compound 2 drug (dose: 80 μCi / animal) was administered to animals placed in the imaging chamber of a MicroPET / CT imaging system. Dynamic MicroPET / CT scans were performed at 30 min and static scans at 1 h, 2 h and 3 h after drug administration.

[1076] One day later, the imaging experiment was performed again on mouse number 2, while the control experiment was performed on mouse number 1. Both mice were injected via tail vein. 68 Ga-FAPI46 drug (80 μCi / animal) was administered to animals placed in a MicroPET / CT imaging chamber. Dynamic MicroPET / CT scans were performed at 30 min and static scans at 1 h, 2 h, and 3 h after drug administration.

[1077] The scanned images and the radioactive uptake values ​​of various tissues and organs were analyzed (expressed as %ID / g).

[1078] 68 Ga-compound 2 and 68 Figure 22 shows the PET / CT imaging results of Ga-FAPI46 in the B-hFAP MC38 mouse model, and Figure 23 shows the uptake results of Ga-FAPI46 in different tissues of the B-hFAP MC38 mouse model.

[1079] The results showed that, compared to 68 Ga-FAPI46, 68 Ga-compound 2 can rapidly accumulate in tumor tissue (as indicated by the arrow in Figure 22) within a short period of time, and its uptake in other non-specifically binding organs is low. It can form a clear, high-contrast image at the tumor site within a short period of time.68 Ga-FAPI46 drugs exhibit low uptake at tumor sites, but high uptake in non-specific binding organs such as the heart, lungs, liver, and kidneys.

[1080] Table 5. 68 Radioactive uptake values ​​of various tissues and organs after Ga-FAPI46 administration

[1081] Table 6. 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 2

[1082] 1.5 177 SPECT scan tissue distribution and targeting verification of Lu-compound 2B-hFAP MC38 model

[1083] Experimental steps:

[1084] Two animals were selected as the model, and the tail vein was injected with... 177 Lu-compound 2 drug (dose: 1 mCi / animal) was administered to small animals, and SPECT / CT scans were performed at 4h, 24h, 48h, 96h, 120h, and 168h after administration. The acquired PET / CT image data were reconstructed using the system's built-in software and processed using PMOD. The radioactivity distribution of each tissue and organ was quantitatively analyzed, and the radioactive uptake value (expressed as %ID / g) was calculated.

[1085] 177 Figure 24 shows the SPECT / CT imaging results of Lu-compound 2 in two B-hFAP MC38 mouse models.

[1086] The results showed that 177 Lu-compound 2 has a long retention time in tumor tissues, and significant uptake can still be detected 168 hours after administration. Its radioactive uptake in other non-target organs gradually decreases over time, thereby reducing exposure to normal tissues and reducing toxic side effects on normal tissues.

[1087] 1.6 68 Ga-compound 2ICR mouse blood pharmacokinetic experiment

[1088] The experimental mice were female ICR mice, purchased from Hengjia Biotechnology (Suzhou) Co., Ltd. One of these ICR mice was randomly selected and injected via the tail vein. 68Ga-compound 2 drug (100 μCi / animal) was administered via submandibular blood samples at 5 min, 15 min, 30 min, 1 h, 1.5 h, and 2 h post-administration. The radioactivity in the blood was measured using a gamma counter, and the blood drug concentration (%ID / g) at each time point was calculated. The results are shown in Table 7 and Figure 25. Non-compartmental model analysis was performed using the pharmacokinetic counting software Mas to calculate pharmacokinetic parameters. The results are shown in Table 8.

[1089] The results showed that eliminating the half-life T 1 / 2 = 1.88h, peak time T max It takes approximately 0.08 hours.

[1090] Table 7. Blood drug concentrations at different time points after drug administration

[1091] Table 8. Pharmacokinetic Parameter Results of Non-Compartmental Model

[1092] 1.7 68 Ga-compound 3, 68 Ga-FAPI46, 68 Ga-FAPI04 and 68 Distribution and targeting of Ga-compound 4 in A549 model MicroPET / CT scan tissues

[1093] Experimental steps:

[1094] Four animal models were selected, and three of them were randomly chosen and injected with the above-mentioned substance via the tail vein. 68 Ga-compound 3 drug (100 μCi / animal) was administered to animals placed in the imaging chamber of a MicroPET / CT imaging system. Dynamic MicroPET / CT scans were performed at 30 min, static scans at 1 h, and static scans at 2 h after drug administration.

[1095] On the second day after the drug administration, the above four experimental mice were given... 68 Ga-FAPI46 drug (100 μCi / animal) was administered, and dynamic MicroPET / CT scans were performed at 30 min, static 1 h, and 2 h after drug administration.

[1096] On the fifth day of the experiment, the above four experimental mice were given... 68 Ga-compound 4 drug (100 μCi / animal) was subjected to dynamic 30 min, static 1 h, and 2 h MicroPET / CT scans after administration;

[1097] On the sixth day of the experiment, the above four experimental mice were given... 68Ga-FAPI04 drug (100 μCi / animal) was administered and static MicroPET / CT scans were performed at 30 min, 1 h, and 2 h after administration.

[1098] The obtained scan images and the radioactive uptake values ​​of various tissues and organs were analyzed (expressed as %ID / g). 68 Ga-FAPI46, 68 Ga-FAPI04, 68 Ga-compound 3, 68 Figure 26 shows the PET / CT imaging results of Ga-compound 4 in the A549 mouse model. 68 Ga-FAPI46, 68 Ga-FAPI04, 68 Ga-compound 3, 68 Figure 27 shows the uptake results of Ga-compound 4 in different tissues of the A549 mouse model.

[1099] The results showed that, compared to 68 Ga-FAPI46, 68 Ga-FAPI04, 68 Ga-compound 3 can rapidly accumulate in tumor tissue (indicated by the arrow in Figure 26) in a short period of time, and its uptake gradually decreases in other non-specifically bound organs. High-contrast images are produced at the tumor site 1 hour after administration.

[1100] 68 Ga-compound 4, 68 Ga-FAPI46, 68 Ga-FAPI04 exhibits low uptake at tumor sites and declines rapidly over time, resulting in low tumor imaging contrast.

[1101] Table 9. 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 3

[1102] Table 10. 68 Radioactive uptake values ​​of various tissues and organs after Ga-FAPI46 administration

[1103] Table 11. 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 4

[1104] Table 12. 68 Radioactive uptake values ​​of various tissues and organs after Ga-FAPI04 administration

[1105] 1.868 Ga-compound 3, 68 Ga-compound 4, 18 F-FDG B-hFAP MC38 model MicroPET / CT scan tissue distribution and targeting experiment

[1106] Experimental steps:

[1107] The experimental animals were B-hFAP MC38 mice, and four mice were randomly selected.

[1108] give 68 Ga-compound 3, 68 Ga-compound 4, 18 F-FDG was used for PET / CT imaging.

[1109] Mouse administration 68 Ga-compound 3 (80 μCi / animal) was injected via the tail vein and then placed in the imaging chamber of the MicroPET / CT imaging system. Dynamic PET / CT scans were performed at 30 min, static scans at 1 h, and static scans at 2 h after administration.

[1110] On the second day after administration, the same experimental mice were given... 68 Ga-compound 4 drug (80 μCi / animal) was subjected to dynamic 30 min, static 1 h, and 2 h MicroPET / CT scans after administration;

[1111] On the sixth day of the experiment, the same experimental mice were given... 18 F-FDG drug (80 μCi / animal) was administered via dynamic MicroPET / CT scan at 30 min, 1 h, and 2 h after administration.

[1112] The scanned images and the radioactive uptake values ​​of various tissues and organs were analyzed (expressed as %ID / g).

[1113] 68 Ga-compound 3, 68 Ga-compound 4, 18 Figure 28 shows the PET / CT imaging results of F-FDG in the B-hFAP MC38 mouse model, and Figure 29 shows the uptake results of F-FDG in different tissues of the B-hFAP MC38 mouse model.

[1114] The results showed that 68 Ga-compound 3 and 68 Ga-compound 4 can rapidly accumulate in tumor tissue after administration and has low distribution in other non-target organs. High-contrast tumor imaging can be obtained in a short time and a high level of tumor uptake can be maintained within 2 hours. 18F-FDG can also visualize tumors in a short time, but it has higher uptake in non-target tissues such as the heart, brain, kidneys, liver, and intestines, resulting in stronger background signals and lower tumor imaging contrast. Compared to 18 F-FDG, 68 Ga-compound 3 and 68 Ga-compound 4 exhibits faster clearance of non-target tissues and a higher tumor / background ratio.

[1115] Table 13. 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 3

[1116] Table 14. 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 4

[1117] Table 15. 18 Radioactive uptake values ​​of various tissues and organs after F-FDG administration

[1118] 6.9 68 Ga-compound 3ICR rat blood pharmacokinetics experiment

[1119] The experimental mice were female ICR mice, purchased from Hengjia Biotechnology (Suzhou) Co., Ltd. One of these ICR mice was randomly selected and administered the above treatments. 68 100 μCi of Ga-compound 3 drug was administered via submandibular blood samples at 5 min, 15 min, 30 min, 1 h, 1.5 h, and 2 h post-administration. The radioactivity in the blood was measured using a gamma counter, and the blood drug concentration at different time points was calculated. The pharmacokinetic parameters of the non-compartmental model were then calculated using the pharmacokinetic counting software Mas (see Table 16). The results are shown in Figure 30.

[1120] The pharmacokinetic calculation result is the elimination half-life T. 1 / 2 = 2.16h, peak time T max It takes approximately 0.02 hours.

[1121] Table 16. Pharmacokinetic parameters of non-compartmental models

[1122] 1.10 177 In vitro tissue distribution experiment using Lu-compound 3A549 / B-hFAP MC38 model

[1123] Experimental steps:

[1124] One animal from each of the A549 and B-hFAP MC38 models was selected, and the animals were injected via the tail vein. 177Lu-compound 3 (300 μCi / animal) was administered, and animals were sacrificed 24 hours after administration. Fourteen tissues and organs were dissected and separated, including the brain, heart, kidneys, large intestine, small intestine, liver, lungs, pancreas, gonads, skeletal muscle, spleen, stomach, fat, and tumor. Each tissue and organ was weighed and subjected to gamma radiation counting to calculate the radioactive uptake per unit mass of tissue (expressed as %ID / g).

[1125] 177 Figure 31 shows the in vitro tissue distribution of Lu-compound 3 in A549 mouse model and B-hFAP MC38 mouse model.

[1126] The results showed that 24 hours after administration, 177 Lu-compound 3 was uptaken significantly higher in tumor tissues of the B-hFAP MC38 model than in the A549 model, while uptake in the liver was relatively low. In both models, except for the kidneys and liver, uptake in other non-specifically binding tissues (such as the heart, lungs, spleen, stomach, and intestines) was low. Therefore, 177 The Lu-compound 3 maintains a high uptake level at tumor sites, while its distribution is low in most normal tissues, suggesting that it has little potential toxicity to non-target tissues and has good prospects for tumor treatment.

[1127] Table 17. 177 Radioactive uptake values ​​of various tissues after administration of Lu-compound 3

[1128] 1.11 68 PET / CT scan tissue distribution and targeting validation of Ga-compound 6B-hFAP MC38 model

[1129] Experimental steps:

[1130] Four animals were selected as the model, and the tail vein was injected with... 68 Ga-compound 6 drug (80 μCi / animal) was administered to animals placed in the imaging chamber of a MicroPET / CT imaging system. Dynamic 30 min, static 1 h, and 2 h MicroPET / CT scans were performed after drug administration. The scan images and the radioactive uptake values ​​of various tissues and organs were analyzed (expressed as %ID / g).

[1131] 68 Figure 32 shows the PET / CT imaging results of Ga-compound 6 in the B-hFAP MC38 mouse model, and Figure 33 shows the uptake results in different tissues of the B-hFAP MC38 mouse model.

[1132] The results showed that 30 minutes after administration, 68Ga compounds can rapidly accumulate in tumor tissue (as indicated by the arrow in Figure 32), while exhibiting low radioactive uptake in other non-target tissues. They can produce high-contrast images at the tumor site in a short period of time, and maintain high uptake at the tumor site for 2 hours after administration, while exhibiting lower uptake in other non-target organs, including the kidneys.

[1133] Table 18. 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 6

[1134] 1.12 68 Ga-compound 6B-hFAP MC38 model in vitro tissue distribution experiment

[1135] Experimental steps:

[1136] Nine animals were selected for this animal model and divided into three groups of three, corresponding to dissection times of 1 hour, 2 hours, and 4 hours. Each mouse was injected via the tail vein. 68 Ga-compound 6 (100 μCi / animal). Animals were sacrificed at the corresponding time points after administration, and tissues and organs including blood, brain, thyroid gland, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonads, skeletal muscle, spleen, stomach, fat, and tumors were collected. After weighing each tissue and organ, gamma radiation was counted, and the radioactive uptake value (%ID / g) was calculated.

[1137] 68 Figure 34 shows the uptake results of Ga-compound 6 in different tissues of the B-hFAP MC38 mouse model.

[1138] The results showed that one hour after administration, 68 Ga-compound 6 showed high uptake in tumors of the B-hFAP MC38 model, but low uptake in normal tissues except for the kidneys. Two hours after administration, the decrease in uptake in tumor tissues was minimal, and four hours after administration, high uptake remained in tumor tissues, while uptake in most normal tissues was low. Overall, 68 Ga-compound 6 is rapidly metabolized in normal tissues and specifically enriched in tumors, exhibiting tumor-targeting properties.

[1139] Table 19. 177 Radioactive uptake values ​​of various tissues after administration of Lu-compound 6

[1140] 1.13 68 Ga-compound 6ICR mouse blood pharmacokinetic experiment

[1141] The experimental mice were female ICR mice, purchased from Hengjia Biotechnology (Suzhou) Co., Ltd. Six of these ICR mice were randomly selected and administered the above-mentioned treatments.68 100 μCi of Ga-compound 6 drug was administered via submandibular blood samples at 1 min, 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, and 3 h post-administration. The radioactivity in the blood was measured using a gamma counter, and the blood drug concentrations at different time points were calculated. The results are shown in Table 20. Pharmacokinetic parameters for the non-compartmental model were calculated using the pharmacokinetic counting software Mas, and the results are shown in Figure 35.

[1142] The pharmacokinetic calculation result is the elimination half-life T. 1 / 2 = 1.40h, peak time T max It takes approximately 0.02 hours.

[1143] Table 20. Pharmacokinetic Parameter Results of Non-Compartmental Model

[1144] 1.14 68 PET / CT scan tissue distribution and targeting validation of Ga-compound 5B-hFAP MC38 model

[1145] Experimental steps:

[1146] Four animals were selected as the model, and the tail vein was injected with... 68 Ga-compound 5 (80 μCi / animal) was administered to animals placed in the imaging chamber of a MicroPET / CT imaging system. Dynamic 30 min, static 1 h, and 2 h MicroPET / CT scans were performed after drug administration. The scan images and the radioactive uptake values ​​of various tissues and organs were analyzed (expressed as %ID / g).

[1147] 68 Figure 36 shows the PET / CT imaging results of Ga-compound 5 in the B-hFAP MC38 mouse model, and Figure 37 shows the uptake results in different tissues of the B-hFAP MC38 mouse model.

[1148] The results showed that the drug rapidly accumulated in the tumor tissue (indicated by the arrow in Figure 36) 30 minutes after administration, while the radioactive uptake in other non-target tissues was low. High-contrast images could be generated at the tumor site in a short time. Two hours after administration, the tumor tissue still maintained high uptake, while the uptake in non-target organs, including the kidneys, was further reduced.

[1149] Table 21. 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 5

[1150] 1.15 68 Ga-compound 5B-hFAP MC38 model in vitro tissue distribution experiment

[1151] Experimental steps:

[1152] Four animals were selected for this model and divided into three groups of three, corresponding to dissection times of 1 hour, 2 hours, and 4 hours. Each mouse was injected via the tail vein. 68 Ga-compound 5 drug (100 μCi / animal). Animals were sacrificed at corresponding time points after drug administration, and tissues and organs including blood, brain, thyroid gland, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonads, skeletal muscle, spleen, stomach, fat, and tumors were collected. After weighing each tissue and organ, gamma radiation was counted, and the radioactive uptake value (%ID / g) was calculated.

[1153] 68 Figure 38 shows the uptake results of Ga-compound 5 in different tissues of the B-hFAP MC38 mouse model.

[1154] The results showed that one hour after administration, 68 Ga-compound 5 showed high uptake in tumors of the B-hFAP MC38 model, but low uptake in normal tissues except the kidneys. Four hours after administration, high uptake levels remained in tumor tissues, while uptake in normal tissues remained low. This indicates that... 68 Ga-compound 5 is rapidly metabolized in normal tissues, but specifically enriches in tumor tissues and remains there for a longer period of time.

[1155] Table 22. Drug Administration 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 5

[1156] 1.16 68 Ga-compound 5ICR mouse blood pharmacokinetic experiment

[1157] The experimental mice were female ICR mice, purchased from Hengjia Biotechnology (Suzhou) Co., Ltd. Six of these ICR mice were randomly selected and administered the above-mentioned treatments. 68 100 μCi of Ga-compound 5 drug was administered via submandibular blood samples at 1 min, 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, and 3 h post-administration. The radioactivity in the blood was measured using a gamma counter, and the blood drug concentrations at different time points were calculated. The results are shown in Figure 39. Pharmacokinetic parameters for the non-compartmental model were calculated using the pharmacokinetic counting software Mas, and the results are shown in Table 23. The pharmacokinetic calculation results are the elimination half-life Ti. 1 / 2 = 1.97h, peak time T max It takes approximately 0.02 hours.

[1158] Table 23. Pharmacokinetic Parameter Results of Non-Compartmental Model

[1159] 1.17 68 PET / CT scan tissue distribution and targeting validation of Ga-compound 7B-hFAP MC38 model

[1160] Experimental steps:

[1161] Four animals were selected as the model, and the tail vein was injected with... 68 Ga-compound 7 drug (80 μCi / animal) was administered to animals placed in the imaging chamber of a MicroPET / CT imaging system. Dynamic 1-hour and static 2-hour MicroPET / CT scans were performed after drug administration. The scan images and the radioactive uptake values ​​of each tissue and organ were analyzed (expressed as %ID / g).

[1162] 68 Figure 40 shows the PET / CT imaging results of Ga-compound 7 in the B-hFAP MC38 mouse model, and Figure 41 shows the uptake results in different tissues of the B-hFAP MC38 mouse model.

[1163] The results showed that 30 minutes after administration, 68 The radioactive uptake of Ga-compound 7 in the B-hFAP MC38 model tumor tissue reached a high level, while uptake in normal tissues, except for the kidneys, was low. One hour after administration, the tumor tissue maintained a high uptake level, while the uptake in normal tissues gradually decreased to below the level of the tumor tissue. Two hours after administration, the tumor tissue still maintained a high uptake. This indicates that... 68 Ga-compound 7 is rapidly metabolized in normal tissues, but exhibits specific enrichment and a longer retention time in tumor tissues.

[1164] Table 24. 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 7

[1165] 1.18 68 PET / CT scan tissue distribution and targeting validation of Ga-compound 8B-hFAP MC38 model

[1166] Experimental steps:

[1167] Four animals were selected as the model, and the tail vein was injected with... 68 Ga-compound 8 drug (80 μCi / animal) was administered to animals placed in the imaging chamber of a MicroPET / CT imaging system. Dynamic scans were performed for 1 hour and static scans for 2 hours after drug administration.

[1168] 68Figure 42 shows the PET / CT imaging results of Ga-compound 8 in the B-hFAP MC38 mouse model, and Figure 43 shows the uptake results in different tissues of the B-hFAP MC38 mouse model.

[1169] The results showed that 30 minutes after administration, 68 Ga-compound 8 showed high radioactive uptake in B-hFAP MC38 model tumor tissue, while uptake in normal tissues was low, except for the kidneys. One hour after administration, the tumor tissue maintained a high uptake level, while the uptake in normal tissues gradually decreased until it fell below the level of the tumor tissue, and the tumor was clearly visualized. Two hours later, the tumor still maintained high uptake, indicating that... 68 Ga-compound 8 is rapidly metabolized in normal tissues and specifically targeted for uptake in tumors.

[1170] Table 25. Drug Administration 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 8

[1171] 1.19 177 Lu-compound 3, 177 Lu-compound 7, 177 Lu-compound 8 and 177 In vitro tissue distribution experiment of Lu-compound 9 on B-hFAP MC38 model

[1172] Experimental steps:

[1173] The animal model was selected and divided into three groups of six mice each. The mice were then administered the above-mentioned treatments accordingly. 177 Lu-compound 3, 177 Lu-compound 7, 177 Lu-compound 8 was administered at a dose of 300 μCi. Mice in each group were sacrificed at 4 h and 48 h after administration, with 3 mice collected at each time point. Tissues and organs, including brain, thyroid, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonads, skeletal muscle, spleen, stomach, fat, and tumors, were collected. After weighing, gamma radiation was counted, and the radioactive uptake value (%ID / g) was calculated.

[1174] Five mice were selected as animal models and given... 177 Three animals were euthanized 4 hours after administration of Lu-compound 9 drug at a dose of 300 μCi, and two animals were euthanized 48 hours after administration. After euthanasia, tissues and organs such as brain, thyroid, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonads, skeletal muscle, spleen, stomach, fat, and tumors were collected. After weighing each tissue and organ, gamma radiation was counted, and the radioactive uptake value (%ID / g) was calculated.

[1175] 177 Lu-compound 3, 177 Lu-compound 7, 177 Figure 44 shows the uptake results of Lu-compound 8 in different tissues of the B-hFAP MC38 mouse model. 177 Figure 45 shows the uptake results of Lu-compound 9 in different tissues of the B-hFAP MC38 mouse model.

[1176] The results showed that 4 hours after administration, all compounds exhibited high radioactive uptake in tumor tissue, while uptake in normal tissues other than the kidneys was low. 48 hours after administration, high radioactivity levels remained in tumor tissue, while other non-target tissues were rapidly cleared primarily by the kidneys. 177 The radioactive uptake of Lu-compound 8 in tumor tissue decreased relatively slowly, while its uptake level in other non-target organs was low, demonstrating good tumor retention ability and specific distribution characteristics.

[1177] Table 26. 177 Lu-compound 3, 177 Lu-compound 7, 177 Lu-compound 8 and 177 Radioactive uptake values ​​of various tissues and organs after administration of Lu-compound 9

[1178] 1.20 177 Lu-compound 8, 177 Tumor Therapy Experiment of Lu-Compound 9

[1179] Eighteen B-hFAP MC38 mice were randomly selected and divided into three groups of six each: a saline group, a single-dose group, and a multiple-dose group. Each animal in the single-dose group received a tail vein injection. 177 Lu-compound 8 drug 2mCi, administered once; in the multiple administration group, each animal was injected via tail vein. 177 Lu-compound 8 drug was administered twice, 2 mCi each time, with a seven-day interval between the two administrations; in the saline group, each animal received an equal volume of saline via the tail vein once.

[1180] Twelve mice were randomly selected for this animal model and divided into a control group and an experimental group, with six mice in each group. Each animal in the experimental group received a tail vein injection. 177 Lu-compound 9 drug 2mCi, administered only once; the control group was given an equal volume of physiological saline once.

[1181] Before the experiment, mouse body weight and tumor volume were measured. After drug administration, body weight and tumor volume were measured at specified times. The major and minor axes of the tumor were measured to calculate the tumor volume using the following formula: Tumor volume (TV) = a × b 2 / 2 (a is the major axis, b is the minor axis). The tumor growth inhibition rate (TGI) and body weight change were calculated. Body weight change was calculated as follows: Body weight change (%) of experimental animals = Body weight at the specified time / Body weight before drug administration.

[1182] 177 The efficacy of Lu-compound 8 in the B-hFAP MC38 mouse model and the changes in body weight after administration are shown in Figure 46.

[1183] 177 The efficacy of Lu-compound 9 in the B-hFAP MC38 mouse model and the changes in body weight after administration are shown in Figure 47.

[1184] Dosage 177 Twenty-five days after administration of Lu-compound 8, the TGI values ​​for the single-dose group and the multiple-dose group were 78.4% and 84.9%, respectively. As shown in Figure 46, compared with the saline group, tumor growth was significantly inhibited in both the single-dose group and the multiple-dose group, demonstrating significant anti-tumor activity. There was no significant decrease in body weight among the three groups of mice.

[1185] Dosage 177 22 days after administration of Lu-compound 9, the TGI value of the experimental group was 60.6%. As shown in Figure 47, compared with the control group, tumor growth in the experimental group was significantly inhibited, and body weight change was not significant, demonstrating significant anti-tumor activity. The results show that... 177 Lu compound 8 and 177 All Lu-compounds 9 exhibit good anti-tumor effects and have high safety.

[1186] 1.21 68 PET / CT scan tissue distribution and targeting validation of Ga-compound 9B-hFAP MC38 model

[1187] Experimental steps:

[1188] Four animals were selected as the model, and the tail vein was injected with... 68 Ga-compound 9 drug (80 μCi / animal) was administered to animals placed in the imaging chamber of a MicroPET / CT imaging system, and MicroPET / CT scans were performed 1 h and 2 h after drug administration.

[1189] 68Figure 48 shows the uptake results of Ga-compound 9 in different tissues of the B-hFAP MC38 mouse model. Figure 49 shows the uptake values ​​in different tissues. Figure 50 shows the ratio of tumor uptake value to muscle or heart uptake value.

[1190] The results showed that giving 68 Ga-compound 9 drugs rapidly accumulate in tumor tissue (as indicated by the arrow in Figure 48) within 1 hour, while exhibiting lower radioactive uptake in other non-target tissues, resulting in a high tumor / background ratio after 1 hour and producing high-contrast images at the tumor site.

[1191] Table 27. 177 Radioactive uptake values ​​of various tissues and organs after administration of Lu-compound 9

[1192] 1.22 68 Ga-compound 10, 68 PET / CT scan tissue distribution and targeting validation of Ga-compound 12B-hFAP MC38 model

[1193] Experimental steps:

[1194] Eight animals were selected as the model and divided into two groups. The above-mentioned drugs were injected into the tail vein of each group respectively. 68 Ga-compound 10, 68 Ga-compound 12 drug (dose: 80 μCi / animal) was administered to animals placed in the imaging chamber of a MicroPET / CT imaging system. Dynamic scans were performed 1 h after drug administration, and static scans were performed 2 h and 4 h after drug administration.

[1195] 68 Figure 51 shows the PET / CT imaging results of Ga-compound 10 in the B-hFAP MC38 mouse model, and Figure 52 shows the uptake results in different tissues of the B-hFAP MC38 mouse model. 68 Figure 53 shows the PET / CT imaging results of Ga-compound 12 in the B-hFAP MC38 mouse model, and Figure 54 shows the uptake results in different tissues of the B-hFAP MC38 mouse model.

[1196] The results showed that 30 minutes after administration, 68 Ga-compound 10, 68 Ga-compound 12 showed high radioactive uptake in tumor tissue of the B-hFAP MC38 model, while uptake in other normal tissues was low. Four hours after administration, the tumor tissue maintained a high uptake level and was rapidly metabolized in normal tissues. The tumor / background ratios reached 18 and 54, respectively, and the tumor was clearly visualized.

[1197] Table 28. 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 10

[1198] Table 29. 68 Radioactive uptake values ​​of various tissues and organs after administration of Ga-compound 12

[1199] 1.23 18 F-compound 11, 18 F-compound 12B-hFAP MC38 model PET / CT scan tissue distribution and targeting validation

[1200] Experimental steps:

[1201] Eight animals were selected as the model and divided into two groups. The above-mentioned drugs were injected into the tail vein of each group respectively. 18 F-compound 11, 18 F-compound 12 drug (dosage: 100 μCi / animal), the animals were placed in the imaging chamber of the MicroPET / CT imaging system and static scans were performed at 1h, 2h and 4h after drug administration;

[1202] 18 Figure 55 shows the PET / CT imaging results of F-compound 11 in the B-hFAP MC38 mouse model, and Figure 56 shows the uptake results in different tissues of the B-hFAP MC38 mouse model. 18 Figure 57 shows the PET / CT imaging results of F-compound 12 in the B-hFAP MC38 mouse model, and Figure 58 shows the uptake results in different tissues of the B-hFAP MC38 mouse model.

[1203] The results showed that one hour after administration, 18 F-compound 11, 18 F-compound 12 showed high radioactive uptake in tumor tissue of the B-hFAP MC38 model, while uptake in other normal tissues was low. Four hours after administration, the tumor tissue maintained a high uptake level and was rapidly metabolized in normal tissues. The tumor / background ratios reached 33 and 11, respectively, and the tumor was clearly visualized.

[1204] Table 30. 18 Radioactive uptake values ​​of various tissues and organs after administration of compound F-11

[1205] Table 31. 18 Radioactive uptake values ​​of various tissues and organs after administration of compound F-12

[1206] Experimental Example 2: Clinical Trial

[1207] This research and clinical trial has been approved by the Ethics Committee of the Affiliated Hospital of Jiangnan University.

[1208] 2.1 Patient 1

[1209] Patient 1 information: Female, 32 years old, previously underwent laparoscopic retroperitoneal tumor resection followed by open surgery, and the postoperative pathological diagnosis was (abdominal) follicular dendritic cell sarcoma (FDCS).

[1210] Intravenous injection for patient 1 18 F-FDG 5.03mCi, whole-body PET / CT static scan was performed 1 hour after injection to obtain scan images;

[1211] 18 After an interval of more than 20 days following F-FDG injection, the patient receives one injection. 68 Ga-compound 1, at a dose of 4.1 mCi, was injected and a whole-body PET / CT static scan was performed 1 hour later to obtain scan images.

[1212] The PET / CT cross-sectional image and PET / CT maximum intensity projection (MIP) image of patient 1 are shown in Figures 59-60.

[1213] As can be seen from Figures 59-60, 18 F-FDG and 68 Ga-compound 1 was detected in dendritic cell sarcoma in the hepatogastric space, compared to 18 F-FDG, 68 Ga-compound 1 showed a higher radioactivity concentration at this primary lesion, and at the same time... 68 Ga-compound 1 also detected multiple metastatic microlesions under the liver capsule, at the same location, 18 No clear radioactive concentration was observed with F-FDG.

[1214] It can be seen that, compared to 18 F-FDG, 68 Ga-compound 1 showed a stronger advantage in detecting both primary and metastatic lesions.

[1215] 2.2 Patient 2

[1216] Patient 2 information: 42 years old. Gastroscopy revealed an ulcerative lesion extending from below the cardia to the lesser curvature of the gastric body, along with erosive gastritis. Endoscopic biopsy pathology showed poorly differentiated adenocarcinoma (lesser curvature mucosa of the gastric body).

[1217] Patient 2 was injected with 6.32 mCi of 18F-FDG. Whole-body PET / CT static scans were performed 1 and 2 hours after the injection to obtain scan images.18 On the third day after F-FDG injection, the patient received 2 injections. 68 Ga-compound 2 (2.94 mCi) was injected, and whole-body PET / CT static scans were performed 1 and 2 hours later to obtain scan images.

[1218] The PET / CT cross-sectional image and PET / CT MIP image of patient 2 are shown in Figures 61-62.

[1219] As can be seen from Figures 61-62, 18 F-FDG and 68 Ga-compound 2 was detected in gastric tumors, compared to 18 F-FDG, 68 Ga-compound 2 shows higher radioactivity concentration at this primary lesion, making it more accurate to detect the location and size of the tumor.

[1220] It can be seen that, compared to 18 F-FDG, 68 Ga-compound 2 showed a stronger advantage in detecting primary lesions of poorly differentiated gastric adenocarcinoma.

[1221] 2.3 Patient 3

[1222] Patient 3 Information: The patient previously underwent radical total gastrectomy (total gastrectomy with esophagojejunostomy) for signet ring cell carcinoma of the gastric antrum, and received multiple chemotherapy sessions postoperatively. Nearly one year postoperatively, tumor markers (CEA, CA125, CA72-4, CA19-9, etc.) were all above the reference range.

[1223] Intravenous injection for patient 3 18 F-FDG 7mCi was injected, and a whole-body PET / CT static scan was performed 1 hour after the injection to obtain scan images; 18 On the 4th day after F-FDG injection, the patient received 3 injections. 68 Ga-compound 9 4.2mCi was injected, and a whole-body PET / CT scan was performed 1 hour later to obtain the scan images.

[1224] The PET / CT cross-sectional images and MIP images of patient 3 are shown in Figures 63-64, and the radioactive uptake values ​​of multiple tissues are shown in Figure 65.

[1225] Imaging results showed mild thickening at the anastomosis site after gastric cancer surgery. 18 F-FDG and 68 All Ga-compound 9s showed mild radioactive uptake. Multiple areas of patchy peritoneal thickening were observed in the abdominal and pelvic cavities. 18 The F-FDG standard intake value (SUV) is slightly increased, while 68The significant radioactivity concentration of Ga-compound 9 indicated multiple peritoneal metastases. Therefore, its clinical application in this patient is not appropriate. 68 Ga-compound 9 PET / CT is significantly superior to other methods in detecting postoperative peritoneal metastases. 18 F-FDG PET / CT can more sensitively reflect the distribution of tumor lesions.

[1226] 2.4 Patient 4

[1227] Patient 4 had previously undergone ultrasound-guided microwave ablation of liver lesions and liver biopsy for hepatocellular carcinoma. Postoperative pathology indicated locally well- to moderately differentiated hepatocellular carcinoma. One and a half months after the procedure, transarterial chemoembolization (TACE) was performed.

[1228] Intravenous injection for patient 4 18 F-FDG 7.6mCi was injected, and a whole-body PET / CT static scan was performed 2.5 hours later to obtain scan images; on the second day after injection, the patient received 3 injections. 68 Ga-compound 9 4.8mCi was injected, and a whole-body PET / CT scan was performed 1 hour later to obtain the scan images.

[1229] The PET / CT cross-sectional images and MIP images of patient 4 are shown in Figures 66-67, and the radioactive uptake values ​​of multiple tissues are shown in Figure 68.

[1230] As shown in Figures 66-68, there is an isodense shadow in the caudate lobe of the liver. 18 The F-FDG standard intake value (SUV) is slightly elevated. 68 Significantly increased radioactive uptake of Ga-compound 9; irregular slightly low-density lesions in the lateral segment of the left lobe of the liver. 18 No increase in F-FDG metabolism was observed. 68 Increased uptake of Ga- compounds suggests a high likelihood of translocation.

[1231] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

Compound of formula (I), or its isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof: in, Ab is a ligand that binds to fibroblast activation proteins, for example R1 and R2 are independently selected from H, D, halogens, OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; Rm is independently selected from chemical bonds, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 alkynyl group, C 6-14 Arene-methionyl or 5-14 heteroaryl compounds, for example Rn is independently selected from CN, OH, NH2 or B(OH)2; m is independently selected from 1, 2, 3, 4, or 5; L1 is the linker base; L2 is an amino acid chain consisting of 2-8 amino acid residues linked together, wherein each amino acid residue may optionally be further replaced by one or more amino acid residues. Z is a chelating group derived from the chelating agent. The compound of claim 1 has the following structure: in, A1, A2, and A3 are amino acid residues; A4 is an H or an amino acid residue; W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6 -、-C(O)O-(CR c R d ) 1-6 -、-NR-(CR c R d ) 1-6 -、-C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0- 6-,-C(O)-3-7-membered heterocyclic group-(CR) c R d ) 0-6 -、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -、-C(O)-5-10-membered heteroaryl-(CR c R d ) 0-6 -; W1 is selected from chemical bonds, -O-, -NR-, -C(O)-, -OC(O)-, -C(O)-NR-, or -NR-C(O)-; W2 is selected from C 1-10 Alkylene, C 2-10 imide or C 2-10 Ethyne group; V1 is selected from chemical bonds or -(CR) a R b ) 1-10 -; V2 is selected from chemical bonds, -O-, -NR-, C(O)-, -NR-C(O)-, or -C(O)-NR-; R a and R b Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-C 6-14 Aryl or -C 1-6 alkylene-5-14-membered heteroaryl; R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups; R is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; The other variables are as defined in claim 1. The compound of claim 1 or 2, wherein, L1 is -W0-W1-V1-V2-W2-W3-, preferably -W0-W1-V1-V2-W2-C(O)-, -W0-W1-V1-V2-W2-OC(O)- or -W0-W1-V1-V2-W2-NR-C(O)-; W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6 -、-C(O)O-(CR c R d ) 1-6 -、-NR-(CR c R d ) 1-6 -、-C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0- 6-,-C(O)-3-7-membered heterocyclic group-(CR) c R d ) 0-6 -、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -、-C(O)-5-10-membered heteroaryl-(CR c R d ) 0-6 -; W1 is selected from chemical bonds, -O-, -NR-, C(O)-, -OC(O)-, -C(O)-NR-, or -NR-C(O)-; W2 is selected from C 1-10 Alkylene, C 2-10 imide or C 2-10 Ethyne group; W3 is selected from -O-, -NR-, C(O)-, -OC(O)-, -C(O)NR- or -NR-C(O)-; V1 is selected from chemical bonds or -(CR) a R b ) 1-10 -; V2 is selected from chemical bonds, -O-, -NR-, C(O)-, -NR-C(O)-, or -C(O)-NR-; R a and R b Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-C 6-14 Aryl or -C 1-6 alkylene-5-14-membered heteroaryl; R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups; R is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; L1 can be optionally replaced by 1, 2, 3, 4 or 5 R*; R* is selected from H, D, halogens, OH, CN, NH2, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Preferably, L1 is selected from -W1-W2-C(O)-, -W1-W2-OC(O)-, -W1-W2-NR-C(O)-, -W0-W1-V1-V2-W2-C(O)- or -W1-V1-V2-W2-C(O)-; W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6 -、-C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -、-C(O)-3-7 membered heterocyclic group-(CR c R d ) 0-6 -、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -、-C(O)-5-10-membered heteroaryl-(CR c R d ) 0-6 -, preferably a chemical bond or -C(O)-(CR c R d ) 1-6 -; W1 is selected from chemical bonds, -NR-, C(O)-, -C(O)-NR-, or -NR-C(O)-; W2 is selected from C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group; V1 is -(CR) a R b ) 1-4 -; V2 is selected from -NR-, -C(O)-, or -NR-C(O)-; R a and R b Independently selected from H or -C 1-4 Alkylene-C 6-14 Aryl; R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; R is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; L1 can be optionally replaced by one, two, or three R*s; R* is selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Preferably, L1 is selected from -C 1-6 Alkylene -C(O)-, -C 2-6 alkenyl-C(O)-, -C 2-6 Ethyne-C(O)-, -NR-C 1-6 Alkylene-C(O)-, -NR-C(O)-C 1-6 Alkylene-C(O)-, Wherein, R is selected from H or C. 1-6 Alkyl, Ar is selected from phenyl, naphthyl, anthraceneyl or phenanthryl, and each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L W Selected from -(CR) c R d ) 1-6 -、C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -, 3-7 membered heterocyclic group-(CR) c R d ) 0-6 -、C 6-10 Aspartic-(CR) c R d ) 0-6 -or 5-10% heteroaryl-(CR) c R d ) 0-6 -, preferably -(CR) c R d ) 1-6 -; R c and R d Independently selected from H and C 1-6 Alkyl or C 3-7 cycloalkyl; L1 can be optionally replaced by one, two, or three R*s; R* is selected from H and C. 1-4 Alkyl or C 3-5 cycloalkyl; More preferably, L1 is selected from -(CH2) 1-6 -C(O)-, -CH=CH-(CH2) 1-4 -C(O)-, -C≡C-(CH2) 1-4 -C(O)-, -NR-(CH2) 1-6 -C(O)-, -NR-C(O)-(CH2) 1-6 -C(O)-、 R is independently selected from H or C. 1-4 Alkyl, Ar is independently selected from phenyl, naphthyl, anthraceneyl or phenanthryl, and each n is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8; L W Independently selected from -(CR c R d ) 1-4 -、C 3-7 Cycloalkylene-(CR) c R d ) 0-4 -, 3-7 membered heterocyclic group-(CR) c R d ) 0-4 -、C 6-10 Aspartic-(CR) c R d ) 0- 4- or 5-10-membered heteroaryl-(CR) c R d ) 0-4 -, preferably -(CR) c R d ) 1-4 -; R c and R d Independently selected from H and C 1-4 Alkyl or C 3-5 cycloalkyl; For example, L1 is selected from: The compound of any one of claims 1-3, wherein, L2 is an amino acid chain consisting of 2-5 amino acid residues linked together, wherein each amino acid residue may optionally be further replaced by one or more amino acid residues. Each amino acid is independently selected from glycine residues, alanine residues, phenylalanine, naphthylalanine, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues. Preferably, L2 is A1, A2, A3, and A4 are amino acid residues; Preferably, L2 is A1, A2, A3, and A4 are independently selected from glycine residues, alanine residues, phenylalanine, naphthylalanine, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues. More preferably, L2 is A1 is a lysine residue; A2 is selected from tyrosine residues, aspartic acid residues, or serine residues; A3 is a lysine residue; A4 is selected from glutamic acid residues, pyroglutamic acid residues, citrulline residues, or aspartic acid residues; For example, L2 is selected from: The compound of any one of claims 1-4, wherein, Z is a chelating group derived from a chelating agent, which is selected from the following: 1,4,7,10-Tetraazacyclododecane-N,N',N",N”'-Tetraacetic acid (DOTA) N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC) 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA), 1,4,7-Triazacyclononanephosphonic acid (TRAP) 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO) Diethyltriaminepentaacetic acid (DTPA) trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA) 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A) p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B), 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA), [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), 6-Hydroxypyridine-3-carboxylic acid (HYNIC) 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA); Preferably, Z is selected from DOTAGA, USE、 NODAGA, DOTA、 HBED-CC、 p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA、 p-SCN-Bn-DOTA. The compound of any one of claims 1-5, wherein, Ab is selected from: R1 and R2 are independently selected from H, D, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; m is selected from 1, 2, 3, 4, or 5; Preferably, Ab is selected from: R1 is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R2 is selected from H, halogen, or C. 1-6 alkyl; m is selected from 1, 2, or 3; Preferably, Ab is Preferred R1 is selected from H or C. 1-6 alkyl; R2 is selected from H or halogen; m is selected from 1, 2, or 3; More preferably, Ab is selected from The compound of any one of claims 1-6, wherein, Ab is selected from: R1 and R2 are independently selected from H, D, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; m is selected from 1, 2, 3, 4, or 5; L1 is -W0-W1-V1-V2-W2-W3-, preferably -W0-W1-V1-V2-W2-C(O)-, -W0-W1-V1-V2-W2-OC(O)- or -W0-W1-V1-V2-W2-NR-C(O)-; W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6 -、-C(O)O-(CR c R d ) 1-6 -、-NR-(CR c R d ) 1-6 -、-C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0- 6-,-C(O)-3-7-membered heterocyclic group-(CR) c R d ) 0-6 -、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -、-C(O)-5-10-membered heteroaryl-(CR c R d ) 0-6 -; W1 is selected from chemical bonds, -O-, -NR-, C(O)-, -OC(O)-, -C(O)-NR-, or -NR-C(O)-; W2 is selected from C 1-10 Alkylene, C 2-10 imide or C 2-10 Ethyne group; W3 is selected from -O-, -NR-, C(O)-, -OC(O)-, -C(O)NR- or -NR-C(O)-; V1 is selected from chemical bonds or -(CR) a R b ) 1-10 -; V2 is selected from chemical bonds, -O-, -NR-, C(O)-, -NR-C(O)-, or -C(O)-NR-; R a and R b Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-C 6-14 Aryl or -C 1-6 alkylene-5-14-membered heteroaryl; R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups; R is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; L1 can be optionally replaced by 1, 2, 3, 4 or 5 R*; R* is selected from H, D, halogens, OH, CN, NH2, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; L2 is an amino acid chain consisting of 2-5 amino acid residues linked together, wherein each amino acid residue may optionally be further replaced by one or more amino acid residues. Z is a chelating group derived from the chelating agent. The compound of any one of claims 1-7, wherein, Ab is selected from: R1 is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R2 is selected from H, halogen, or C. 1-6 alkyl; m is selected from 1, 2, or 3; L1 is selected from -W1-W2-C(O)-, -W1-W2-OC(O)-, -W1-W2-NR-C(O)-, -W0-W1-V1-V2-W2-C(O)- or -W1-V1-V2-W2-C(O)-; W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6 -、-C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -、-C(O)-3-7 membered heterocyclic group-(CR c R d ) 0-6 -、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -、-C(O)-5-10-membered heteroaryl-(CR c R d ) 0-6 -, preferably a chemical bond or -C(O)-C 1-6 alkylene-; W1 is selected from chemical bonds, -NR-, C(O)-, -C(O)-NR-, or -NR-C(O)-; W2 is selected from C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group; V1 is -(CR) a R b ) 1-4 -; V2 is selected from -NR-, C(O)-, or -NR-C(O)-; R a and R b Independently selected from H or -C 1-4 Alkylene-C 6-14 Aryl; R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; R is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; L1 can be optionally replaced by one, two, or three R*s; R* is selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; L2 is A1, A2, A3, and A4 are amino acid residues; Z is a chelating group derived from a chelating agent, which is selected from the following: 1,4,7,10-Tetraazacyclododecane-N,N',N",N”'-Tetraacetic acid (DOTA) N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC) 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA), 1,4,7-Triazacyclononanephosphonic acid (TRAP) 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO) Diethyltriaminepentaacetic acid (DTPA) trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA) 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A) p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B), 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA), [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), 6-Hydroxypyridine-3-carboxylic acid (HYNIC) 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA). The compound of any one of claims 1-8, wherein, Ab is selected from Preferred selection R1 is selected from H or C. 1-6 alkyl; R2 is selected from H or halogen; m is selected from 1, 2, or 3; L1 is selected from -C 1-6 Alkylene -C(O)-, -C 2-6 alkenyl-C(O)-, -C 2-6 Ethyne-C(O)-, -NR-C 1-6 Alkylene-C(O)-, -NR-C(O)-C 1-6 Alkylene-C(O)-, Wherein, R is independently selected from H or C. 1-6 Alkyl, Ar is independently selected from phenyl, naphthyl, anthraceneyl or phenanthryl, and each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L W Selected from -(CR) c R d ) 1-6 -、C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -, 3-7 membered heterocyclic group-(CR) c R d ) 0-6 -、C 6-10 Aspartic-(CR) c R d ) 0-6 -or 5-10% heteroaryl-(CR) c R d ) 0-6 -, preferably -(CR) c R d ) 1-6 -; R c and R d Independently selected from H and C 1-6 Alkyl or C 3-7 cycloalkyl; L1 can be optionally replaced by one, two, or three R*s; R* is selected from H or C 1-4 alkyl; L2 is A1, A2, A3, and A4 are independently selected from glycine residues, alanine residues, phenylalanine, naphthylalanine, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, or citrulline residues. Z is selected from DOTAGA, USE、 NODAGA, DOTA、 HBED-CC、 p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA、 p-SCN-Bn-DOTA. The compound of any one of claims 1-9, wherein, Ab is selected from: L1 is selected from -(CH2) 1-6 -C(O)-, -CH=CH-(CH2) 1-4 -C(O)-, -C≡C-(CH2) 1-4 -C(O)-, -NR-(CH2) 1-6 -C(O)-, -NR-C(O)-(CH2) 1-6 -C(O)-、 Wherein, R is independently selected from H or C. 1-4 Alkyl, Ar is independently selected from phenyl, naphthyl, anthraceneyl or phenanthryl, and each n is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8; L W Selected from -(CR) c R d ) 1-4 -、C 3-7 Cycloalkylene-(CR) c R d ) 0-4 -, 3-7 membered heterocyclic group-(CR) c R d ) 0-4 -、C 6-10 Aspartic-(CR) c R d ) 0-4 -or 5-10% heteroaryl-(CR) c R d ) 0-4 -, preferably -(CR) c R d ) 1-4 -; R c and R d Independently selected from H and C 1-4 Alkyl or C 3-5 cycloalkyl; Preferably, L1 is selected from: L2 is A1 is a lysine residue; A2 is selected from tyrosine residues, aspartic acid residues, or serine residues; A3 is a lysine residue; A4 is selected from glutamic acid residues, pyroglutamic acid residues, citrulline residues, or aspartic acid residues; Z is selected from DOTAGA, USE、 NODAGA, DOTA、 HBED-CC、 p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA; 2-(4-isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid p-SCN-Bn-DOTA;2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. The compound of any one of claims 1-10, wherein, L2 is selected from: The compound of claim 2, wherein, The compound has a structure of formula (II), (II-1), or (II-2): in, R1 and R2 are independently selected from H, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; m is selected from 0, 1, 2, 3, 4 or 5; L1 is selected from -W1-W2-C(O)- or -W1-V1-V2-W2-C(O)-; W1 is selected from chemical bonds, -NR-, C(O)-, or -NR-C(O)-; W2 is selected from C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group; V1 is -(CR) a R b ) 1-6 -; V2 is selected from -NR-, C(O)-, or -NR-C(O)-; R a and R b Independently selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-C 6-14 Aryl or -C 1-6 alkylene-5-14-membered heteroaryl; R is selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; L1 can be optionally replaced by one, two, or three R*s; R* is selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; L2 is A1, A2, A3, and A4 are amino acid residues; Z is a chelating group derived from the chelating agent; Preferably, R1 is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, preferably H or C 1-6 alkyl; R2 is selected from H, halogen, or C. 1-6 Alkyl groups, preferably H or halogens; m is selected from 0, 1, 2, or 3; L1 is selected from -C 1-6 Alkylene -C(O)-, -C 2-6 alkenyl-C(O)-, -C 2-6 Ethyne-C(O)-, -NR-C 1-6 Alkylene-C(O)-, -NR-C(O)-C 1-6 Alkylene-C(O)-, Wherein, R is independently selected from H or C. 1-6 Alkyl group, Ar is independently selected from phenyl, naphthyl, anthraceneyl or phenanthryl, and n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L1 can be optionally replaced by one, two, or three R*s; R* is selected from H or C 1-4 alkyl; L2 is A1 is a lysine residue; A2 is selected from tyrosine residues, aspartic acid residues, or serine residues; A3 is a lysine residue; A4 is selected from glutamic acid residues, pyroglutamic acid residues, citrulline residues, or aspartic acid residues; Z is a chelating group derived from a chelating agent, which is selected from the following: 1,4,7,10-Tetraazacyclododecane-N,N',N",N”'-Tetraacetic acid (DOTA) N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC) 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA), 1,4,7-Triazacyclononanephosphonic acid (TRAP) 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO) Diethyltriaminepentaacetic acid (DTPA) trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA) 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A) p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B), 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA), [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), 6-Hydroxypyridine-3-carboxylic acid (HYNIC) 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA); Preferably, R1 is selected from H or C. 1-6 Alkyl groups, such as H or CH3; R2 is selected from H or halogens, such as H or F; m is selected from 1 or 2; L1 is selected from -C 1-6 alkylene-C(O)- or Wherein, R is selected from H or C. 1-6 Alkyl, Ar is selected from phenyl, naphthyl, anthraceneyl or phenanthryl, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L1 can be optionally replaced by one, two, or three R*s; R* is selected from H or C 1-4 alkyl; For example, L1 is selected from: L2 is selected from: Z is selected from DOTAGA, USE、 NODAGA, DOTA、 HBED-CC、 p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA、 p-SCN-Bn-DOTA. The compound of claim 2, wherein, The compound has a structure of formula (VII), (VII-1), or (VII-2): in, R1 and R2 are independently selected from H, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Rn is selected from CN, OH, or NH2; m is selected from 0, 1, 2, 3, 4 or 5; W0 is selected from chemical bonds, -C(O)-(CR) c R d ) 1-6 -、-C(O)-C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -、-C(O)-3-7 membered heterocyclic group-(CR c R d ) 0-6 -、-C(O)-C 6-10 Aspartic-(CR) c R d ) 0-6 -or-C(O)-5-10 heteroaryl-(CR c R d ) 0-6 -; W1 is selected from -C(O)-, -OC(O)-, -C(O)-NR-, or -NR-C(O)-; W2 is selected from C 1-10 Alkylene, C 2-10 imide or C 2-10 Ethyne group; V1 is selected from chemical bonds or -(CR) a R b ) 1-10 -; V2 is selected from chemical bonds, -O-, -NR-, C(O)-, or -NR-C(O)-; R a and R b Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-C 6-14 Aryl or -C 1-6 alkylene-5-14-membered heteroaryl; R c and R d Independently selected from H, D, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups; A1, A2, A3, and A4 are amino acid residues; Z is a chelating group derived from the chelating agent; Preferably, R1 is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, preferably H or C 1-6 alkyl; R2 is selected from H, halogen, or C. 1-6 Alkyl groups, preferably H or halogens; Rn is selected from CN, OH, or NH2; m is selected from 0, 1, 2, or 3; -W0-W1-V1-V2-W2-C(O)- is for R is selected from H or C. 1-6 alkyl; Ar is selected from phenyl, naphthyl, anthraceneyl, or phenanthrene; n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; L W Selected from -(CR) c R d ) 1-6 -、-C 3-7 Cycloalkylene-(CR) c R d ) 0-6 -, 3-7 membered heterocyclic group-(CR) c R d ) 0-6 -、C 6-10 Aspartic-(CR) c R d ) 0-6 -or 5-10% heteroaryl-(CR) c R d ) 0-6 -, preferably -(CR) c R d ) 1-6 -, for example -CH2-; R c and R d Independently selected from H and C 1-6 Alkyl or C 3-5 Cycloalkyl, preferably H; L1 can be optionally replaced by one, two, or three R*s; R* is selected from H and C. 1-4 Alkyl or C 3-5 cycloalkyl; A1 is a lysine residue; A2 is selected from tyrosine residues, aspartic acid residues, or serine residues; A3 is a lysine residue; A4 is selected from glutamic acid residues, pyroglutamic acid residues, citrulline residues, or aspartic acid residues; Z is a chelating group derived from a chelating agent, which is selected from the following: 1,4,7,10-Tetraazacyclododecane-N,N',N",N”'-Tetraacetic acid (DOTA) N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC) 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA), 1,4,7-Triazacyclononanephosphonic acid (TRAP) 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO) Diethyltriaminepentaacetic acid (DTPA) trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA) 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A) p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B), 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA), [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), 6-Hydroxypyridine-3-carboxylic acid (HYNIC) 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA); Preferably, R1 is selected from H or C. 1-6 Alkyl groups, such as H or CH3; R2 is selected from H or halogens, such as H or F; Rn is selected from CN, OH or NH2, preferably CN; m is selected from 1 or 2; -W0-W1-V1-V2-W2-C(O)- is selected from the following structures: Preferred Selected from: Z is selected from DOTAGA, USE、 NODAGA, DOTA、 HBED-CC、 p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA、 p-SCN-Bn-DOTA. The compound of any one of claims 1-13, wherein, The compound is selected from: *1, *2, *3, *4, *5, *6, *7 and *8 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; R1 is selected from H or C. 1-4 Alkyl groups, such as H or methyl groups; W1 is selected from chemical bonds, -O-, or -NR-; R is selected from H or C. 1-4 Alkyl groups, such as H or methyl groups; Ar is selected from phenyl, naphthyl, or anthracene, preferably phenyl or naphthyl; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8. The compound of any one of claims 1-14, wherein, The compound is selected from: Compounds, including compounds of formula (I), or isotopic variants thereof, hydrates, esters or solvates thereof, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, and M complexed therewith, in, Compound (I) is defined as claimed in any one of claims 1-15; M is selected from at least one of a radioactive nuclide or a non-radioactive element; Preferably, the radionuclide is selected from at least one of diagnostic or therapeutic radionuclides; Preferably, the diagnostic radionuclide is selected from... 68 Ga、 18 F, 99 mTc, 89 Zr、 124 I, 76 Br、 43 Sc、 111 In、 45 Ti、 52 Mn, 59 Fe、 64 Cu、 94 mTc, 67 Ga、 71 / 72 / 74 As、 82m Rb or 86 Y; Preferably, the therapeutic radionuclide is selected from... 177 Lu、 161 Tb, 90 Y、 131 I, 153 Sm、 67 Cu、 89 Sr、 166 Ho、 177 Yb、 47 Sc、 186 / 188 Re、 212 / 213 Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 225 Ac or 227 Th; Preferably, the radionuclide is selected from... 68 Ga、 18 F, 89 Zr、 99 mTc or 177 Lu; Preferably, M is selected from... 68 Ga、 18 F or 177 Lu; Preferably, the radionuclide 18 F is through 18 Formed by FAl complexation. Compound of formula (X), or its isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof: in, Ab, L1, and L2 are as defined in any one of claims 1-15; Z' is the coordination group formed by the complexation of Z and M, and Z is defined as in any one of claims 1-15; M is selected from at least one of a radioactive nuclide or a non-radioactive element; Preferably, the radionuclide is selected from at least one of diagnostic or therapeutic radionuclides; Preferably, the diagnostic radionuclide is selected from... 68 Ga、 18 F, 99 mTc, 89 Zr、 124 I, 76 Br、 43 Sc、 111 In、 45 Ti、 52 Mn, 59 Fe、 64 Cu、 94 mTc, 67 Ga、 71 / 72 / 74 As、 82m Rb or 86 Y; Preferably, the therapeutic radionuclide is selected from... 177 Lu、 161 Tb, 90 Y、 131 I, 153 Sm、 67 Cu、 89 Sr、 166 Ho、 177 Yb、 47 Sc、 186 / 188 Re、 212 / 213 Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 225 Ac or 227 Th; Preferably, the radionuclide is selected from... 68 Ga、 18 F, 89 Zr、 99 mTc, 161 Tb or 177 Lu; Preferably, M is selected from... 68 Ga、 18 F or 177 Lu; Preferably, the radionuclide 18 F is through 18 Formed by FAl complexation. A pharmaceutical composition comprising the compound of claims 1-17, or an isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient. Use of the compound of claims 1-17, or its isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 18, in the preparation of a medicament for inhibiting FAP expression. The compound of claims 1-17, or its isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 18, for inhibiting FAP expression. A method for inhibiting FAP expression, wherein, The method is to administer to a subject the compound of claims 1-17, or an isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18. Use of the compound of claims 1-17, or its isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 18, in the preparation of reagents and / or pharmaceuticals for the diagnosis and / or treatment of one or more tumors, cancers or cells expressing FAP. The compound of claims 1-17, or its isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 18, for the diagnosis and / or treatment of one or more tumors, cancers or cells expressing FAP. A method for diagnosing and / or treating one or more tumors or cancers expressing FAP, wherein, The method is to administer to a subject the compound of claims 1-17, or an isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18. The use of claim 22, the compound or pharmaceutical composition of claim 23, or the method of claim 24, wherein, The diagnostic method is selected from emission computed tomography, including PET imaging and / or SPECT imaging; Preferably, the treatment is selected from radiotherapy. The use, compound, pharmaceutical composition, or method of claim 25, wherein, The tumors and cancers expressing FAP are selected from melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, head and neck cancer, gastric cancer, follicular dendritic cell sarcoma (FDCS), fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, cervical cancer, bladder cancer, brain cancer, or neuroendocrine tumors. Preferably, the tumors or cancers expressing FAP are selected from follicular dendritic cell sarcoma (FDCS), gastric cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, and ovarian cancer. A method for imaging tissues expressing FAP, wherein, This includes administering the compound of claims 1-17, or isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 18, to the tissue, and imaging the tissue after administration. Preferably, the imaging is emission computed tomography, performed by positron emission tomography or single-photon emission computed tomography.

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