Radiopharmaceutical targeting carbonic anhydrase ix protein

Abstract

Disclosed in the present invention is a radiopharmaceutical targeting the carbonic anhydrase IX protein. Specifically, the radiopharmaceutical is a compound of formula (I) and can be used for diagnosing or treating diseases in which the carbonic anhydrase IX protein is overexpressed.

Description

Radiopharmaceuticals targeting carbonic anhydrase IX protein

[0001] This application claims priority to Chinese application CN202411595249.1 filed on November 8, 2024, Chinese application CN202510993967.2 filed on July 17, 2025, and Chinese application CN202511591437.1 filed on October 31, 2025, which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention relates to the pharmaceutical field, specifically to a radiopharmaceutical targeting the carbonic anhydrase IX (CAIX) protein. Background Technology

[0003] Various α-carbonic anhydrases (α-CAs) are distributed in most organs and tissues of the human body, while one type of CA dominates in some organs and tissues. The dominant CAs in the liver are CAVA / XIV, while CAIX / XII are dominant in most hypoxic solid tumors. In the blood, CAAI / II is one of the main protein components of erythrocytes. Tumor-specifically expressed CAIX / XII are transmembrane proteins. CAIX is stably expressed in tumors such as renal cell carcinoma (RCC), not expressed in normal kidney tissue, and only weakly expressed in organs and tissues other than the kidney. Therefore, CAIX is a potentially excellent target for the diagnosis and treatment of ccRCC. CAIX is also overexpressed in many other types of tumors, such as lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, melanoma, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head and neck cancer, astrocytoma, and oral cancer.

[0004] Overexpressed CAIX in tumors catalyzes the hydration of carbon dioxide, generating bicarbonate ions and protons, thus regulating the pH of the cellular environment. Increased acidity in the local cellular microenvironment activates the VEGF signaling pathway, promoting angiogenesis and playing a crucial role in tumor development and progression. Most CA-targeting inhibitors bind to the metal-active center of the extracellular enzyme catalytic domain of CAIX to block its catalytic activity. Phosphorylation of the intracellular CAIX domain allows it to participate in the regulation of glucose metabolism. The structures of CAIX-specific inhibitors are mostly based on sulfonamide structures, with modifications such as ionization, hypoxia-activated structuring, glycosylation, and nanoparticle inclusion. Labeling of small CAIX inhibitor molecules with therapeutic radionuclides can be used for molecular imaging diagnosis and treatment of tumors.

[0005] Currently, surgical resection is the effective treatment for RCC. However, the 5-year recurrence rate for localized RCC is 30% (or approximately 50%), while surgery is not an option for advanced or metastatic RCC. High-dose interleukin-2 is the classic effective drug for metastatic RCC, but it only produces a sustained complete response in 7-10% of patients. Therefore, developing more sensitive and accurate early diagnostic strategies, as well as effective systemic therapies for advanced and metastatic RCC, remains a challenge that needs to be addressed and resolved for patients at high risk of recurrence. Developing better CAIX-targeted drugs and CAIX inhibitors for molecular imaging diagnosis and treatment has significant research value and broad application prospects. Summary of the Invention

[0006] This invention provides a radiopharmaceutical of carbonic anhydrase IX protein, which can be used to diagnose and / or treat diseases that overexpress carbonic anhydrase IX protein.

[0007] The radiopharmaceutical targeting carbonic anhydrase IX protein described in this invention has the following advantages:

[0008] (1) It is metabolized quickly in the body and has little toxic side effects on non-target organs;

[0009] (2) It specifically targets tumors and has low uptake of non-target organs in the body, which facilitates imaging and is beneficial to clinical diagnosis.

[0010] (3) It specifically targets the tumor and stays at the tumor site for a long time, resulting in good therapeutic effects on the tumor;

[0011] (4) It has low uptake in non-target organs, low toxicity to normal tissues, and good safety.

[0012] 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:

[0013] The variables are as defined in this invention.

[0014] 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,

[0015] Compounds of formula (I) are as defined in this invention;

[0016] M is selected from at least one of radioactive nuclides or non-radioactive elements.

[0017] In another respect, the present invention relates to compounds of formula (V), or isotopic variants, hydrates, esters or solvates thereof, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0018] Wherein, Ab, L1 and L2 are as defined in this invention;

[0019] 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;

[0020] M is selected from at least one of radioactive nuclides or non-radioactive elements.

[0021] 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.

[0022] Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0023] In another aspect, the present invention relates to the use of the compounds of the present invention, or isotopic variants thereof, hydrates, esters or solvates, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical compositions of the present invention in the preparation of a medicament for inhibiting the expression of carbonic anhydrase IX.

[0024] In another aspect, the present invention relates to compounds of the present invention, or isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention for inhibiting the expression of carbonic anhydrase IX.

[0025] In another aspect, the present invention relates to a method for inhibiting the expression of carbonic anhydrase IX, the method comprising administering to a subject a compound of the present invention, or an isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0026] In another aspect, the present invention relates to the use of compounds of the present invention, or isotopic variants thereof, hydrates, esters or solvates, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or 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 carbonic anhydrase IX.

[0027] In another aspect, the present invention relates to compounds of the present invention, or isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention for the diagnosis and / or treatment of one or more tumors, cancers or cells expressing carbonic anhydrase IX.

[0028] In another aspect, the present invention relates to a method for diagnosing and / or treating one or more tumors, cancers or cells expressing carbonic anhydrase IX, the method comprising administering to a subject a compound of the present invention, or an isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0029] 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.

[0030] On the other hand, the treatment is selected from radiotherapy and / or fluorescent surgical navigation to assist in surgery.

[0031] On the other hand, the diseases associated with carbonic anhydrase IX expression are selected from tumors.

[0032] On the other hand, the diseases associated with carbonic anhydrase IX expression are selected from kidney cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, melanoma, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head and neck cancer, astrocytoma, and oral cancer.

[0033] In another aspect, the present invention relates to a method for imaging tissues expressing carbonic anhydrase IX, comprising administering to the tissue a compound of the present invention, or an isotopic variant thereof, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and imaging the tissue after administration.

[0034] On the other hand, the imaging is emission computed tomography, performed by positron emission tomography or single-photon emission computed tomography.

[0035] definition

[0036] Chemical definition

[0037] The definitions of specific functional groups and chemical terms are described in more detail below.

[0038] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C1-5 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.

[0039] “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.

[0040] “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 2-6Examples 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.

[0041] “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 The alkynyl group is 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.

[0042] “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 1-2Alkylenes 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.

[0043] “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 2-3 Alkenyl 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.

[0044] “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.

[0045] “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.

[0046] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0047] 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 Halogenated alkyl groups are particularly preferred. In some embodiments, C 1-6 Halogenated alkyl groups are particularly preferred. In some embodiments, C 1-4 Halogenated alkyl 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.

[0048] “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 5-6 Cycloalkyl 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.

[0049] “C 3-10 "Cycloalkylene" refers to the alkylene group after removing C24. 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.

[0050] "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.

[0051] "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 cyclopropylene, tetrahydrofuranylene, and pyranylene.

[0052] “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.

[0053] "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.

[0054] “C 6-14 "Asyl" refers to the group that has been depleted of C.6-14 The 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 the preferred option.

[0055] "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 is preferred. In some embodiments, 5-6-membered heteroaryl is preferred, for example, pyridine (e.g., ... ), furanyl (e.g.) ) or thiophene group (e.g. ).

[0056] "Optionally replaced by..." means that it can be replaced by a specified substituent or not replaced.

[0057] 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".

[0058] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0059] 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 bbCO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )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 bbP(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )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;

[0060] 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;

[0061] 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;

[0062] 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, ynyl, 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;

[0063] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, 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;

[0064] 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(Rff )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;

[0065] 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;

[0066] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ffThe 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. gg Group substitution;

[0067] 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 1-6Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -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.

[0068] 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、-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 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.

[0069] Other definitions

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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).

[0075] 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.

[0076] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0077] 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”).

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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

[0082] Figure 1 shows the detection patterns of compound 1: (a) LCMS detection pattern, (b) HPLC detection pattern;

[0083] Figure 2 shows the detection patterns of compound 2: (a) LCMS detection pattern, (b) HPLC detection pattern;

[0084] Figure 3 shows the results of radioactive thin-layer chromatography scanning of compound 1 after radiolabeling: (a) 68 Ga-Compound 1, (b) 177 Lu-compound 1;

[0085] Figure 4 shows the results of radioactive thin-layer chromatography (TLC) scanning of compound 2 after radiolabeling: (a) 68 Ga-Compound 2, (b) 177 Lu-compound 2;

[0086] Figure 5 shows the different time points after drug administration. 68 PET / CT imaging results of Ga-compound 1 on OS-RC-2 model mice;

[0087] Figure 6 shows the different time points after drug administration. 68 Figure 1 shows the uptake results of Ga-compound 1 in different tissues of OS-RC-2 model mice;

[0088] Figure 7 shows the results 1 hour after drug administration. 68 PET / CT imaging results of Ga-compound 1 on OS-RC-2 model mice;

[0089] Figure 8 shows the results at 1 hour and 4 hours after drug administration. 68 Distribution of Ga-compound 1 in in vitro tissues of the OS-RC-2 model;

[0090] Figure 9 shows the different time points after drug administration. 177 PET / CT imaging results of Lu-compound 1 on OS-RC-2 model mice;

[0091] Figure 10 shows the results at 4 hours and 48 hours after drug administration. 177 Distribution of Lu-compound 1 in in vitro tissues of the OS-RC-2 model;

[0092] Figure 11 shows the post-administration results. 68Changes in blood drug concentrations of Ga-compound 1 in ICR mice;

[0093] Figure 12 illustrates the drug administration. 177 Changes in tumor volume and body weight in OS-RC-2 model mice of Lu-compound 1;

[0094] Figure 13 shows the different time points after drug administration. 68 PET / CT imaging results of Ga-compound 2 on OS-RC-2 model mice;

[0095] Figure 14 shows the different time points after drug administration. 68 Figure 1. Uptake of Ga-compound 2 in different tissues of OS-RC-2 model mice;

[0096] Figure 15 shows the results at 4 hours and 48 hours after drug administration. 677 Distribution of Lu-compound 2 in in vitro tissues of the OS-RC-2 model;

[0097] Figure 16 illustrates the drug administration. 177 (a) Tumor volume and (b) body weight changes in OS-RC-2 model mice of Lu-compound 2;

[0098] Figure 17 shows the detection patterns of compound 3: (a) LCMS detection pattern, (b) HPLC detection pattern;

[0099] Figure 18 shows the detection patterns of compound 4: (a) LCMS detection pattern, (b) HPLC detection pattern;

[0100] Figure 19 shows 161 Radiometric thin-layer chromatography scan of Tb-compound 2;

[0101] Figure 20 shows 68 Radiometric thin-layer chromatography scan results of Ga-compound 3;

[0102] Figure 21 shows 18 Radiometric thin-layer chromatography scan results of compound F-4;

[0103] Figure 22 shows the different time points after drug administration. 161 Distribution of Tb-compound 2 in in vitro tissues of the OS-RC-2 model;

[0104] Figure 23 illustrates the drug administration. 161 (a) Tumor volume and (b) body weight changes in OS-RC-2 model mice of Tb-compound 2;

[0105] Figure 24 shows the different time points after drug administration. 68 PET / CT imaging results of Ga-compound 3 on OS-RC-2 model mice;

[0106] Figure 25 shows the different time points after drug administration. 68 Figure 1. Uptake of Ga-compound 3 in different tissues of OS-RC-2 model mice;

[0107] Figure 26 shows the different time points after drug administration. 18 PET / CT imaging results of compound F4 in OS-RC-2 model mice;

[0108] Figure 27 shows the different time points after drug administration. 18 Figure 1. Uptake of F-compound 4 in different tissues of OS-RC-2 model mice;

[0109] Figure 28 shows the maximum intensity projection (MIP) images of patients in the clinical trial;

[0110] Figure 29 shows the detection patterns of compound 5: (a) LCMS detection pattern, (b) HPLC detection pattern;

[0111] Figure 30 shows the detection patterns of compound 6: (a) LCMS detection pattern, (b) HPLC detection pattern;

[0112] Figure 31 shows 68 Radiometric thin-layer chromatography scan of Ga-compound 5;

[0113] Figure 32 shows 68 Radiometric thin-layer chromatography scan of Ga-compound 6;

[0114] Figure 33 shows the different time points after drug administration. 68 PET / CT imaging results of Ga-compound 5 on OS-RC-2 model mice. Detailed Implementation Plan

[0115] In this document, “compounds of the present invention” refers to compounds of formula (I), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (IV-1), (IV-2), (IV-3), (V), etc., their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof.

[0116] 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.

[0117] 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:

[0118] in,

[0119] Ab is a ligand targeting carbonic anhydrase IX, for example

[0120] Ring A is selected from C 6-10 Aromatic and C 5-10 Hybrid aryl groups; optionally bounded by 1, 2, 3 or 4 R groups A replace;

[0121] R A Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups;

[0122] R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0123] Or R4 and R A Connected together to form C 1-4 Alkylene, C 2-4 imide and C 2-4 The ynyl group, wherein one or more methylene units are optionally and independently replaced by -CR*2-, -NR*-, -NR*C(O)-, -C(O)NR*-, -NR*S(O)2-, -S(O)2NR*-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; and R4 and RA The ring formed after connecting is a parallel ring structure of ring A;

[0124] V3 is selected from chemical bonds, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne and

[0125] Ring B is a 3-7 membered heterocyclic group;

[0126] W3 is selected from chemical bonds, -NR-, -O-, -S-, and -C(O)-;

[0127] R* is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0128] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0129] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-10 membered heterocyclic groups;

[0130] L1 is the linker base;

[0131] L2 is an amino acid chain consisting of 2-8 amino acid residues linked together, wherein each amino acid residue may optionally be further substituted by one or more amino acid residues, and said amino acid residues may optionally be substituted by 1, 2, 3, 4, 5 or 6 R's. L replace;

[0132] R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group;

[0133] Z is a chelating group derived from the chelating agent.

[0134] In another 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:

[0135] in,

[0136] Ab is a ligand targeting carbonic anhydrase IX, for example

[0137] Ring A is selected from C 6-10 Aromatic and C 5-10 Hybrid aryl groups; optionally bounded by 1, 2, 3 or 4 R groups A replace;

[0138] R A Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups;

[0139] R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0140] Or R4 and R A Connected together to form C 1-4 Alkylene, C 2-4 imide and C 2-4 The ynyl group, wherein one or more methylene units are optionally and independently replaced by -CR*2-, -NR*-, -NR*C(O)-, -C(O)NR*-, -NR*S(O)2-, -S(O)2NR*-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; and R4 and R A The ring formed after connecting is a parallel ring structure of ring A;

[0141] V3 is selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group;

[0142] W3 is selected from chemical bonds, -NR-, -O-, -S-, and -C(O)-;

[0143] R* is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0144] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0145] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-10 membered heterocyclic groups;

[0146] L1 is the linker base;

[0147] L2 is an amino acid chain consisting of 2-8 amino acid residues linked together, wherein each amino acid residue may optionally be further substituted by one or more amino acid residues, and said amino acid residues may optionally be substituted by 1, 2, 3, 4, 5 or 6 R's. L replace;

[0148] R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group;

[0149] Z is a chelating group derived from the chelating agent.

[0150] 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:

[0151] in,

[0152] A1, A2, and A3 are amino acid residues;

[0153] A4 is an H or an amino acid residue;

[0154] V1 is selected from C 1-10 Alkylene, C 2-10 imidene group, C2-10 Ethyne group, C 6-10 Aromatic and C 5-10 A heteroaryl group, optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. 1s replace;

[0155] R 1s Independently selected from H, D, -OR a -SR a -NR b R c Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0156] V2 is a chemical bond or -(CR'R”). 1-6 -;

[0157] R' and R" are independently selected from H, D, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-Ar;

[0158] Ar is independently selected from C 6-14 Aryl and 5-14 heteroaryl groups;

[0159] W4 is selected from chemical bonds, -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)O-, -C(O)NR-, and -O-;

[0160] n is 0, 1, 2, 3, 4, 5, or 6;

[0161] The remaining variables are as defined in this article.

[0162] 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.

[0163] in,

[0164] Compounds of formula (I) are as defined herein;

[0165] M is selected from at least one of radioactive nuclides or non-radioactive elements.

[0166] In another embodiment, the present invention provides a compound of formula (V), or an isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0167] in,

[0168] Ab, L1, and L2 are as defined in this paper;

[0169] 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;

[0170] M is selected from at least one of radioactive nuclides or non-radioactive elements.

[0171] In the compounds of this invention, the variables can be defined as follows.

[0172] Ab

[0173] In one implementation, Ab is a ligand targeting carbonic anhydrase IX, for example... In another implementation, Ab is Preferred Preferred In another implementation, Ab is Preferred Preferred In another implementation, Ab is Preferred Preferred In another implementation, Ab is Preferred Preferred Preferred

[0174] In a more specific implementation, Ab is selected from: In another, more specific implementation, Ab is selected from: In another, more specific implementation, Ab is selected from:

[0175] In a more specific implementation, Ab is selected from: In another, more specific implementation, Ab is selected from: In another, more specific implementation, Ab is selected from:

[0176] Ring A

[0177] In one implementation, ring A is C. 6-10 arylene, preferably phenylene; in another embodiment, ring A is C 5-10 Hybrid aryl, preferably C5-6 Heteroaryl, such as 1,3,4-thiadiazolyl; in another embodiment, ring A is optionally surrounded by 1, 2, 3 or 4 R groups. A Replacement; in another embodiment, ring A is not replaced.

[0178] In a more specific implementation, ring A is selected from C. 6-10 Aromatic and C 5-10 Heteroaryl; in another, more specific embodiment, ring A is selected from phenylene and C 5-6 Heteroaryl; in another more specific embodiment, ring A is selected from phenylene and 1,3,4-thiamethazolyl.

[0179] R A

[0180] 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 CN; in another embodiment, R A For -OR a In another implementation, R A For -SR a In another implementation, R A For -NR b R c In another implementation, R A C 1-6 Alkyl; in another embodiment, R A C 1-6 Halogenated alkyl; in another embodiment, R A C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R A It is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; in another embodiment, R A C 6-10 Aryl, preferably phenyl; in another embodiment, R A It is a 5-10 nucleotide heteroaryl group, preferably a 5-6 nucleotide heteroaryl group.

[0181] In a more specific implementation, R A Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl, C1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl; in another more specific embodiment, R A Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; in another more specific embodiment, R A Independently selected from H, D, halogens, and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0182] R3 and R4

[0183] In one embodiment, R3 is H; in another embodiment, R3 is a halogen; in yet another embodiment, R3 is C. 1-6 Alkyl; in another embodiment, R3 is C 1-6 Haloalkyl; in another embodiment, R3 is C 3-7 Cycloalkyl; in another embodiment, R3 is a 3-7 membered heterocyclic group.

[0184] In one embodiment, R4 is H; in another embodiment, R4 is a halogen; in yet another embodiment, R4 is C. 1-6 Alkyl; in another embodiment, R4 is C 1-6 Halogenated alkyl; in another embodiment, R4 is C 3-7 Cycloalkyl; in another embodiment, R4 is a 3-7 membered heterocyclic group.

[0185] In a more specific embodiment, R3 is independently selected from H, halogens, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; in another more specific embodiment, R3 is independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0186] In a more specific embodiment, R3 is independently selected from H, halogens, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups; in another, more specific embodiment, R4 is independently selected from H, halogen, C1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0187] In one implementation, R4 and R A Connected together to form C 1-4 Alkylene, preferably C 1-2 Alkylene; in another embodiment, R4 and R A Connected together to form C 2-4 alkenyl; in another embodiment, R4 and R A Connected together to form C 2-4 Alynyl group; in another embodiment, R4 and R A One or more (preferably 1, 2, or 3, preferably 1) methylene units in the linked groups are optionally and independently replaced by -CR*2-, -NR*-, -NR*C(O)-, -C(O)NR*-, -NR*S(O)2-, -S(O)2NR*-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; in another embodiment, R4 and R A One or more (preferably 1, 2, or 3, preferably 1) methylene units in the linked groups are optionally and independently replaced by -CR*2-, -NR*-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; in another embodiment, R4 and R A One or more (preferably 1, 2, or 3, preferably 1) methylene units in the linked groups are optionally and independently replaced by -CR*2-, -C(O)-, -OC(O)-, or -C(O)O- (preferably -C(O)-); in another embodiment, R4 and R A The ring formed after connecting is a parallel ring structure of ring A.

[0188] In a more specific implementation, R4 and R A Connected together to form C 1-4 Alkylene, C 2-4 imide and C 2-4 The ynyl group, wherein one or more methylene units are optionally and independently replaced by -CR*2-, -NR*-, -NR*C(O)-, -C(O)NR*-, -NR*S(O)2-, -S(O)2NR*-, -O-, -C(O-, -OC(O-), -C(O)O-, -S-, -S(O-, or -S(O)2-; in another more specific embodiment, R4 and R A Connected together to form C 1-4 Alkylene, preferably C 1-2Alkylene, wherein one, two, or three (preferably one) methylene units are optionally and independently replaced by -CR*2-, -NR*-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, preferably replaced by -CR*2-, -C(O)-, -OC(O)-, or -C(O)O-, preferably replaced by -C(O); in another more specific embodiment, R4 and R A The ring formed after connecting is a parallel ring structure of ring A.

[0189] V3 and Ring B

[0190] In one embodiment, V3 is a chemical bond; in another embodiment, V3 is a carbon bond. 1-10 Alkylene, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene, preferably C 1-2 Alkylene, such as -CH2CH2-, for example methylene; in another embodiment, V3 is C 2-10 alkenyl groups, preferably C 2-6 Ideonyl; in another embodiment, V3 is C 2-10 Alkyne group, preferably C 2-6 Ethyne group; in another embodiment, V3 is...

[0191] In one embodiment, ring B is a 3-7 membered heterocyclic group; in another embodiment, ring B is a 4-6 membered heterocyclic group; in yet another embodiment, ring B is a 5 membered heterocyclic group; in still another embodiment, ring B is...

[0192] In a more specific implementation, V3 is selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group; in another, more specific embodiment, V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group; in another, more specific embodiment, V3 is selected from chemical bonds and C 1-6 Alkylene (preferably C) 1-4 Alkylene, preferably C 1-2 (alkylene).

[0193] In a more specific implementation, V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne and In another, more specific embodiment, V3 is selected from chemical bonds, C 1-6 Alkylene (preferably C) 1-4 Alkylene, preferably C 1-2 alkylene) and In another, more specific embodiment, V3 is selected from chemical bonds and

[0194] W3

[0195] In one embodiment, W3 is a chemical bond; in another embodiment, W3 is -NR-, preferably -NH-; in another embodiment, W3 is -O-; in another embodiment, W3 is -S-; in another embodiment, W3 is -C(O)-.

[0196] In one more specific embodiment, W3 is selected from chemical bonds, -NR-, -O-, -S-, and -C(O)-; in another more specific embodiment, W3 is selected from -NR- and -O-.

[0197] In one more specific embodiment, W3 is selected from -NR-, -O-, and -C(O)-; in another more specific embodiment, W3 is selected from -NR- and -C(O)-.

[0198] R*

[0199] In one embodiment, R* is H; in another embodiment, R* is D; in yet another embodiment, R* is a halogen; in yet another embodiment, R* is C. 1-6 Alkyl; in another embodiment, R* is C 1-6 Halogenated alkyl groups.

[0200] In a more specific embodiment, R* is independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Haloalkyl; in another, more specific embodiment, R* is independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0201] R

[0202] In one implementation, R is H; in another implementation, R is C. 1-6 Alkyl; in another embodiment, R is C 1-6 Halogenated alkyl groups.

[0203] In a more specific implementation, R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0204] n

[0205] In one implementation, n is 0; in another 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.

[0206] In one more specific embodiment, n is 0, 1, 2, 3, 4, 5, or 6; in another more specific embodiment, n is 0, 1, 2, 3, or 4; in another more specific embodiment, n is 0, 1, or 2; in another more specific embodiment, n is 0 or 2.

[0207] R a R b and R c

[0208] In one implementation, R a H; in another embodiment, R a C 1-6 Alkyl; in another embodiment, R a C 1-6 Halogenated alkyl groups.

[0209] In one implementation, R b H; in another embodiment, R b C 1-6 Alkyl; in another embodiment, R b C 1-6 Halogenated alkyl groups.

[0210] In one implementation, R c H; in another embodiment, R c C 1-6 Alkyl; in another embodiment, R c C 1-6 Halogenated alkyl groups.

[0211] In a more specific implementation, R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0212] In one implementation, R b R c Together with the atoms they are connected to form 3-10 membered heterocyclic groups, preferably 3-7 membered heterocyclic groups.

[0213] L1

[0214] In one embodiment, L1 is a linker; in another embodiment, L1 is -W1-V1-W4-V2-W2-; in yet another embodiment, L1 is -C(O)-V1-W4-V2-C(O)-; in yet 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 In another implementation, L1 is In another implementation, L1 is Preferred In another implementation, L1 is Preferred In another implementation, L1 is Preferred

[0215] In a more specific implementation, L1 is selected from: (preferred) In another, more specific implementation, L1 is... (preferred) In another, more specific implementation, L1 is... (preferred) ).

[0216] In a more specific implementation, L1 is selected from: (preferred) ), (preferred) )and (preferred) In another, more specific implementation, L1 is... (preferred) )or (preferred) ).

[0217] W1

[0218] In one embodiment, W1 is a chemical bond; in another embodiment, W1 is -NR-; in another embodiment, W1 is -C(O)-; in another embodiment, W1 is -C(O)O-; in another embodiment, W1 is -C(O)NR-.

[0219] In one more specific embodiment, W1 is selected from chemical bonds, -NR-, -C(O)-, -C(O)O-, and -C(O)NR-; in another more specific embodiment, W1 is selected from -C(O)-, -C(O)O-, and -C(O)NR-.

[0220] In one more specific embodiment, W1 is selected from -NR-, -C(O)-, -C(O)O-, and -C(O)NR-; in another more specific embodiment, W1 is -NR- or -C(O)-.

[0221] W2

[0222] In one embodiment, W2 is -C(O)-; in another embodiment, W2 is -OC(O)-; in another embodiment, W2 is -NRC(O)-; in another embodiment, W2 is -NR-; in another embodiment, W2 is -C(O)NR-; in another embodiment, W2 is -O-.

[0223] In one more specific embodiment, W2 is selected from -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)NR- and -O-; in another more specific embodiment, W2 is selected from -C(O)-, -OC(O)- and -NRC(O)-.

[0224] V1 and m

[0225] In one implementation, V1 is C 1-10 Alkylene, preferably C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene, for example -(CH2) m -; In another implementation, V1 is C 2-10 alkenyl groups, preferably C 2-8 Ideonyl; in another embodiment, V1 is C 2-10 Alkyne group, preferably C 2-8 Ethyne group; in another embodiment, V1 is C 6-10 arylene, preferably phenylene; in another embodiment, V1 is C 5-10 Hybrid aryl, preferably C 5-6Hybrid aryl; in another embodiment, V1 is optionally surrounded by 1, 2, 3, 4, 5 or 6 R... 1s Substitution; in another embodiment, V1 is not substituted; in another embodiment, one or more (preferably 1, 2 or 3) methylene units of the alkylene, alkenylene and alkyneylene groups are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -NRS(O)2-, -S(O)2NR-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; in another embodiment, one or more (preferably 1, 2 or 3) methylene units of the alkylene, alkenylene and alkyneylene groups are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -C(O)-, -OC(O)- or -C(O)O-.

[0226] In a more specific implementation, V1 is selected from C. 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne group, C 6-10 Aromatic and C 5-10 Hypoaryl; in another more specific embodiment, V1 is selected from C 1-8 Alkylene, C 2-8 imidene group, C 2-8 Alynyl, phenylene and C 5-6 Hypoaryl; in another more specific embodiment, V1 is selected from C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group; in another, more specific embodiment, V1 is selected from C 1-6 Alkylene (e.g., -(CH2)) m -), phenylene and C 5-6 Hypoaryl; in another more specific embodiment, V1 is selected from C 1-6 Alkylene (e.g., -(CH2)) m-), phenylene, pyrrolidine, furanyl, or thiophene; in another more specific embodiment, one or more methylene units of the alkylene, alkenyl, and alkyneyl groups are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -NRS(O)2-, -S(O)2NR-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; in another more specific embodiment, one, two, or three methylene units of the alkylene, alkenyl, and alkyneyl groups are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -C(O)-, -OC(O)-, or -C(O)O-.

[0227] In one embodiment, m is 1; in another embodiment, m is 2; in another embodiment, m is 3; in another embodiment, m is 4; in another embodiment, m is 5; in another embodiment, m is 6; in another embodiment, m is 7; in another embodiment, m is 8.

[0228] In one more specific embodiment, m is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8; in another more specific embodiment, m is independently selected from 1, 2, 3, 4, 5 or 6; in yet another more specific embodiment, m is independently selected from 1, 2, 3 or 4.

[0229] R 1s

[0230] In one implementation, R 1s H; in another embodiment, R 1s For D; in another implementation, R 1s For -OR a In another implementation, R 1s For -SR a In another implementation, R 1s For -NR b R c In another implementation, R 1s It is a halogen; in another embodiment, R 1s C 1-6 Alkyl; in another embodiment, R 1s C 1-6 Halogenated alkyl; in another embodiment, R 1s C 3-7 cycloalkyl; in another embodiment, R 1s It is a 3-7 membered heterocyclic group; in another embodiment, R 1sFor the (S) configuration; in another embodiment, R 1s For the (R) configuration; in another embodiment, R 1s It is in racemic form.

[0231] In a more specific implementation, R 1s Independently selected from H, D, -OR a -SR a -NR b R c Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; in another more specific embodiment, R 1s Independently selected from H, D, -OR a -NR b R c Halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in another, more specific embodiment, R 1s Independently selected from H, D, -OR a and -NR b R c In another, more specific implementation, R 1s Independently selected from H, D, -OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl; in another, more specific embodiment, R 1s Independently selected from H and -OR a In another, more specific implementation, R 1s Independently selected from H and D; in another, more specific implementation, R 1s It can be independently of the (S) or (R) configuration, or in a racemic form.

[0232] In a more specific implementation, R 1s Independently selected from H, -OR a -NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl; in another, more specific embodiment, R 1s Independently selected from H, -OR a and -NR b R c In another, more specific implementation, R 1s Independently selected from H and -NR b R c ;

[0233] V2

[0234] In one embodiment, V2 is a chemical bond; in another embodiment, V2 is -(CR'R”). 1-6 -, for example -CR'R”-, for example -(CR'R”)2-, for example -(CR'R”)3-, for example -(CR'R”)4-, for example -(CR'R”)5-, for example -(CR'R”)6-, preferably -(CR'R”) 1-4 -, Preferred - (CR'R”) 1-2 -, preferred -CHR'-.

[0235] In a more specific embodiment, V2 is a chemical bond or -(CR'R”). 1-6 -; In another, more specific embodiment, V2 is a chemical bond or -(CR'R”). 1-4 -; In another, more specific embodiment, V2 is a chemical bond or -(CR'R”). 1-2 -; In another, more specific embodiment, V2 is a chemical bond or -CHR'-.

[0236] R', R" and Ar

[0237] In one embodiment, R' is H; in another embodiment, R' is D; in yet another embodiment, R' is a halogen; in yet another embodiment, R' is C. 1-6 Alkyl; in another embodiment, R' is C 1-6 Halogenated alkyl; in another embodiment, R' is -C 1-6 Alkylene-Ar, preferably -C 1-4 Alkylene-Ar, preferably -CH2-Ar; in another embodiment, R' is in the (S) configuration; in another embodiment, R' is in the (R) configuration; in another embodiment, R' is in the racemic form.

[0238] In one embodiment, R” is H; in another embodiment, R” is D; in yet another embodiment, R” is a halogen; in yet another embodiment, R” is C. 1-6 Alkyl; in another embodiment, R” is C 1-6 Haloalkyl; in another embodiment, R” is -C 1-6 Alkylene-Ar, preferably -C 1-4 Alkylene-Ar, preferably -CH2-Ar; in another embodiment, R” is in the (S) configuration; in another embodiment, R” is in the (R) configuration; in another embodiment, R” is in the racemic form.

[0239] In a more specific embodiment, R' is independently selected from H, D, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-Ar; in another, more specific embodiment, R' is independently selected from H, D, or -C. 1-4 Alkylene-Ar; in another, more specific embodiment, R' is independently selected from H or -C. 1-4 Alkylene-Ar; in another more specific embodiment, R' is independently H or -CH2-Ar; in another more specific embodiment, R' is independently (S) or (R) configuration, or racemic form.

[0240] In a more specific implementation, R is independently selected from H, D, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-Ar; in another, more specific embodiment, R" is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; in another, more specific embodiment, R” is independently selected from H, D, C. 1-6 Alkyl and C 1-6 Halogenated alkyl; in another more specific embodiment, R” is independently H or D.

[0241] In one implementation, Ar is C 6-14 Aryl groups, such as phenyl, naphthyl, anthraceneyl, or phenanthrene, preferably C 6-10 Aryl, such as phenyl or naphthyl, preferably naphthyl, preferably 2-naphthyl; in another embodiment, Ar is a 5-14-membered heteroaryl, preferably a 5-10-membered heteroaryl.

[0242] In a more specific implementation, Ar is independently selected from C. 6-14 Aryl and 5-14 heteroaryl; in another, more specific embodiment, Ar is C 6-10 Aryl, such as phenyl or naphthyl, preferably naphthyl, preferably 2-naphthyl; in another more specific embodiment, Ar is independently selected from C 6-10 Aryl and 5-10 heteroaryl compounds.

[0243] W4

[0244] In one embodiment, W4 is a chemical bond; in another embodiment, W4 is -C(O)-; in another embodiment, W4 is -OC(O)-; in another embodiment, W4 is -NRC(O)-; in another embodiment, W4 is -NR-; in another embodiment, W4 is -C(O)O-; in another embodiment, W4 is -C(O)NR-, preferably -C(O)NH-; in another embodiment, W4 is -O-.

[0245] In one more specific embodiment, W4 is selected from chemical bonds, -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)O-, -C(O)NR-, and -O-; in another more specific embodiment, W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O-, and -C(O)NR-; in another more specific embodiment, W4 is a chemical bond or -C(O)NR-.

[0246] L2

[0247] 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 embodiment, the amino acid residues in L2 are optionally surrounded by 1, 2, 3, 4, 5 or 6 (preferably 1, 2, 3 or 4) R L Substitution; in another embodiment, the amino acid residues in L2 are not substituted.

[0248] In another implementation, L2 is Preferred Preferred In another implementation, L2 is In another implementation, L2 is In another implementation, L2 is Preferred In another implementation, L2 is In another implementation, L2 is In another implementation, L2 is Preferred In another implementation, L2 is Preferred In another implementation, L2 is Preferred In another implementation, L2 is Preferred In another implementation, L2 is Preferred In another implementation, L2 is Preferred In another implementation, L2 is Preferred

[0249] In a more specific embodiment, L2 is an amino acid chain consisting of 2-8 amino acid residues linked together, wherein each amino acid residue is optionally further substituted by one or more amino acid residues, and said amino acid residues are optionally substituted by 1, 2, 3, 4, 5 or 6 R... L Substitution; in another more specific embodiment, L2 is an amino acid chain of 2-5 amino acid residues linked together, wherein each amino acid residue may optionally be further substituted by one or more (preferably 1, 2 or 3, preferably 1) amino acid residues, and said amino acid residues may optionally be substituted by 1, 2, 3, 4, 5 or 6 R L Replace; in another, more specific implementation, L2 is It can be optionally divided by 1, 2, 3, 4, 5 or 6 Rs. L Instead; in another, more specific implementation, L2 is selected from: (preferred) In another, more specific implementation, L2 is selected from: (preferred) Preferred ), (preferred) ), (preferred) ), (preferred) ), (preferred) ), (preferred) ), (preferred) ), (preferred) )and (preferred) ).

[0250] R L

[0251] In one implementation, R L It is a halogen, such as I; in another embodiment, R L For NO2; in another embodiment, R L For -OR a In another implementation, R L For -NR b R c In another implementation, R L C 1-6 Alkyl; in another embodiment, R L C 1-6 Halogenated alkyl; in another embodiment, R L The group is urea (-NHC(O)NH2); in another embodiment, R L C 1-6 Acyl group, such as acetyl group; in another embodiment, R L -C(O)-C 1-6 Alkylene-COOH, such as -C(O)-(CH2)4-COOH; in another embodiment, R L It is a sulfonic acid group; in another embodiment, R L It is methanesulfonyl; in another embodiment, R L It is a phosphate group; in another embodiment, R L It is a phosphorous group.

[0252] In a more specific implementation, R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group; in another more specific embodiment, R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 alkylene-COOH; in another, more specific embodiment, R L Independently selected from halogens, C1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 alkylene-COOH; in another, more specific embodiment, R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and urea groups; in another more specific embodiment, R L Independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and urea groups.

[0253] A1, A2, A3 and A4

[0254] 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 an arginine residue; in another embodiment, A1 is... Preferred Preferred In another embodiment, A1 is optionally represented by 1, 2, 3, 4, 5, or 6 R's. L Replacement; in another embodiment, A1 is not replaced.

[0255] 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 an arginine residue; in another embodiment, A2 is... Preferred Preferred In another implementation, A2 is Preferred In another implementation, A2 is In another implementation, A2 is In another implementation, A2 is Preferred In another implementation, A2 is Preferred In another implementation, A2 is Preferred In another implementation, A2 is Preferred In another embodiment, A2 is optionally represented by 1, 2, 3, 4, 5, or 6 R's. L In another embodiment, A2 is not replaced.

[0256] 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 an arginine residue; in another embodiment, A3 is... Preferred Preferred In another embodiment, A3 is optionally represented by 1, 2, 3, 4, 5, or 6 R's. L Replacement; in another implementation, A3 is not replaced.

[0257] 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; in another embodiment, A4 is an arginine residue; in another embodiment, A4 is... Preferred In another implementation, A4 is Preferred In another implementation, A4 is Preferred In another implementation, A4 is Preferred In another implementation, A4 is In another implementation, A4 is In another embodiment, A4 is optionally divided by 1, 2, 3, 4, 5 or 6 Rs. L Substitution, for example, A4 is an N-acetylglutamic acid residue, such as A4 being N-(4-carboxybutyryl)glutamic acid; in another embodiment, A4 is not substituted.

[0258] 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, citrulline residues, or arginine 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, citrulline residues, phenylalanine residues, or arginine residues; in yet another more specific embodiment, A1 is a lysine residue, preferably. Preferred Preferred

[0259] 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, citrulline residues, or arginine 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, citrulline residues, phenylalanine residues, or arginine residues; in yet another more specific embodiment, A2 is selected from tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, phenylalanine residues, or arginine residues; in yet another more specific embodiment, A2 is selected from... (Preferred) Preferred ), (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) )and (Preferred) ).

[0260] 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, citrulline residues, or arginine 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, citrulline residues, phenylalanine residues, or arginine residues; in yet another more specific embodiment, A3 is a lysine residue, preferably. Preferred Preferred

[0261] 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 residues, alanine residues, phenylalanine residues, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, or arginine residues; in yet another more specific embodiment, A4 is selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, phenylalanine residues, or arginine residues; in yet another more specific embodiment, A4 is selected from N-acetylglutamic acid residues, N-(4-carboxybutyryl)glutamic acid, glutamic acid residues, pyroglutamic acid residues, citrulline residues, and aspartic acid residues; in yet another more specific embodiment, A4 is selected from... (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ),

[0262] Z

[0263] 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).

[0264] 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.

[0265] 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).

[0266] N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC)

[0267] 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA)

[0268] 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA),

[0269] 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA),

[0270] 1,4,7-Triazacyclononanephosphonic acid (TRAP)

[0271] 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO),

[0272] 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA),

[0273] N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO)

[0274] Diethyltriaminepentaacetic acid (DTPA)

[0275] trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA)

[0276] 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A)

[0277] p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA),

[0278] 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M),

[0279] 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B),

[0280] 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA),

[0281] [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA),

[0282] 6-Hydroxypyridine-3-carboxylic acid (HYNIC)

[0283] 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or

[0284] 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA).

[0285] 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 or NOTA; In another, more specific implementation, Z is DOTA.

[0286] Chiral centers *1, *2, *3, *4, *5, *6 and *7

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] In one embodiment, *8 is an (S) configuration; in another embodiment, *8 is an (R) configuration; in yet another embodiment, *8 is a racemic form.

[0295] In one embodiment, *9 is an (S) configuration; in another embodiment, *9 is an (R) configuration; in yet another embodiment, *9 is a racemic form.

[0296] *1, *2, *3, *4, *5, *6, *7, *8 and *9 are independently selected from (S) or (R) configurations, or are racemic forms.

[0297] M

[0298] 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 is43 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 64 Cu; 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 implementation, 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.

[0299] 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 / 74 As、 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.

[0300] Z'

[0301] In one embodiment, Z' is a coordinating group formed by the complexation of a chelating group Z derived from a chelating agent and M.

[0302] 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 of Ab or any combination thereof can be combined with rings A and R. A, R3, R4, V3, W3, ring B, R*, R, n, R a R b R c L1, W1, W2, V1, m, R 1s This invention may combine any technical solution or any combination thereof, including V2, R', R”, Ar, W4, L2, A1, A2, A3, A4, Z, M, Z', *1, *2, *3, *4, *5, *6, *7, *8, and *9. The present invention aims to include combinations of all these technical solutions; due to space limitations, they will not be listed individually.

[0303] In a more specific 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:

[0304] in,

[0305] Ab is a ligand targeting carbonic anhydrase IX, for example

[0306] Ring A is selected from C 6-10 Aromatic and C 5-10 Hybrid aryl groups; optionally bounded by 1, 2, 3 or 4 R groups A replace;

[0307] R A Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups;

[0308] R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0309] Or R4 and R A Connected together to form C 1-4 Alkylene, C 2-4 imide and C 2-4The ynyl group, wherein one or more methylene units are optionally and independently replaced by -CR*2-, -NR*-, -NR*C(O)-, -C(O)NR*-, -NR*S(O)2-, -S(O)2NR*-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; and R4 and R A The ring formed after connecting is a parallel ring structure of ring A;

[0310] V3 is selected from chemical bonds, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne and

[0311] Ring B is a 3-7 member subheterocyclic group;

[0312] W3 is selected from chemical bonds, -NR-, -O-, -S-, and -C(O)-;

[0313] R* is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0314] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0315] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-10 membered heterocyclic groups;

[0316] L1 is the linker base;

[0317] L2 is an amino acid chain consisting of 2-8 amino acid residues linked together, wherein each amino acid residue may optionally be further substituted by one or more amino acid residues, and said amino acid residues may optionally be substituted by 1, 2, 3, 4, 5 or 6 R's. L replace;

[0318] R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group;

[0319] Z is a chelating group derived from the chelating agent.

[0320] In a more specific 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:

[0321] in,

[0322] Ab is a ligand targeting carbonic anhydrase IX, for example

[0323] Ring A is selected from C 6-10 Aromatic and C 5-10 Hybrid aryl groups; optionally bounded by 1, 2, 3 or 4 R groups A replace;

[0324] R A Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups;

[0325] R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0326] Or R4 and R A Connected together to form C 1-4 Alkylene, C 2-4 imide and C 2-4 The ynyl group, wherein one or more methylene units are optionally and independently replaced by -CR*2-, -NR*-, -NR*C(O)-, -C(O)NR*-, -NR*S(O)2-, -S(O)2NR*-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; and R4 and R A The ring formed after connecting is a parallel ring structure of ring A;

[0327] V3 is selected from chemical bonds, C 1-10 Alkylene, C 2-10imide and C 2-10 Ethyne group;

[0328] W3 is selected from chemical bonds, -NR-, -O-, -S-, and -C(O)-;

[0329] R* is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0330] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0331] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-10 membered heterocyclic groups;

[0332] L1 is the linker base;

[0333] L2 is an amino acid chain consisting of 2-8 amino acid residues linked together, wherein each amino acid residue may optionally be further substituted by one or more amino acid residues, and said amino acid residues may optionally be substituted by 1, 2, 3, 4, 5 or 6 R's. L replace;

[0334] R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group;

[0335] Z is a chelating group derived from the chelating agent.

[0336] In a more specific embodiment, the present invention provides the above-described compound having the following structure:

[0337] in,

[0338] A1, A2, and A3 are amino acid residues;

[0339] A4 is an H or an amino acid residue;

[0340] V1 is selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne group, C 6-10 Aromatic and C 5-10 A heteroaryl group, optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. 1s replace;

[0341] R 1s Independently selected from H, D, -OR a -SR a -NR b R c Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups;

[0342] V2 is a chemical bond or -(CR'R”). 1-6 -;

[0343] R' and R" are independently selected from H, D, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-Ar;

[0344] Ar is selected from C 6-14 Aryl and 5-14 heteroaryl groups;

[0345] W4 is selected from chemical bonds, -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)O-, -C(O)NR-, and -O-;

[0346] n is 0, 1, 2, 3, 4, 5, or 6;

[0347] The remaining variables are as defined in this article.

[0348] In a more specific embodiment, the present invention provides the above-described compound, wherein...

[0349] L1 is -W1-V1-W4-V2-W2-;

[0350] W1 is selected from chemical bonds, -NR-, -C(O)-, -C(O)O-, and -C(O)NR-;

[0351] W2 is selected from -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)NR- and -O-;

[0352] V1 is selected from C 1-10 Alkylene, C 2-10 imidene group, C2-10 Ethyne group, C 6-10 Aromatic and C 5-10 A heteroaryl group, optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. 1s Substitution; wherein one or more methylene units among the alkylene, alkenylene, and ynylene groups are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -NRS(O)2-, -S(O)2NR-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0353] R is independently selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0354] R 1s Independently selected from H, D, -OR a -SR a -NR b R c Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclic group; preferably, R 1s It can be independently of the (S) or (R) configuration, or in a racemic form;

[0355] V2 is a chemical bond or -(CR'R”). 1-6 -;

[0356] R' and R" are independently selected from H, D, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form;

[0357] Ar is independently selected from C 6-14 Aryl and 5-14 heteroaryl groups;

[0358] W4 is selected from chemical bonds, -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)O-, -C(O)NR-, and -O-;

[0359] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-7 membered heterocyclic groups.

[0360] Preferably,

[0361] L1 is -W1-V1-W4-V2-W2-;

[0362] W1 is selected from -C(O)-, -C(O)O- and -C(O)NR-; preferably -C(O)-;

[0363] W2 is selected from -C(O)-, -OC(O)- and -NRC(O)-; preferably -C(O)-;

[0364] V1 is selected from C 1-8 Alkylene, C 2-8 imidene group, C 2-8 Alynyl, phenylene and C 5-6 Hypoaryl, preferably C 1-8 Alkylene (e.g., -(CH2)) m -); it is optionally bounded by 1, 2, 3, 4, 5 or 6 R's. 1s Substitution; wherein one, two or three methylene units in the alkylene, alkenylene and ynylene groups are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -C(O)-, -OC(O)- or -C(O)O-;

[0365] m is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8;

[0366] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0367] R 1s Independently selected from H, D, -OR a -NR b R c Halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H, D, or -OR a and -NR b R c ;

[0368] V2 is a chemical bond or -(CR'R”). 1-4 -;

[0369] R' is independently selected from H, D, or -C. 1-4 Alkylene-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form; preferably in (S) configuration; preferably in (R) configuration;

[0370] "R" is independently selected from H, D, halogen, C. 1-6 Alkyl and C1-6 Halogenated alkyl groups;

[0371] Ar is independently selected from C 6-14 Aryl and 5-14 membered heteroaryl, preferably C 6-14 Aryl;

[0372] W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O-, and -C(O)NR-;

[0373] Preferably,

[0374] L1 is -C(O)-V1-W4-V2-C(O)-;

[0375] V1 is selected from C 1-6 Alkylene (e.g., -(CH2)) m -), phenylene and C 5-6 Hybrid aryl; preferably selected from C 1-6 Alkylene (e.g., -(CH2)) m -), phenylene, pyrrolidine, furanyl or thiophene; preferably C 1-6 Alkylene (e.g., -(CH2)) m -); C is preferred. 1-4 Alkylene (e.g., -(CH2)) m -); it is optionally bounded by 1, 2, 3, 4, 5 or 6 R's. 1s Substitution; wherein one, two or three methylene units in the alkylene group are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -C(O)-, -OC(O)- or -C(O)O-;

[0376] m is independently selected from 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4;

[0377] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0378] R 1s Independently selected from H, D, -OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H and -OR a ;

[0379] V2 is a chemical bond or -(CR'R”). 1-2 -(preferably -CHR'-);

[0380] R' is independently selected from H or -C 1-4Alkylene-Ar, preferably H or -CH2-Ar; preferably, R' is independently of the (S) or (R) configuration, or is racemic; preferably (S) configuration; preferably (R) configuration;

[0381] "R" is independently selected from H, D, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D;

[0382] Ar independently for C 6-14 Aryl, such as phenyl, naphthyl, anthraceneyl or phenanthrene; preferably C 6-10 Aryl, such as phenyl or naphthyl, preferably naphthyl, preferably 2-naphthyl;

[0383] W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O- and -C(O)NR-; preferably chemical bonds, -C(O)O- and -C(O)NR-; more preferably chemical bonds or -C(O)NR-;

[0384] For example,

[0385] L1 is selected from: (preferred) );

[0386] Among them, *1, *2 and *3 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; preferably (S) configuration; preferably (R) configuration.

[0387] In a more specific embodiment, the present invention provides the above-described compound, wherein...

[0388] L2 is an amino acid chain consisting of 2-5 amino acid residues, wherein each amino acid residue may optionally be further substituted by one or more (preferably 1, 2 or 3, preferably 1) amino acid residues, and said amino acid residues may optionally be substituted by 1, 2, 3, 4, 5 or 6 R's. L replace;

[0389] R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group;

[0390] Preferably,

[0391] L2 is

[0392] A1, A2, A3, and A4 are amino acid residues, and said amino acid residues are optionally surrounded by 1, 2, 3, 4, 5, or 6 R's. L replace;

[0393] R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group;

[0394] Preferably,

[0395] L2 is

[0396] A1, A2, A3, and A4 are selected from glycine residues, alanine residues, phenylalanine residues, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, or arginine residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, phenylalanine residues, or arginine residues, optionally marked with 1, 2, 3, or 4 R's. L replace;

[0397] R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably C 1-6 Acyl group;

[0398] More preferably,

[0399] L2 is

[0400] A1 is a lysine residue; preferably... Preferred Preferred

[0401] A2 is selected from tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, phenylalanine residues, or arginine residues, optionally separated by 1, 2, 3, or 4 R groups. L replace;

[0402] R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and urea groups; preferably halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and urea groups;

[0403] A2 is preferred and selected from (Preferred) Preferred ), (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) )and (Preferred) );

[0404] A3 is a lysine residue; preferred. Preferred Preferred

[0405] A4 is selected from N-acetylglutamic acid residues, N-(4-carboxybutyryl)glutamic acid, glutamic acid residues, pyroglutamic acid residues, citrulline residues, and aspartic acid residues; preferably. (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ),

[0406] Among them, *4, *5, *6 and *7 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; preferably (S) configuration; preferably (R) configuration;

[0407] For example,

[0408] L2 is selected from:

[0409] (preferred) Preferred ), (preferred) ), (preferred) ), (preferred) ), (preferred) ), (preferred) ), (preferred) ), (preferred) )and (preferred) ).

[0410] In a more specific embodiment, the present invention provides the above-described compound, wherein...

[0411] Z is a chelating group derived from a chelating agent, which is selected from the following:

[0412] 1,4,7,10-Tetraazacyclododecane-N,N',N",N”'-Tetraacetic acid (DOTA)

[0413] N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC)

[0414] 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA)

[0415] 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA),

[0416] 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA),

[0417] 1,4,7-Triazacyclononanephosphonic acid (TRAP)

[0418] 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO),

[0419] 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA),

[0420] N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO)

[0421] Diethyltriaminepentaacetic acid (DTPA)

[0422] trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA)

[0423] 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A)

[0424] p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA),

[0425] 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M),

[0426] 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B),

[0427] 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA),

[0428] [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA),

[0429] 6-Hydroxypyridine-3-carboxylic acid (HYNIC)

[0430] 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or

[0431] 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA);

[0432] Preferably,

[0433] 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; Preferred DOTA or NOTA; Preferred DOTA.

[0434] In a more specific embodiment, the present invention provides the above-described compound, wherein...

[0435] Ab is

[0436] Ring A is selected from phenylene and C 5-6 Heteroaryl; preferably selected from phenylene and 1,3,4-thiadiazolyl; optionally surrounded by 1, 2, 3 or 4 R groups. A replace;

[0437] R A Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl groups and 3-7 membered heterocyclic groups; preferably selected from H, D, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0438] R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0439] Or R4 and R A Connected together to form C 1-4 Alkylene, preferably C 1-2 Alkylene, wherein one, two, or three (preferably one) methylene units are optionally and independently replaced by -CR*2-, -NR*-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, preferably replaced by -CR*2-, -C(O)-, -OC(O)-, or -C(O)O-, preferably replaced by -C(O)-; and R4 and R A The ring formed after connecting is a parallel ring structure of ring A;

[0440] V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6Ethyne group;

[0441] W3 is selected from -NR- and -O-;

[0442] R* is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0443] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0444] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-7 membered heterocyclic groups;

[0445] Preferably,

[0446] Ab is selected from:

[0447] R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0448] V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group;

[0449] W3 is selected from -NR- and -O-;

[0450] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0451] Preferably,

[0452] Ab is selected from:

[0453] V3 is selected from chemical bonds and C. 1-6 Alkylene (preferably C) 1-4 Alkylene, preferably C 1-2 Alkylene);

[0454] More preferably,

[0455] Ab is selected from:

[0456] n can be 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3 or 4, preferably 0 or 2.

[0457] In a more specific embodiment, the present invention provides the above-described compound, wherein...

[0458] Ab is

[0459] Ring A is selected from phenylene and C 5-6 Heteroaryl; preferably selected from phenylene and 1,3,4-thiadiazolyl; optionally surrounded by 1, 2, 3 or 4 R groups. A replace;

[0460] R A Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl groups and 3-7 membered heterocyclic groups; preferably selected from H, D, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0461] R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0462] Or R4 and R A Connected together to form C 1-4 Alkylene, preferably C 1-2 Alkylene, wherein one, two, or three (preferably one) methylene units are optionally and independently replaced by -CR*2-, -NR*-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, preferably replaced by -CR*2-, -C(O)-, -OC(O)-, or -C(O)O-, preferably replaced by -C(O)-; and R4 and R A The ring formed after connecting is a parallel ring structure of ring A;

[0463] V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group;

[0464] W3 is selected from -NR- and -O-;

[0465] R* is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6Halogenated alkyl groups;

[0466] L1 is -W1-V1-W4-V2-W2-;

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

[0468] W2 is selected from -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)NR- and -O-;

[0469] V1 is selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne group, C 6-10 Aromatic and C 5-10 A heteroaryl group, optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. 1s Substitution; wherein one or more methylene units among the alkylene, alkenylene, and ynylene groups are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -NRS(O)2-, -S(O)2NR-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0470] R 1s Independently selected from H, D, -OR a -SR a -NR b R c Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclic group; preferably, R 1s It can be independently of the (S) or (R) configuration, or in a racemic form;

[0471] V2 is a chemical bond or -(CR'R”). 1-6 -;

[0472] R' and R” are independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form;

[0473] Ar is independently selected from C 6-14 Aryl and 5-14 heteroaryl groups;

[0474] W4 is selected from chemical bonds, -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)O-, -C(O)NR-, and -O-;

[0475] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0476] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-7 membered heterocyclic groups;

[0477] L2 is an amino acid chain consisting of 2-5 amino acid residues, wherein each amino acid residue may optionally be further substituted by one or more (preferably 1, 2 or 3, preferably 1) amino acid residues, and said amino acid residues may optionally be substituted by 1, 2, 3, 4, 5 or 6 R's. L replace;

[0478] R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group;

[0479] Z is a chelating group derived from the chelating agent.

[0480] In a more specific embodiment, the present invention provides the above-described compound, wherein...

[0481] Ab is selected from:

[0482] R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0483] V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group;

[0484] W3 is selected from -NR- and -O-;

[0485] L1 is -W1-V1-W4-V2-W2-;

[0486] W1 is selected from -C(O)-, -C(O)O- and -C(O)NR-; preferably -C(O)-;

[0487] W2 is selected from -C(O)-, -OC(O)- and -NRC(O)-; preferably -C(O)-;

[0488] V1 is selected from C 1-8 Alkylene, C 2-8 imidene group, C 2-8 Alynyl, phenylene and C 5-6 Hypoaryl, preferably C 1-8 Alkylene (e.g., -(CH2)) m -); it is optionally bounded by 1, 2, 3, 4, 5 or 6 R's. 1s Substitution; wherein one, two or three methylene units in the alkylene, alkenylene and ynylene groups are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -C(O)-, -OC(O)- or -C(O)O-;

[0489] m is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8;

[0490] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0491] R 1s Independently selected from H, D, -OR a -NR b R c Halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H, D, or -OR a and -NR b R c ;

[0492] V2 is a chemical bond or -(CR'R”). 1-4 -;

[0493] R' is independently selected from H, D, or -C. 1-4 Alkylene-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form; preferably in (S) configuration; preferably in (R) configuration;

[0494] "R" is independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0495] Ar is independently selected from C6-14 Aryl and 5-14 membered heteroaryl, preferably C 6-14 Aryl;

[0496] W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O-, and -C(O)NR-;

[0497] L2 is

[0498] A1, A2, A3, and A4 are amino acid residues, and said amino acid residues are optionally surrounded by 1, 2, 3, 4, 5, or 6 R's. L replace;

[0499] R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group;

[0500] Z is a chelating group derived from the chelating agent.

[0501] In a more specific embodiment, the present invention provides the above-described compound, wherein...

[0502] Ab is selected from:

[0503] n is 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3 or 4, preferably 0 or 2;

[0504] L1 is -C(O)-V1-W4-V2-C(O)-;

[0505] V1 is selected from C 1-6 Alkylene (e.g., -(CH2)) m -), phenylene and C 5-6 Hybrid aryl; preferably selected from C 1-6 Alkylene (e.g., -(CH2)) m -), phenylene, pyrrolidine, furanyl or thiophene; preferably C 1-6 Alkylene (e.g., -(CH2)) m -); C is preferred. 1-4 Alkylene (e.g., -(CH2)) m -); it is optionally bounded by 1, 2, 3, 4, 5 or 6 R's. 1sSubstitution; wherein one, two or three methylene units in the alkylene group are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -C(O)-, -OC(O)- or -C(O)O-;

[0506] m is independently selected from 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4;

[0507] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0508] R 1s Independently selected from H, D, -OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H and -OR a ;

[0509] V2 is a chemical bond or -(CR'R”). 1-2 -(preferably -CHR'-);

[0510] R' is independently selected from H or -C 1-4 Alkylene-Ar; preferably H or -CH2-Ar; preferably, R' is independently of the (S) or (R) configuration, or is racemic; preferably (S) configuration; preferably (R) configuration;

[0511] "R" is independently selected from H, D, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D;

[0512] Ar independently for C 6-14 Aryl, such as phenyl, naphthyl, anthraceneyl or phenanthrene; preferably C 6-10 Aryl, such as phenyl or naphthyl, preferably naphthyl, preferably 2-naphthyl;

[0513] W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O- and -C(O)NR-; preferably chemical bonds, -C(O)O- and -C(O)NR-; more preferably chemical bonds or -C(O)NR-;

[0514] L2 is

[0515] A1, A2, A3, and A4 are selected from glycine residues, alanine residues, phenylalanine residues, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, or arginine residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, phenylalanine residues, or arginine residues, optionally marked with 1, 2, 3, or 4 R's. L replace;

[0516] R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably C 1-6 Acyl group;

[0517] Z is a chelating group derived from a chelating agent, which is selected from the following:

[0518] 1,4,7,10-Tetraazacyclododecane-N,N',N",N”'-Tetraacetic acid (DOTA)

[0519] N,N"-Bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC)

[0520] 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA)

[0521] 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA),

[0522] 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA),

[0523] 1,4,7-Triazacyclononanephosphonic acid (TRAP)

[0524] 1,4,7-Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO),

[0525] 3,6,9,15-Tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA),

[0526] N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO)

[0527] Diethyltriaminepentaacetic acid (DTPA)

[0528] trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA)

[0529] 1-Oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A)

[0530] p-Isocyanothiobenzyl-DTPA (SCN-Bz-DTPA),

[0531] 1-(p-isocyanothiobenzyl)-3-methyl-DTPA(1B3M),

[0532] 2-(p-isocyanothiobenzyl)-4-methyl-DTPA(1M3B),

[0533] 1-(2)-Methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA),

[0534] [(R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA),

[0535] 6-Hydroxypyridine-3-carboxylic acid (HYNIC)

[0536] 2-(4-Isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or

[0537] 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA).

[0538] In a more specific embodiment, the present invention provides the above-described compound, wherein...

[0539] Ab is selected from:

[0540] n is 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3 or 4, preferably 0 or 2;

[0541] L1 is selected from: (preferred) );

[0542] Wherein, *1, *2 and *3 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; preferably (S) configuration; preferably (R) configuration;

[0543] L2 is

[0544] A1 is a lysine residue; preferably... Preferred Preferred

[0545] A2 is selected from tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, phenylalanine residues, or arginine residues, optionally separated by 1, 2, 3, or 4 R groups. L replace;

[0546] R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and urea groups; preferably halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and urea groups;

[0547] A2 is preferred and selected from (Preferred) Preferred ), (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) )and (Preferred) );

[0548] A3 is a lysine residue; preferred. Preferred Preferred

[0549] A4 is selected from N-acetylglutamic acid residues, N-(4-carboxybutyryl)glutamic acid, glutamic acid residues, pyroglutamic acid residues, citrulline residues, or aspartic acid residues; preferably. (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ),

[0550] Among them, *4, *5, *6 and *7 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; preferably (S) configuration; preferably (R) configuration;

[0551] 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; Preferred DOTA or NOTA; Preferred DOTA;

[0552] Preferably,

[0553] L2 is selected from:

[0554] (preferred) Preferred ), (preferred) ), (preferred) ), (preferred) ), (preferred) ), (preferred) ), (preferred) ), (preferred) )and (preferred) ).

[0555] In a more specific embodiment, the present invention provides the above-described compound, wherein V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne and Preferred chemical bonds, C 1-6 Alkylene (preferably C) 1-4 Alkylene, preferably C 1-2 alkylene) and Preferred chemical bonds and

[0556] Preferably,

[0557] Ring B is a 3-7 membered heterocyclic group; preferably a 4-6 membered heterocyclic group; preferably a 5 membered heterocyclic group, for example...

[0558] Wherein, *8 is a chiral center, independently selected from the (S) configuration; the (R) configuration is preferred;

[0559] The remaining variables are as defined in this invention.

[0560] In a more specific embodiment, the present invention provides the above-described compound, wherein W3 is selected from -NR-, -O-, and -C(O)-, preferably -NR- and -C(O)-; the remaining variables are as defined in the present invention.

[0561] In a more specific embodiment, the present invention provides the above-described compound, wherein Ab is selected from: Preferred Preferred Wherein, *8 is a chiral center, independently selected from (S) or (R) configurations, or racemic form; preferably (S) configuration; preferably (R) configuration;

[0562] The remaining variables are as defined in this invention.

[0563] In a more specific embodiment, the present invention provides the above-described compound, wherein L1 is -W1-V1-W4-V2-W2-;

[0564] W1 is selected from -NR-, -C(O)-, -C(O)O- and -C(O)NR-; preferably -NR- or -C(O)-;

[0565] Preferably, R 1s Independently selected from H, -OR a -NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H or -ORa and -NR b R c H and -NR are preferred. b R c ;

[0566] The remaining variables are as defined in this invention;

[0567] Preferably,

[0568] L1 is selected from: (preferred) ), (preferred) )and (preferred) );

[0569] Among them, *1, *2, *3 and *9 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; preferably (S) configuration; preferably (R) configuration;

[0570] The remaining variables are as defined in this invention.

[0571] In a more specific embodiment, the present invention provides the above-described compound having the structure shown in formula (III-1) or formula (IV-1).

[0572] in,

[0573] V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group;

[0574] L1 is -W1-V1-W4-V2-W2-;

[0575] W1 is selected from -C(O)-, -C(O)O- and -C(O)NR-; preferably -C(O)-;

[0576] W2 is selected from -C(O)-, -OC(O)- and -NRC(O)-; preferably -C(O)-;

[0577] V1 is selected from C 1-8 Alkylene, C 2-6 imide and C 2-6 Alynyl group, preferably C 1-8 Alkylene (e.g., -(CH2)) m -), which is optionally divided by 1, 2, 3, 4, 5 or 6 R 1s replace;

[0578] m is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8;

[0579] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0580] R 1s Independently selected from H, D, -OR a -NR b R c Halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H, D, or -OR a and -NR b R c Preferably, R 1s It can be independently of the (S) or (R) configuration, or in a racemic form;

[0581] V2 is a chemical bond or -(CR'R”). 1-6 -;Preferred-(CR'R”) 1-6 -;

[0582] R' is independently selected from H, D, or -C. 1-4 Alkylene-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form;

[0583] "R" is independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0584] Ar is independently selected from C 6-14 Aryl and 5-14 quinone heteroaryl groups; C is preferred. 6-14 Aryl;

[0585] W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O-, and -C(O)NR-;

[0586] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-7 membered heterocyclic groups;

[0587] A1, A2, A3, and A4 are selected from glycine residues, alanine residues, phenylalanine residues, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, or arginine residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, phenylalanine residues, or arginine residues, optionally marked with 1, 2, 3, or 4 R's. L replace;

[0588] R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably C 1-6 Acyl group;

[0589] Z is as defined in this article.

[0590] In a more specific embodiment, the present invention provides the above-described compound, wherein...

[0591] V3 is selected from chemical bonds and C. 1-6 Alkylene (preferably C) 1-4 Alkylene, preferably C 1-2 Alkylene); preferably chemical bond;

[0592] L1 is -W1-V1-W4-V2-W2-;

[0593] W1 is -C(O)-;

[0594] W2 is -C(O)-;

[0595] V1 is selected from C 1-6 Alkylene, C 2-6 imide and C 2-6 Alynyl group, preferably C 1-6 Alkylene (e.g., -(CH2)) m -), C is preferred 1-4 Alkylene (e.g., -(CH2)) m -), which is optionally divided by 1, 2, 3, 4, 5 or 6 R 1s replace;

[0596] m is independently selected from 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4;

[0597] R 1s Independently selected from H, D, -OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H and -OR a Preferred selections are from H and D;

[0598] V2 is a chemical bond or -(CR'R”). 1-4 -; preferably a chemical bond or -(CR'R”) 1-2 -(preferably -CHR'-); preferably -(CR'R”) 1-2 -(preferably -CHR'-);

[0599] R' is independently selected from H or -C 1-4 Alkylene-Ar, preferably H or -CH2-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form; preferably in (S) configuration;

[0600] "R" is independently selected from H, D, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D;

[0601] Ar independently for C 6-14 Aryl, such as phenyl, naphthyl, anthraceneyl or phenanthrene; preferably C 6-10 Aryl, such as phenyl or naphthyl, preferably naphthyl, preferably 2-naphthyl;

[0602] W4 is selected from chemical bonds or -C(O)NR-;

[0603] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0604] R a Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0605] A1 is a lysine residue;

[0606] A2 is a tyrosine residue;

[0607] A3 is a lysine residue;

[0608] A4 is a glutamic acid residue or an N-acetylglutamic acid residue, preferably a glutamic acid residue;

[0609] Z is selected from DOTA NOTA、 NODAGA、 DOTAGA, p-SCN-Bn-NOTA and p-SCN-Bn-DOTA; Preferred DOTA or NOTA; Preferred DOTA;

[0610] Preferably, for Preferred

[0611] Among them, *4, *5, *6 and *7 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; the (R) configuration is preferred;

[0612] Preferably, L1 is (preferred) ), preferably (preferred) );

[0613] Among them, *3 is a chiral center, which is independently selected from the (S) or (R) configuration, or is a racemic form; the (S) configuration is preferred.

[0614] In a more specific embodiment, the present invention provides the above-described compound having the structure shown in formula (Ⅱ-4).

[0615] in,

[0616] V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne and

[0617] Ring B is a 3-7 membered heterocyclic group;

[0618] W3 is selected from -NR- and -C(O)-; preferably -C(O)-;

[0619] L1 is -W1-V1-W4-V2-W2-;

[0620] W1 is selected from -NR-, -C(O)-, -C(O)O- and -C(O)NR-; preferably -NR- or -C(O)-;

[0621] W2 is selected from -C(O)-, -OC(O)- and -NRC(O)-; preferably -C(O)-;

[0622] V1 is selected from C 1-8 Alkylene, C 2-6 imide and C 2-6 Alynyl group, preferably C 1-8 Alkylene (e.g., -(CH2)) m -), which is optionally divided by 1, 2, 3, 4, 5 or 6 R 1s replace;

[0623] m is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8;

[0624] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0625] R 1s Independently selected from H, D, -OR a -NR b R c Halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H, D, or -OR a and -NR b R c Preferably, R 1s It can be independently of the (S) or (R) configuration, or in a racemic form;

[0626] V2 is a chemical bond or -(CR'R”). 1-6 -;Preferred-(CR'R”) 1-6 -;

[0627] R' is independently selected from H, D, or -C. 1-4 Alkylene-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form;

[0628] "R" is independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0629] Ar is independently selected from C 6-14 Aryl and 5-14 quinone heteroaryl groups; C is preferred. 6-14 Aryl;

[0630] W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O-, and -C(O)NR-;

[0631] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or Rb R c Together with the atoms they connect, they form 3-7 membered heterocyclic groups;

[0632] L2 is

[0633] A1, A2, A3, and A4 are selected from glycine residues, alanine residues, phenylalanine residues, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, or arginine residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, phenylalanine residues, or arginine residues, optionally marked with 1, 2, 3, or 4 R's. L replace;

[0634] R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably C 1-6 Acyl group;

[0635] Z is as defined in claim 1 or 5.

[0636] In a more specific embodiment, the present invention provides the above-described compound, wherein...

[0637] V3 is selected from chemical bonds, C 1-6 Alkylene (preferably C) 1-4 Alkylene, preferably C 1-2 alkylene) and Preferred chemical bonds and

[0638] Ring B is a 4-6 membered heterocyclic group; preferably a 5-membered heterocyclic group, for example...

[0639] W3 is selected from -NR- and -C(O)-; preferably -C(O)-;

[0640] L1 is -W1-V1-W4-V2-W2-;

[0641] W1 is -NR-; preferably -NH-;

[0642] W2 is -C(O)-;

[0643] V1 is selected from C 1-6 Alkylene, C 2-6 imide and C 2-6 Alynyl group, preferably C 1-6 Alkylene (e.g., -(CH2)) m -), C is preferred 1-4 Alkylene (e.g., -(CH2)) m -), which is optionally divided by 1, 2, 3, 4, 5 or 6 R 1s replace;

[0644] m is independently selected from 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4;

[0645] R 1s Independently selected from H, D, -OR a -NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H, -OR a and -NR b R c Preferred selections are H and -NR. b R c ;

[0646] V2 is a chemical bond or -(CR'R”). 1-4 -; preferably a chemical bond or -(CR'R”) 1-2 -(preferably -CHR'-); preferably -(CR'R”) 1-2 -(preferably -CHR'-);

[0647] R' is independently selected from H or -C 1-4 Alkylene-Ar, preferably H or -CH2-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form; preferably in (S) configuration;

[0648] "R" is independently selected from H, D, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D;

[0649] Ar independently for C 6-14 Aryl, such as phenyl, naphthyl, anthraceneyl or phenanthrene; preferably C 6-10 Aryl, such as phenyl or naphthyl, preferably naphthyl, preferably 2-naphthyl;

[0650] W4 is selected from chemical bonds or -C(O)NR-; preferably -C(O)NR-;

[0651] R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0652] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably H;

[0653] L2 is

[0654] A1 is a lysine residue;

[0655] A2 is a tyrosine residue;

[0656] A3 is a lysine residue;

[0657] A4 is a glutamic acid residue or an N-acetylglutamic acid residue, preferably a glutamic acid residue;

[0658] Z is selected from DOTA NOTA、 NODAGA、 DOTAGA, p-SCN-Bn-NOTA and p-SCN-Bn-DOTA; Preferred DOTA or NOTA; Preferred DOTA;

[0659] Preferably, for Preferred

[0660] Among them, *4, *5, *6, *7 and *8 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; the (R) configuration is preferred;

[0661] Preferably, L1 is (preferred) )or (preferred) );

[0662] Among them, *3 and *9 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; the (S) configuration is preferred.

[0663] In a more specific embodiment, the present invention provides the above-described compounds, wherein the compounds are selected from:

[0664] 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.

[0665] in,

[0666] Compounds of formula (I) are as defined herein;

[0667] M is selected from at least one of radioactive nuclides or non-radioactive elements (preferably radioactive nuclides);

[0668] Preferably, the radionuclide is selected from at least one of diagnostic or therapeutic radionuclides;

[0669] Preferably, the 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; or selected from 177 Lu、 90 Y、 131 I, 153 Sm、 67 Cu、 89 Sr、 166 Ho、 177Yb、 47 Sc、 186 / 188 Re、 212 / 213 Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 161 Tb, 225 Ac or 227 Th;

[0670] 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;

[0671] Preferably, 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;

[0672] Preferably, the radionuclide is selected from... 68 Ga、 18 F, 89 Zr、 99 mTc, 64 Cu、 161 Tb or 177 Lu;

[0673] Preferably, the radionuclide 18 F is through18 FAl forms by complexation with a compound of formula (I);

[0674] Preferably, M is selected from... 68 Ga、 18 F, 161 Tb or 177 Lu; Preferred 68 Ga or 177 Lu.

[0675] In a more specific embodiment, the present invention provides a compound of formula (V), or an isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0676] in,

[0677] Ab, L1, and L2 are as defined in this paper;

[0678] Z' is a coordinating group formed by the complexation of a chelating group Z derived from a chelating agent with M, where Z is as defined in any of the items herein;

[0679] M is selected from at least one of radioactive nuclides or non-radioactive elements (preferably radioactive nuclides);

[0680] Preferably, the radionuclide is selected from at least one of diagnostic or therapeutic radionuclides;

[0681] Preferably, the 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, or selected from 177 Lu、 90 Y、 131 I, 153 Sm、 67 Cu、 89 Sr、 166 Ho、 177 Yb、 47 Sc、 186 / 188 Re、 212 / 213Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 161 Tb, 225 Ac or 227 Th;

[0682] 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;

[0683] Preferably, 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;

[0684] Preferably, the radionuclide is selected from... 68 Ga、 18 F, 89 Zr、 99 mTc, 64 Cu、 161 Tb or 177 Lu;

[0685] Preferably, the radionuclide 18 F is through 18 Formed by FAl complexation;

[0686] Preferably, M is selected from... 68 Ga、 18 F, 161 Tb or 177 Lu; Preferred 68 Ga or 177 Lu.

[0687] 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.

[0688] 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.

[0689] 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.

[0690] 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.

[0691] 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)).

[0692] 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.

[0693] 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 15 N、 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.

[0694] 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.

[0695] 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.

[0696] 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.

[0697] Pharmaceutical Compositions and Kits

[0698] 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.

[0699] 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.

[0700] 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.

[0701] 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.

[0702] Dosage

[0703] 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.

[0704] 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.

[0705] 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.

[0706] 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.

[0707] 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.

[0708] 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.

[0709] 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.

[0710] 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.

[0711] 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.

[0712] 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.

[0713] 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.

[0714] 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.

[0715] 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.

[0716] 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.

[0717] 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.

[0718] 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).

[0719] Indications

[0720] For tumors that overexpress CAIX, the development of CAIX 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 CAIX within tumor cells, and after labeling with therapeutic radionuclides, they can be used for molecular imaging diagnosis and treatment of tumors.

[0721] 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, stomach cancer, pancreatic cancer, melanoma, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head and neck cancer, astrocytoma, and oral cancer.

[0722] Example

[0723] 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.

[0724] 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.

[0725] Table 1

[0726] Example 1: Synthesis of the compound

[0727] 1.1 Synthesis of Compound 1

[0728] peptide synthesis

[0729] 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 the 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 0.40 mL of MeOH dropwise into the reaction column. After a nitrogen atmosphere for 30 minutes, wash with DMF and remove waste.

[0730] 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 resin.

[0731] 3) Coupling of amino acids: Weigh 0.60 mmol of Fmoc-D-Tyr(tBu)-OH and 0.57 mmol of HBTU into the resin obtained in the previous step. Add 30.0 mL of DMF, then add 1.20 mmol of DIEA 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.

[0732] 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 resin.

[0733] 5) Coupling of amino acids: Weigh Fmoc-D-Lys(Alloc)-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, then remove the reaction solution, add DMF to wash, and drain the waste until no liquid flows out.

[0734] 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 resin.

[0735] 7) Coupling of amino acids: Weigh Fmoc-D-Glu(tBu)-OH (0.60 mmol) and HBTU (0.57 mmol) 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. 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.

[0736] 8) 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 resin.

[0737] 9) Boc protection: Prepare the end-capping solution: Boc anhydride: DIEA: DMF (V:V:V) = 10:5:85. Add the end-capping solution (30.0 mL) 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.

[0738] 10) Alloc removal: Wash the resin sequentially with DMF (40.0 mL) and DCM (40.0 mL). Add an appropriate amount of DCM (20.0 mL) and purge with nitrogen gas. Add PhSiH3 (2.00 mmol) and Pd(PPh3)4 (0.02 mmol) sequentially, react for 20 minutes, and repeat the reaction 3 times. Wash the resin with DMF and dry it under vacuum to obtain the resin.

[0739] 11) Coupling of chelating groups: Weigh DOTA (0.30 mmol) and HATU (0.28 mmol) into the resin obtained in the previous step, add 30.0 mL of DMF, and then add DIEA (0.60 mmol) dropwise into the reaction column. Adjust the nitrogen atmosphere to make the resin bulge evenly. After reacting at 20°C for 1 hour, remove the reaction solution, add DMF to wash, and discharge the waste until no liquid flows out.

[0740] 12) De-Dde removal: Prepare a 3% (w / w) hydrazine hydrate / DMF solution. Add 40.0 mL of the hydrazine hydrate solution to the resin and agitate with nitrogen gas to induce a reaction. Wash the resin with DMF and dry it under vacuum to obtain the final resin.

[0741] 13) Ligand coupling: Weigh Int C (0.24 mmol) and HOAt (0.24 mmol) into the resin obtained in the previous step, add 30.0 mL of DMF, and then add DIC (0.24 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.

[0742] 14) Shrink the resin with MeOH (30.0 mL), drain the waste until no liquid flows out, pour out the resin and dry it for later use.

[0743] Peptide cleavage:

[0744] 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 cut for 2 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 1 (250 mg).

[0745] Peptide purification:

[0746] The crude product was purified by preparative high performance liquid chromatography to obtain the final product, compound 1 (15.0 mg, 97.5% purity). The detection results are shown in Figure 1.

[0747] The structures of Fmoc-D-Lys(Dde)-OH, Fmoc-D-Tyr(tBu)-OH, Fmoc-D-Lys(Alloc)-OH, Fmoc-D-Glu(tBu)-OH, and the intermediate Int C are as follows:

[0748] The synthesis method of the intermediate Int C is as follows:

[0749] 1) Compound Int 2 (3.00 g, 1.00 eq) and pyridine (2.69 mL, 2.00 eq) were dissolved in DMF (30.0 mL). Compound Int 4a (2.97 g, 1.00 eq) was dissolved in DCM (20.0 mL) and slowly added to the reaction solution at 0 °C. The reaction solution was stirred at 25 °C for 14 hours. After concentrating the reaction solution, water and a saturated sodium bicarbonate aqueous solution were added, and the mixture was filtered to obtain compound Int 4 (5.00 g, 96.7% purity).

[0750] 2) Compound Int 4 (5.00 g, 1.00 eq) and NaOH (3.45 g, 5.76 eq) were dissolved in H2O (70.0 mL), and the reaction solution was stirred at 60 °C for 1 hour. After the reaction solution was cooled to room temperature, the pH was adjusted to 4 with 1N HCl. After the solid precipitated, it was filtered and purified to obtain Int C (2.00 g, 95.9% purity).

[0751] The relevant characterization data for Int C are as follows:

[0752] LCMS:MS:[M+H] + =308.8.

[0753] HPLC: Purity: 95.9%

[0754] 1 HNMR: 400MHz DMSO-d6

[0755] δppm: 12.51 (br s, 2H), 8.30 (br s, 2H), 2.56-2.52 (m, 2H), 2.23 (t, J = 7.2Hz, 2H), 1.70-1.58 (m, 2H), 1.58-1.47 (m, 2H).

[0756] 1.2 Synthesis of Compound 2

[0757] Polypeptide synthesis:

[0758] This peptide was synthesized using standard Fmoc chemical methods.

[0759] 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. After agitating with nitrogen for 30 minutes, purge the column. Add DMF to wash the column, then purge again until no liquid flows out.

[0760] 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 resin.

[0761] 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, 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.

[0762] Repeat steps 2)-3) above to couple the following amino acids:

[0763] Table 2

[0764] Shrink the resin with MeOH (100mL), drain the waste until no liquid flows out, pour out the resin and dry it for later use.

[0765] Note: Alloc removal conditions were: PhSiH3 (5.00 mmol, 10.0 eq), Pd(PPh3)4 (0.05 mmol, 0.10 eq), 10 min * 3.

[0766] The conditions for Dde removal were: 3% hydrazine hydrate / DMF, 15 min * 2.

[0767] The structure of Fmoc-2-Nal-OH is as follows:

[0768] Peptide cleavage:

[0769] 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 cut. 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 to obtain the unpurified crude peptide compound 2 (450 mg).

[0770] Peptide purification:

[0771] 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 2 (13.0 mg, purity 95.4%, TFA). The detection results are shown in Figure 2.

[0772] LCMS:MS:[M+H] + =1440.6.

[0773] HPLC: Purity: 95.4%.

[0774] 1.3 Synthesis of Compound 3

[0775] Polypeptide synthesis:

[0776] This peptide was synthesized using standard Fmoc chemical methods.

[0777] 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 uniform resin bubbling. After reacting at 20°C for 2 hours, add 1.00 mL of MeOH dropwise into the reaction column. After bubbling with nitrogen for 30 minutes, wash with DMF and remove waste.

[0778] 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.

[0779] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.90 mmol) and HBTU (0.85 mmol) into the above resin, add 30.0 mL of DMF, and then add DIEA (1.80 mmol) 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 discharge waste until no liquid flows out.

[0780] 4) Repeat steps 2-3 above to couple the following amino acids:

[0781] Table 3

[0782] Shrink the resin with MeOH (100mL), drain the waste until no liquid flows out, pour out the resin and dry it for later use.

[0783] Note: Alloc removal conditions were: PhSiH3 (5.00 mmol, 10.0 eq), Pd(PPh3)4 (0.05 mmol, 0.10 eq), 10 min * 3

[0784] The conditions for Dde removal were: 3% hydrazine hydrate / DMF, 15 min * 2

[0785] Peptide cleavage:

[0786] 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 cut. 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 to obtain crude peptide compound 3.

[0787] Peptide purification:

[0788] The crude peptide was purified by preparative high-performance liquid chromatography to obtain the final product, compound 3 (13.0 mg, purity 97.2%, TFA). The detection results are shown in Figure 17.

[0789] 1.4 Synthesis of Compound 4

[0790] Polypeptide synthesis:

[0791] This peptide was synthesized using standard Fmoc chemical methods.

[0792] 1) Weigh 0.50 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and 1.00 mmol of Fmoc-D-Lys(Dde)-OH into the reaction column. Add 50.0 mL of DCM, then add 4.00 mmol of DIEA 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, wash with DMF to remove waste.

[0793] 2) Deprotection: Add 20% piperidine / DMF (V:V (50.0 mL) to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry it to obtain the final resin.

[0794] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (3.00 mmol) and HBTU (2.85 mmol) into the above resin, add 50.0 mL of DMF, and then add DIEA (6.00 mmol) 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 discharge the waste until no liquid flows out.

[0795] Repeat steps 2-3 above to couple the following amino acids:

[0796] Table 4

[0797] Shrink the resin with MeOH (100mL), drain the waste until no liquid flows out, pour out the resin and dry it for later use.

[0798] Note: Deallylating conditions were: PhSiH3 (10.0 mmol, 10.0 eq), Pd(PPh3)4 (0.10 mmol, 0.10 eq), 15 min * 3

[0799] The conditions for Dde removal are: 3% hydrazine hydrate / DMF, 10 min * 2

[0800] Peptide cleavage:

[0801] 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, 6.00 mL) and cut. 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 to obtain unpurified crude peptide compound 4 (450 mg).

[0802] Peptide purification:

[0803] The crude peptide was purified by preparative high-performance liquid chromatography to obtain the final product, compound 4 (22.2 mg, purity 97.8%, TFA). The detection results are shown in Figure 18.

[0804] 1.5 Synthetic compound 5

[0805] Polypeptide synthesis:

[0806] This peptide was synthesized using standard Fmoc chemical methods.

[0807] 1) In a solid-phase synthesis column, 0.15 mmol of 2-CTC resin (degree of substitution 0.50 mmol / g) and 1.0 eq of Fmoc-D-Lys(Dde)-OH were reacted in DCM at 20 °C for 2 hours. A small amount of methanol was added and the reaction was continued for 30 minutes. After washing to remove the residue, the solution was washed several times with DMF.

[0808] 2) Deprotection of Fmoc: Treat with 20% piperidine / DMF (10 mL) for 15 minutes, then wash 5 times with DMF (30 mL) to obtain deprotected resin.

[0809] 3) Coupling reaction: Fmoc-D-Tyr(tBu)-OH, HBTU and DIEA were added to the resin, and the reaction was carried out in DMF at 20°C for 1 hour. After the reaction was completed, the residue was washed away.

[0810] Repeat steps 2-3 above to couple the following amino acids (3-8):

[0811] Table 5

[0812] Shrink the resin with MeOH, discharge the waste until no more liquid flows out, pour out the resin and dry it for later use.

[0813] Remark:

[0814] De-Alloc: Add DCM (30.0 mL) to the reaction column, then weigh PhSiH3 (10.0 eq) and Pd(PPh3)4 (0.10 eq) and add them sequentially. Adjust the nitrogen atmosphere to ensure the resin bulges evenly. React at 20°C for 15 min, then remove the reaction solution and wash five times with DMF.

[0815] De-Dde: Add 3% hydrazine hydrate / DMF (10.0 mL) to the reaction column, and adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20°C for 15 min, remove the reaction solution, add DMF for washing, and then discharge the waste.

[0816] Peptide cleavage:

[0817] At room temperature, the prepared cutting solution (90.0% TFA / 5.0% TIS / 2.5% H2O / 2.5% 3-mercaptopropionic acid) was added to the dried resin and stirred at room temperature for 2 hours. The solution was then centrifuged with ice-cold methyl tert-butyl ether to settle, washed with methyl tert-butyl ether, and dried.

[0818] Peptide purification:

[0819] The concentrate was purified by preparative high-performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain compound 5 (18.0 mg, purity 97.32%, TFA). The test results are shown in Figure 29.

[0820] 1.6 Synthesis of Compound 6

[0821] Polypeptide synthesis:

[0822] This peptide was synthesized using standard Fmoc chemical methods.

[0823] 1) In a solid-phase synthesis column, 0.15 mmol of 2-CTC resin (degree of substitution 0.50 mmol / g) and 1.0 eq of Fmoc-D-Lys(Dde)-OH were reacted in DCM at 20 °C for 2 hours. A small amount of methanol was added and the reaction was continued for 30 minutes. After washing to remove the residue, the solution was washed several times with DMF.

[0824] 2) Deprotection of Fmoc: Treat with 20% piperidine / DMF (10 mL) for 15 minutes, then wash 5 times with DMF (30 mL) to obtain deprotected resin.

[0825] 3) Coupling reaction: Fmoc-D-Tyr(tBu)-OH, HBTU and DIEA were added to the resin, and the reaction was carried out in DMF at 20°C for 1 hour. After the reaction was completed, the residue was washed away.

[0826] Repeat steps 2-3 above to couple the following amino acids (3-9):

[0827] Table 6

[0828] Shrink the resin with MeOH, discharge the waste until no more liquid flows out, pour out the resin and dry it for later use.

[0829] Remark:

[0830] De-Alloc: Add DCM (30.0 mL) to the reaction column, then weigh PhSiH3 (10.0 eq) and Pd(PPh3)4 (0.10 eq) and add them sequentially. Adjust the nitrogen atmosphere to ensure the resin bulges evenly. React at 20°C for 15 min, then remove the reaction solution and wash five times with DMF.

[0831] De-Dde: Add 3% hydrazine hydrate / DMF (10.0 mL) to the reaction column, and adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20°C for 15 min, remove the reaction solution, add DMF for washing, and then discharge the waste.

[0832] Peptide cleavage:

[0833] At room temperature, the prepared cutting solution (90.0% TFA / 5.0% TIS / 2.5% H2O / 2.5% 3-mercaptopropionic acid) was added to the dried resin and stirred at room temperature for 2 hours. The solution was then centrifuged with ice-cold methyl tert-butyl ether to settle, washed with methyl tert-butyl ether, and dried.

[0834] Peptide purification:

[0835] The concentrate was purified by preparative high-performance liquid chromatography (A: 0.075% TFA in water, B: acetonitrile) to obtain compound 6 (12.3 mg, purity 98.3%, TFA). The test results are shown in Figure 30.

[0836] Example 2 Radiolabeling

[0837] 2.1 68 Ga-compound 1, 68 Ga-compound 2, 68 Ga-compound 3. 68 Ga-compound 5, 68 Labeling process of Ga-compound 6

[0838] 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 precursor aqueous solution of compound 1, compound 2, compound 3, compound 5, or compound 6. Mix thoroughly and then add 1 mL of the solution. 68 The GaCl3 solution was reacted with 0.1M hydrochloric acid at 80-100℃ for 10 min, and the reaction was terminated. The reaction solution was purified using a C18 column: first, the eluent was washed with sterile water and discarded, then eluted with 1 mL of 70% ethanol. The eluent was collected, diluted with 6 mL of physiological saline, and sterilely filtered to obtain the product solution, which was then sampled and tested. The radiochemical purity of the product was determined using Radio-iTLC, and the radiochemical purity was >95%.

[0839] 2.2 177 Lu-compound 1 labeling process

[0840] Add 0.45 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to the reaction flask, then add 60 μL of aqueous solution of the precursor of compound 1 (containing 60 μg of the precursor), mix thoroughly, and then add 0.45 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, purified, and sampled for analysis. The radiochemical purity of the product was determined by Radio-iTLC, and the radiochemical purity was >95%.

[0841] 2.3 177 Labeling process of Lu-compound 2

[0842] 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 2 (containing 60 μg of compound 2), mix thoroughly, and then add 1 mL of [unclear text - possibly a typo, should be "1 mL"]. 177 The reaction solution of LuCl3 in 0.05M hydrochloric acid was reacted at 80℃ for 15 min. The reaction was then terminated, and the product was purified and sampled for analysis. The radiochemical purity of the product was determined using Radio-iTLC, and the radiochemical purity was >95%.

[0843] 2.4 161 Labeling process of Tb-compound 2

[0844] 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 2 (containing 60 μg of compound 2), mix thoroughly, and then add 1 mL of […]. 161 The reaction solution of [Tb]-terbium chloride in 0.05M hydrochloric acid was reacted at 80°C for 15 min. The reaction was then terminated, and the product was purified and sampled for analysis. The radiochemical purity of the product was determined using Radio-iTLC, and the radiochemical purity was >95%.

[0845] 2.5 18 Labeling process of F-compound 4

[0846] 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 1 (containing 1200 μg of precursor compound) 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. Sampling and testing were performed, and the radiochemical purity of the product was determined to be >95% by HPLC. The results are shown in Figure 21.

[0847] Preclinical trials:

[0848] Mouse model:

[0849] The OS-RC-2 model mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. They are a subcutaneous heterotopic tumor model of OS-RC-2 tumors established using BALB / c nude mice. This model is a mouse model constructed from human renal cancer cells.

[0850] ICR mice were purchased from Hengjia Biotechnology (Suzhou) Co., Ltd.

[0851] MicroPET / CT equipment: SNPC-303 Super Nova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.

[0852] Scanning procedure: After administration of the drug, the pre-anesthetized animals were placed in the MicroPET / CT imaging chamber for scanning within a specified time. The acquired image data was reconstructed by 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).

[0853] Experiment Example 1: SPR Affinity Test

[0854] The affinity of compound 1 for CAIX was determined using the Biacore 8K protein interaction system. CAIX (purchased from ACROBiosystems Inc.) was coupled to the surface of a CM5 chip. The analyte compound 1 molecule was diluted with buffer, and a series of solutions of different concentrations were diluted, injected, and the affinity of compound 1 for CAIX was measured. The affinity of compound 1 for CAIX 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 K is the dissociation constant. a As the associative constant, K D The smaller the value, the higher the affinity between the compound and the protein.

[0855] The test results are as follows: the equilibrium dissociation constants (KD) of compounds 1 and 2 bound to CAIX are (9.69±0.32)E-9M and (8.16±0.51)E-11M, respectively. This indicates that compounds 1 and 2 have a strong affinity for the CAIX protein.

[0856] Experimental Example 2 68 Tissue distribution and targeting experiments of Ga-compound 1 in OS-RC-2 model mice

[0857] Experimental steps:

[0858] Four OS-RC-2 model mice were selected. Each animal was given... 6880 μCi of Ga-compound 1 drug was administered to pre-anesthetized animals placed in a MicroPET / CT imaging chamber (SNPC-303 SuperNova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.). Dynamic MicroPET / CT scans were performed 30 min after drug administration, and static MicroPET / CT scans were performed 1 and 2 h after drug administration. The acquired image data were reconstructed by 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).

[0859] The results are shown in Figure 5 (the arrow indicates the tumor). 68 Ga-compound 1 rapidly accumulates at tumor sites while exhibiting low uptake in non-target organs, primarily being rapidly metabolized and cleared via the renal pathway. Based on the tumor-to-non-target tissue uptake ratio (see Figure 6 and Table 7), at 1 hour post-administration, the tumor-to-muscle and tumor-to-heart uptake ratios were approximately 6:1 and 2:1, respectively, and remained at high levels even 2 hours post-administration. This compound demonstrates significant targeted enrichment capacity and a high target-to-protein ratio, contributing to improved clarity and contrast in tumor imaging, exhibiting favorable imaging properties and potential clinical applications.

[0860] Table 7

[0861] Experimental Example 3 68 Distribution and targeting validation of Ga-compound 1 in OS-RC-2 model PET / CT scans

[0862] Experimental steps:

[0863] Six OS-RC-2 model mice were selected for the experimental model. Each animal was given... 68 80 μCi of Ga-compound 1 drug was administered to pre-anesthetized animals placed in a MicroPET / CT imaging chamber (SNPC-303 SuperNova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.). MicroPET / CT scans were performed 1 hour after drug administration to obtain and analyze the scanned images.

[0864] The results, as shown in Figure 7 (the arrow indicates the tumor location), 68 Ga-compound 1 rapidly accumulates at the tumor site 1 hour after administration, and the tumor site is clearly visualized, which has guiding significance for clinical tumor diagnosis.

[0865] Experiment Example 4 68 Distribution of Ga-compound 1 in ex vivo tissues of the OS-RC-2 model

[0866] Experimental steps:

[0867] Six OS-RC-2 model mice were selected. Each animal was given... 68 100 μCi of Ga-compound 1 drug was administered, and three animals were dissected at 1 h and 4 h after administration. Fourteen tissues and organs were collected, including the brain, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonads, skeletal muscle, spleen, stomach, fat, and tumor, and gamma ray radioactivity counts were detected.

[0868] Table 8 lists the radioactivity distribution of each tissue at different time points. As can be seen from Figure 8 and Table 8, 68 Ga-compound 1 was significantly enriched in tumor tissue 1 hour after administration and maintained a high uptake level 4 hours later. Meanwhile, radioactive uptake in the kidneys, lungs, and brown adipose tissue (brown adipose tissue in the scapula) decreased rapidly over time, while radioactivity distribution in other non-target organs was low. This indicates... 68 Ga-compound 1 can rapidly target tumor tissue and maintain high tumor uptake in vivo, while being rapidly cleared through renal metabolism, reducing non-specific background signals. This is beneficial for improving tumor imaging contrast and diagnostic accuracy, and it also has good in vivo safety.

[0869] Table 8

[0870] Experimental Example 5 177 Tissue distribution and targeting experiments of Lu-compound 1 in the OS-RC-2 model

[0871] Experimental steps:

[0872] One OS-RC-2 model mouse was selected. The animal was intravenously injected with... 177 Lu-compound 1, with a radioactive dose of 300 μCi. Small animal SPECT / CT scans were performed at 4, 24, 48, 96, 120, and 168 hours after administration. Animals were pre-anesthetized with an appropriate concentration of isoflurane / air gas before scanning and maintained under anesthesia throughout the scan. The acquired image data were reconstructed using the device software, 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).

[0873] As can be seen from Figure 9 and Table 9, 177 Lu-compound 1 was significantly enriched in tumor tissue 6 hours after administration (area indicated by arrows in the figure), and uptake in non-target organs decreased significantly after 48 hours, while significant radioactive uptake remained at the tumor site even after 168 hours. These results indicate that... 177Lu-compound 1 exhibits good accumulation capacity and long retention time in tumor tissues, making it suitable for radiotherapy of tumors. Simultaneously, its uptake in non-target organs is low and its clearance is rapid, suggesting minimal potential toxicity to non-target tissues and demonstrating good targeting and safety.

[0874] Table 9

[0875] Experimental Example 6 177 In vitro tissue distribution experiment of Lu-compound 1 in OS-RC-2 model

[0876] Experimental steps:

[0877] Nine OS-RC-2 model mice were selected. Each animal was given... 177 300 μCi of Lu-compound 1 drug was administered, and three animals were dissected at 4h, 48h, and 168h after administration. Fifteen tissues and organs were collected, including the brain, thyroid gland, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonads, skeletal muscle, spleen, stomach, fat, and tumor, and gamma radiation counts were measured.

[0878] Table 10 lists the radioactivity levels of different tissues at different time points, as shown in Figure 10. 177 Four hours after administration, Lu-compound 1 was enriched at the tumor site. Except for higher radioactive uptake in the kidneys and lungs, uptake in other normal tissues was not high.

[0879] Within 48 hours of administration, uptake by normal tissues such as the kidneys, lungs, and brown adipose tissue (brown adipose tissue in the scapula) decreased rapidly, while high uptake remained at the tumor site. 177 Lu-compound 1 can specifically target tumors and can be rapidly cleared from non-target organs, showing good safety and clinical therapeutic potential.

[0880] Table 10

[0881] Experimental Example 7 68 Blood pharmacokinetic assay of Ga-compound 1 in ICR mice

[0882] Six ICR mice were randomly selected, and each mouse was given the above-mentioned treatment. 68 100 μCi of Ga-compound 1 drug was administered via submandibular blood sampling at 5 min, 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, and 4 h post-administration. The gamma radioactivity count in the blood was measured, and the blood drug concentration at different time points was calculated. The pharmacokinetic parameters were calculated by fitting the data to the pharmacokinetic software Mas based on a non-compartmental model (see table below for details).

[0883] The results are shown in Table 11 and Figure 11. 68 The pharmacokinetic calculations for Ga-compound 1 show that the elimination half-life T is... 1 / 2 =3.51h, and the time to peak concentration (Tmax) is approximately 0.08h, indicating that the drug has good pharmacokinetic characteristics.

[0884] Table 11 Pharmacokinetic parameters of the non-compartmental model calculated using the pharmacokinetic counting software MAS

[0885] Experimental Example 8 177 Lu-compound 1 tumor therapy experiment

[0886] Eighteen OS-RC-2 model mice were randomly selected and divided into three groups of six mice each: a saline group, a single-dose group, and a multiple-dose group. The single-dose group administered the following treatment to each animal: 177 Lu-compound 1 drug 2mCi, administered once per mouse via tail vein injection; multiple administration groups were administered to each animal separately. 177 Lu-compound 1 was administered twice, 2 mCi each time, four days apart, via tail vein injection. Mouse body weight and tumor volume were measured before the experiment, and every two or three days after administration. The major and minor axes of the tumor were measured to calculate tumor volume using the following formula: Tumor volume (TV) = a × b 2 / 2 (a is the major axis, b is the minor axis). Calculate the tumor growth inhibition rate (TGI).

[0887] Twenty days after administration, the TGI values ​​for the single-dose group and the multiple-dose group were 41.7% and 57.2%, respectively. As shown in Figure 12, compared to the saline group, both the single-dose and multiple-dose groups exhibited significant antitumor activity, effectively inhibiting tumor growth. Furthermore, the tumor growth in the multiple-dose group was slower, demonstrating a dose-dependent effect. There were no significant differences in the weight changes of the mice across the three groups. This indicates that the drug possesses good antitumor efficacy and safety.

[0888] Experimental Example 9 68 Ga-compound 2OS-RC-2 model PET / CT scan tissue distribution and targeting validation

[0889] Experimental steps:

[0890] Four OS-RC-2 model mice were selected. Each animal was given... 6880 μCi of Ga-compound 2 drug was administered. Animals were pre-anesthetized with an appropriate concentration of isoflurane / air gas before scanning. They were then placed in a MicroPET / CT imaging chamber (SNPC-303 SuperNova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.) and anesthesia was maintained using isoflurane / air gas. Dynamic MicroPET / CT scans were performed 1 hour after drug administration, followed by static MicroPET / CT scans 2 hours later. The acquired image data were reconstructed using the equipment software, 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).

[0891] The results, as shown in Figure 13 (the arrow indicates the tumor location), 68 Ga-compound 2 rapidly accumulates at the tumor site after administration, with low uptake in other non-target organs, and is rapidly metabolized by the kidneys. Good imaging effect can be achieved at the tumor site within half an hour after administration. As can be seen from Figure 14 and Table 12, the kidney uptake is low 1 hour after administration, and the tumor imaging is more obvious, which has guiding significance for clinical tumor diagnosis.

[0892] Table 12

[0893] Experimental Example 10 177 Lu-compound 2OS-RC-2 model in vitro tissue distribution experiment

[0894] Experimental steps:

[0895] Six OS-RC-2 model mice were selected. Each animal was given... 177 Lu-compound 2 drug 300 μCi was administered, and 3 animals were dissected at 4h and 48h after administration. A total of 15 tissues and organs were collected, including brain, thyroid, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonads, skeletal muscle, spleen, stomach, fat, and tumor, and gamma radiation counts were measured.

[0896] Table 13 lists the radioactivity levels of different tissues at different time points, as shown in Figure 15. 177 Lu-compound 2 was enriched at the tumor site 4 hours after administration. Except for the kidneys, lungs, stomach, and brown fat (brown fat in the scapula), the radioactive uptake was high in other normal tissues, while the uptake level was low.

[0897] Forty-eight hours after administration, radioactive uptake in other normal tissues such as the kidneys, lungs, stomach, and brown adipose tissue (brown adipose tissue in the scapula) decreased significantly, while tumor tissue maintained a high uptake level. 177Lu-compound 2 can specifically target tumor tissue and maintain a high level of radioactivity at the tumor site for a long time, while achieving rapid clearance in non-target organs, suggesting that it has good safety and potential clinical therapeutic value.

[0898] Table 13

[0899] Experimental Example 11 177 Experiment on efficacy verification of Lu-compound 2 in OS-RC-2 model

[0900] Experimental steps:

[0901] Eighteen OS-RC-2 model mice were randomly selected and divided into three groups of six mice each: a saline group, a single-dose group, and a multiple-dose group. The single-dose group administered the following treatment to each animal: 177 Lu-compound 2 drug 2mCi, administered once per mouse via tail vein injection; multiple administration groups were administered to each animal separately. 177 Lu-compound 2 was administered twice, 2 mCi each time, with a seven-day interval between doses, via tail vein injection. Mouse body weight and tumor volume were measured before the experiment, and every three days after administration. The major and minor axes of the tumor were measured to calculate tumor volume using the following formula: Tumor volume (TV) = a × b 2 / 2 (a is the major axis, b is the minor axis). Calculate the tumor growth inhibition rate (TGI).

[0902] Thirty-two days after administration, the TGI values ​​for the single-dose group and the multiple-dose group were 81.0% and 85.6%, respectively. As shown in Figure 16, compared to the saline group, the single-dose group and the multiple-dose group exhibited significant antitumor activity, effectively inhibiting tumor growth. There was no significant difference in the weight change trend of mice among the three groups. This demonstrates that the drug has good antitumor efficacy and safety.

[0903] Experimental Example 12 68 Ga / 177 Safety evaluation experiment of Lu-compound 2

[0904] The experimental mice were female ICR mice, purchased from Hengjia Biotechnology (Suzhou) Co., Ltd.

[0905] Eighteen mice were randomly selected for this animal model and divided into three groups of six mice each: group A, group B, and group C. Group A received the following treatment: 68 Ga-compound 2 drug 300 μCi; Group B was administered to each animal. 177Lu-compound 2 drug 1.5mCi; Group C was given an equal volume of physiological saline to each animal; all three groups of mice were injected via tail vein; animal weight and food intake were observed 3 times a week for 2 weeks, and dissection was performed after the observation period to observe the major organs.

[0906] The results showed that none of the three groups of mice died or exhibited other significant abnormalities throughout the experiment, and there were no significant differences in body weight or food intake. Autopsies revealed no significant abnormalities in the major organs.

[0907] Example 13 161 Distribution of Tb-compound 2 in ex vivo tissues in the OS-RC-2 model

[0908] Experimental steps:

[0909] Twelve OS-RC-2 model mice were selected. Each animal was given... 161 Approximately 300 μCi of Tb-compound 2 drug was administered. Three animals were dissected at 4h, 24h, 48h, and 120h after administration. Fourteen tissues and organs, including the brain, thyroid gland, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonads, skeletal muscle, spleen, stomach, and fat, as well as tumors, were collected, and gamma radiation counts were measured.

[0910] Table 14 lists the radioactivity levels of different tissues at different time points, as shown in Figure 22. 161 Tb-compound 2 showed high radioactive uptake in tumor tissue 24 hours after administration, while the uptake levels in other normal tissues were low. High radioactive accumulation remained at the tumor site 48 hours after administration.

[0911] Table 14

[0912] Example 14 161 Therapeutic effects of Tb-compound 2 on OS-RC-2 model mice

[0913] Experimental steps:

[0914] Sixteen mice were randomly selected for the OS-RC-2 model experiment and divided into two groups of eight mice each: G1 and G2. In group G2, each animal received... 161 Tb-compound 2 was administered at a dose of 0.67 mCi per mouse via tail vein injection once per mouse; in group G1, each animal was given glucose solution. Mouse body weight and tumor volume were measured before the experiment and twice weekly after administration. The long and short diameters of the tumor were measured to calculate 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) is then calculated.

[0915] 29 days after administration, the TGI value of the G2 group was 60.0%. As shown in Figure 23, the G2 group exhibited significant antitumor activity and effectively inhibited tumor growth, indicating that this drug has good antitumor efficacy and safety.

[0916] Example 15 68 Tissue distribution and targeting experiments of Ga-compound 3 in OS-RC-2 model mice

[0917] Experimental steps:

[0918] Four OS-RC-2 model mice were selected. Each animal was given... 68 80 μCi of Ga-compound 3 drug was administered to pre-anesthetized animals placed in a MicroPET / CT imaging chamber (SNPC-303 SuperNova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.). Dynamic MicroPET / CT scans were performed 1 hour after drug administration, followed by static MicroPET / CT scans 2 hours later. The acquired image data were reconstructed using the equipment software, 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).

[0919] As shown in Figure 24 (the arrow indicates the location of the tumor) and Table 15. 68 Ga-compound 3 rapidly accumulates at the tumor site after administration, with low uptake at other non-target organs, and is mainly eliminated by renal metabolism. Good imaging results can be obtained at the tumor site within half an hour after administration. As can be seen from Figures 24 and 25, the renal radioactive uptake is further reduced 2 hours after administration, and the tumor imaging contrast is significantly enhanced.

[0920] Table 15

[0921] Example 16 18 Tissue distribution and targeting experiments of compound F4 in OS-RC-2 model mice

[0922] Experimental steps:

[0923] Four OS-RC-2 model mice were selected. Each animal was given... 18F-compound 4 drug 80 μCi was administered to pre-anesthetized animals placed in a MicroPET / CT imaging chamber (SNPC-303 SuperNova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.). Dynamic MicroPET / CT scans were performed 1 hour after drug administration, and static MicroPET / CT scans were performed 2 hours after drug administration. The scanned images were obtained after reconstruction by the equipment software and analyzed using the software.

[0924] The results, as shown in Figure 26 (the arrow indicates the location of the tumor), 18 Compound F-4 rapidly accumulates at the tumor site after administration, with minimal uptake at other non-target organs. Good imaging results can be obtained at the tumor site within half an hour after administration. As shown in Figures 26 and 27, the renal radioactive uptake further decreases 2 hours after administration, and the tumor imaging contrast is significantly enhanced.

[0925] Table 16

[0926] Example 17 68 Ga-compound 5, 68 Tissue distribution and targeting experiments of Ga-compound 6 in OS-RC-2 model mice

[0927] Experimental steps:

[0928] Three OS-RC-2 model mice were randomly selected for the experiment. Two of them were given... 68 Ga-compound 5 drug 80 μCi, another one was given 68 Ga-compound 6 drug, 80 μCi; dynamic 1-hour MicroPET / CT scans were performed after administration, and static MicroPET / CT scans were performed at 2 and 4 hours after administration (compound 5 drug group). Tissue distribution maps were obtained, and the radioactive uptake values ​​of each tissue and organ were quantitatively measured (expressed as %ID / g).

[0929] The results, as shown in Figure 33 (the arrow indicates the tumor location), 68 Ga-compound 5 and 68 Ga-compound 6 rapidly accumulates at the tumor site after administration, with low uptake in other non-target organs, and is rapidly metabolized by the kidneys. Good imaging results can be achieved at the tumor site within half an hour after administration. As shown in Figure 33, the kidney uptake is low and the tumor imaging is more obvious 2 hours after administration, which has guiding significance for clinical tumor diagnosis.

[0930] Table 17

[0931] Table 18

[0932] Example 18 68 Clinical trials of Ga-compound 2

[0933] Clinical trials:

[0934] The patient, a 37-year-old female weighing 80 kg, had previously undergone radical resection of her right kidney for a mass. Postoperative pathology revealed clear cell carcinoma with sarcomatoid differentiation. Multiple lung metastases were discovered postoperatively (1.3 cm in the right upper lobe and 1.4 × 0.7 cm in the left lower lobe). She received pepapanib combined with immunotherapy, achieving partial remission (PR). Subsequent bone scans revealed lumbar spine metastases, and she received denosumab for bone marrow treatment; immunotherapy has been discontinued. To clarify the distribution of systemic lesions, the patient underwent various procedures. 18 F-FDG and 68 Ga-compound 2 PET / CT imaging. The procedure involves first intravenous injection. 68 Ga-compound 21.96 mCi was injected, and a scan was performed 56 minutes after injection; intravenous injection was performed one day later. 18 F-FDG 5.99 mCi was injected, and a scan was performed 156 minutes post-injection. The scan yielded raw images, which were then reconstructed to generate maximum intensity projection (MIP) images (Figure 28), used for a comprehensive assessment of the distribution of the radiotracer throughout the body and the metabolic characteristics of lesion sites. The radioactive uptake values ​​of lesions and tissues are shown in Table 19. It can be seen that CA9 imaging results showed high radioactive uptake in multiple sites, including vertebral lesions, the sacroiliac joint, the ilium, and the digestive system, suggesting significant CA9 expression activity at the tumor site. Compared to... 18 F-FDG imaging results, same area 18 Low F-FDG intake. 18 Compared to F-FDG imaging 68 Ga-compound 2 imaging showed higher targeted uptake and contrast at tumor metastases, indicating that CA9 PET / CT has high sensitivity and specificity for the detection and evaluation of active lesions in clear cell carcinoma.

[0935] Table 19

[0936] 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

1. A compound of formula (I), or an isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, Ab is a ligand targeting carbonic anhydrase IX, for example Ring A is selected from C 6-10 Aromatic and C 5-10 Hybrid aryl groups; optionally bounded by 1, 2, 3 or 4 R groups A replace; R A Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; Or R4 and R A Connected together to form C 1-4 Alkylene, C 2-4 imide and C 2-4 The ynyl group, wherein one or more methylene units are optionally and independently replaced by -CR*2-, -NR*-, -NR*C(O)-, -C(O)NR*-, -NR*S(O)2-, -S(O)2NR*-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; and R4 and R A The ring formed after connecting is a parallel ring structure of ring A; V3 is selected from chemical bonds, C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne and Ring B is a 3-7 member subheterocyclic group; W3 is selected from chemical bonds, -NR-, -O-, -S-, and -C(O)-; R* is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-10 membered heterocyclic groups; 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 substituted by one or more amino acid residues, and said amino acid residues may optionally be substituted by 1, 2, 3, 4, 5 or 6 R's. L replace; R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group; Z is a chelating group derived from the chelating agent.

2. The compound of claim 1, having the following structure: in, A1, A2, and A3 are amino acid residues; A4 is an H or an amino acid residue; V1 is selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne group, C 6-10 Aromatic and C 5-10 A heteroaryl group, optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. 1s replace; R 1s Independently selected from H, D, -OR a -SR a -NR b R c Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; V2 is a chemical bond or -(CR'R”). 1-6 -; R' and R" are independently selected from H, D, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-Ar; Ar is selected from C 6-14 Aryl and 5-14 heteroaryl groups; W4 is selected from chemical bonds, -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)O-, -C(O)NR-, and -O-; n is 0, 1, 2, 3, 4, 5, or 6; The remaining variables are as defined in claim 1.

3. The compound of claim 1 or 2, wherein, L1 is -W1-V1-W4-V2-W2-; W1 is selected from chemical bonds, -NR-, -C(O)-, -C(O)O-, and -C(O)NR-; W2 is selected from -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)NR- and -O-; V1 is selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne group, C 6-10 Aromatic and C 5-10 A heteroaryl group, optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. 1s Substitution; wherein one or more methylene units among the alkylene, alkenylene, and ynylene groups are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -NRS(O)2-, -S(O)2NR-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; R is independently selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 1s Independently selected from H, D, -OR a -SR a -NR b R c Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclic group; preferably, R 1s It can be independently of the (S) or (R) configuration, or in a racemic form; V2 is a chemical bond or -(CR'R”). 1-6 -; R' and R" are independently selected from H, D, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -C 1-6 Alkylene-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form; Ar is independently selected from C 6-14 Aryl and 5-14 heteroaryl groups; W4 is selected from chemical bonds, -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)O-, -C(O)NR-, and -O-; R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-7 membered heterocyclic groups; Preferably, L1 is -W1-V1-W4-V2-W2-; W1 is selected from -C(O)-, -C(O)O- and -C(O)NR-; preferably -C(O)-; W2 is selected from -C(O)-, -OC(O)- and -NRC(O)-; preferably -C(O)-; V1 is selected from C 1-8 Alkylene, C 2-8 imidene group, C 2-8 Alynyl, phenylene and C 5-6 Hypoaryl, preferably C 1-8 Alkylene (e.g., -(CH2)) m -); it is optionally bounded by 1, 2, 3, 4, 5 or 6 R's. 1s Substitution; wherein one, two or three methylene units in the alkylene, alkenylene and ynylene groups are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -C(O)-, -OC(O)- or -C(O)O-; m is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 1s Independently selected from H, D, -OR a -NR b R c Halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H, D, or -OR a and -NR b R c ; V2 is a chemical bond or -(CR'R”). 1-4 -; R' is independently selected from H, D, or -C. 1-4 Alkylene-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form; preferably in (S) configuration; preferably in (R) configuration; "R" is independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Ar is independently selected from C 6-14 Aryl and 5-14 membered heteroaryl, preferably C 6-14 Aryl; W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O-, and -C(O)NR-; Preferably, L1 is -C(O)-V1-W4-V2-C(O)-; V1 is selected from C 1-6 Alkylene (e.g., -(CH2)) m -), phenylene and C 5-6 Hybrid aryl; preferably selected from C 1-6 Alkylene (e.g., -(CH2)) m -), phenylene, pyrrolidine, furanyl or thiophene; preferably C 1-6 Alkylene (e.g., -(CH2)) m -); C is preferred. 1-4 Alkylene (e.g., -(CH2)) m -); it is optionally bounded by 1, 2, 3, 4, 5 or 6 R's. 1s Substitution; wherein one, two or three methylene units in the alkylene group are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -C(O)-, -OC(O)- or -C(O)O-; m is independently selected from 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 1s Independently selected from H, D, -OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H and -OR a ; V2 is a chemical bond or -(CR'R”). 1-2 -(preferably -CHR'-); R' is independently selected from H or -C 1-4 Alkylene-Ar, preferably H or -CH2-Ar; preferably, R' is independently of the (S) or (R) configuration, or is racemic; preferably (S) configuration; preferably (R) configuration; "R" is independently selected from H, D, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D; Ar independently for C 6-14 Aryl, such as phenyl, naphthyl, anthraceneyl or phenanthrene; preferably C 6-10 Aryl, such as phenyl or naphthyl, preferably naphthyl, preferably 2-naphthyl; W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O- and -C(O)NR-; preferably chemical bonds, -C(O)O- and -C(O)NR-; more preferably chemical bonds or -C(O)NR-; For example, L1 is selected from: (preferred) )； Among them, *1, *2 and *3 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; preferably (S) configuration; preferably (R) configuration.

4. The compound according to any one of claims 1-3, wherein, L2 is an amino acid chain consisting of 2-5 amino acid residues, wherein each amino acid residue may optionally be further substituted by one or more (preferably 1, 2 or 3, preferably 1) amino acid residues, and said amino acid residues may optionally be substituted by 1, 2, 3, 4, 5 or 6 R's. L replace; R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group; Preferably, L2 is A1, A2, A3, and A4 are amino acid residues, and said amino acid residues are optionally surrounded by 1, 2, 3, 4, 5, or 6 R's. L replace; R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group; Preferably, L2 is A1, A2, A3, and A4 are selected from glycine residues, alanine residues, phenylalanine residues, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, or arginine residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, phenylalanine residues, or arginine residues, optionally marked with 1, 2, 3, or 4 R's. L replace; R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably C 1-6 Acyl group; More preferably, L2 is A1 is a lysine residue; preferably... Preferred Preferred A2 is selected from tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, phenylalanine residues, or arginine residues, optionally separated by 1, 2, 3, or 4 R groups. L replace; R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and urea groups; preferably halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and urea groups; A2 is preferred and selected from (Preferred) Preferred )、 (Preferred) )、 (Preferred) )、 (Preferred) )、 (Preferred) )and (Preferred) )； A3 is a lysine residue; preferred. Preferred Preferred A4 is selected from N-acetylglutamic acid residues, N-(4-carboxybutyryl)glutamic acid, glutamic acid residues, pyroglutamic acid residues, citrulline residues, and aspartic acid residues; preferably. (Preferred) )、 (Preferred) )、 (Preferred) )、 (Preferred) )、 Among them, *4, *5, *6 and *7 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; preferably (S) configuration; preferably (R) configuration; For example, L2 is selected from: (preferred) Preferred )、 (preferred) )、 (preferred) )、 (preferred) )、 (preferred) )、 (preferred) )、 (preferred) )、 (preferred) )and (preferred) )。 5. The compound according to 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 DOTA、 USE、 NODAGA, DOTAGA, HBED-CC、 p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA and p-SCN-Bn-DOTA; Preferred DOTA or NOTA; Preferred DOTA.

6. The compound according to any one of claims 1-5, wherein, Ab is Ring A is selected from phenylene and C 5-6 Heteroaryl; preferably selected from phenylene and 1,3,4-thiadiazolyl; optionally surrounded by 1, 2, 3 or 4 R groups. A replace; R A Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl groups and 3-7 membered heterocyclic groups; preferably selected from H, D, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Or R4 and R A Connected together to form C 1-4 Alkylene, preferably C 1-2 Alkylene, wherein one, two, or three (preferably one) methylene units are optionally and independently replaced by -CR*2-, -NR*-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, preferably replaced by -CR*2-, -C(O)-, -OC(O)-, or -C(O)O-, preferably replaced by -C(O)-; and R4 and R A The ring formed after connecting is a parallel ring structure of ring A; V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group; W3 is selected from -NR- and -O-; R* is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-7 membered heterocyclic groups; Preferably, Ab is selected from: R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group; W3 is selected from -NR- and -O-; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Preferably, Ab is selected from: V3 is selected from chemical bonds and C. 1-6 Alkylene (preferably C) 1-4 Alkylene, preferably C 1-2 Alkylene); More preferably, Ab is selected from: n can be 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3 or 4, preferably 0 or 2.

7. The compound according to any one of claims 1-6, wherein, Ab is Ring A is selected from phenylene and C 5-6 Heteroaryl; preferably selected from phenylene and 1,3,4-thiadiazolyl; optionally surrounded by 1, 2, 3 or 4 R groups. A replace; R A Independently selected from H, D, halogen, CN, -OR a -SR a -NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl groups and 3-7 membered heterocyclic groups; preferably selected from H, D, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Or R4 and R A Connected together to form C 1-4 Alkylene, preferably C 1-2 Alkylene, wherein one, two, or three (preferably one) methylene units are optionally and independently replaced by -CR*2-, -NR*-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, preferably replaced by -CR*2-, -C(O)-, -OC(O)-, or -C(O)O-, preferably replaced by -C(O)-; and R4 and R A The ring formed after connecting is a parallel ring structure of ring A; V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group; W3 is selected from -NR- and -O-; R* is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; L1 is -W1-V1-W4-V2-W2-; W1 is selected from chemical bonds, -NR-, -C(O)-, -C(O)O-, and -C(O)NR-; W2 is selected from -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)NR- and -O-; V1 is selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne group, C 6-10 Aromatic and C 5-10 A heteroaryl group, optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. 1s Substitution; wherein one or more methylene units among the alkylene, alkenylene, and ynylene groups are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -NRS(O)2-, -S(O)2NR-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; R 1s Independently selected from H, D, -OR a -SR a -NR b R c Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclic group; preferably, R 1s It can be independently of the (S) or (R) configuration, or in a racemic form; V2 is a chemical bond or -(CR'R”). 1-6 -; R' and R” are independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form; Ar is independently selected from C 6-14 Aryl and 5-14 heteroaryl groups; W4 is selected from chemical bonds, -C(O)-, -OC(O)-, -NRC(O)-, -NR-, -C(O)O-, -C(O)NR-, and -O-; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-7 membered heterocyclic groups; L2 is an amino acid chain consisting of 2-5 amino acid residues, wherein each amino acid residue may optionally be further substituted by one or more (preferably 1, 2 or 3, preferably 1) amino acid residues, and said amino acid residues may optionally be substituted by 1, 2, 3, 4, 5 or 6 R's. L replace; R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group; Z is a chelating group derived from the chelating agent.

8. The compound of any one of claims 1-7, wherein, Ab is selected from: R3 and R4 are independently selected from H, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group; W3 is selected from -NR- and -O-; L1 is -W1-V1-W4-V2-W2-; W1 is selected from -C(O)-, -C(O)O- and -C(O)NR-; preferably -C(O)-; W2 is selected from -C(O)-, -OC(O)- and -NRC(O)-; preferably -C(O)-; V1 is selected from C 1-8 Alkylene, C 2-8 imidene group, C 2-8 Alynyl, phenylene and C 5-6 Hypoaryl, preferably C 1-8 Alkylene (e.g., -(CH2)) m -); it is optionally bounded by 1, 2, 3, 4, 5 or 6 R's. 1s Substitution; wherein one, two or three methylene units in the alkylene, alkenylene and ynylene groups are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -C(O)-, -OC(O)- or -C(O)O-; m is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 1s Independently selected from H, D, -OR a -NR b R c Halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H, D, or -OR a and -NR b R c ; V2 is a chemical bond or -(CR'R”). 1-4 -; R' is independently selected from H, D, or -C. 1-4 Alkylene-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form; preferably in (S) configuration; preferably in (R) configuration; "R" is independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Ar is independently selected from C 6-14 Aryl and 5-14 membered heteroaryl, preferably C 6-14 Aryl; W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O-, and -C(O)NR-; L2 is A1, A2, A3, and A4 are amino acid residues, and said amino acid residues are optionally surrounded by 1, 2, 3, 4, 5, or 6 R's. L replace; R L Independently selected from halogens, NO2, and -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group, -C(O)-C 1-6 Alkylene-COOH, sulfonic acid group, methanesulfonyl group, phosphoric acid group, and phosphorous acid group; Z is a chelating group derived from the chelating agent.

9. The compound according to any one of claims 1-8, wherein, Ab is selected from: n is 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3 or 4, preferably 0 or 2; L1 is -C(O)-V1-W4-V2-C(O)-; V1 is selected from C 1-6 Alkylene (e.g., -(CH2)) m -), phenylene and C 5-6 Hybrid aryl; preferably selected from C 1-6 Alkylene (e.g., -(CH2)) m -), phenylene, pyrrolidine, furanyl or thiophene; preferably C 1-6 Alkylene (e.g., -(CH2)) m -); C is preferred. 1-4 Alkylene (e.g., -(CH2)) m -); it is optionally bounded by 1, 2, 3, 4, 5 or 6 R's. 1s Substitution; wherein one, two or three methylene units in the alkylene group are optionally and independently replaced by -NR-, -NRC(O)-, -C(O)NR-, -C(O)-, -OC(O)- or -C(O)O-; m is independently selected from 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 1s Independently selected from H, D, -OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H and -OR a ; V2 is a chemical bond or -(CR'R”). 1-2 -(preferably -CHR'-); R' is independently selected from H or -C 1-4 Alkylene-Ar; preferably H or -CH2-Ar; preferably, R' is independently of the (S) or (R) configuration, or is racemic; preferably (S) configuration; preferably (R) configuration; "R" is independently selected from H, D, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D; Ar independently for C 6-14 Aryl, such as phenyl, naphthyl, anthraceneyl or phenanthrene; preferably C 6-10 Aryl, such as phenyl or naphthyl, preferably naphthyl, preferably 2-naphthyl; W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O- and -C(O)NR-; preferably chemical bonds, -C(O)O- and -C(O)NR-; more preferably chemical bonds or -C(O)NR-; L2 is A1, A2, A3, and A4 are selected from glycine residues, alanine residues, phenylalanine residues, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, or arginine residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, phenylalanine residues, or arginine residues, optionally marked with 1, 2, 3, or 4 R's. L replace; R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably C 1-6 Acyl group; 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).

10. The compound of any one of claims 1-9, wherein, Ab is selected from: n is 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3 or 4, preferably 0 or 2; L1 is selected from: (preferred) )； Wherein, *1, *2 and *3 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; preferably (S) configuration; preferably (R) configuration; L2 is A1 is a lysine residue; preferably... Preferred Preferred A2 is selected from tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, phenylalanine residues, or arginine residues, optionally separated by 1, 2, 3, or 4 R groups. L replace; R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and urea groups; preferably halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and urea groups; A2 is preferred and selected from (Preferred) Preferred )、 (Preferred) )、 (Preferred) )、 (Preferred) )、 (Preferred) )and (Preferred) )； A3 is a lysine residue; preferred. Preferred Preferred A4 is selected from N-acetylglutamic acid residues, N-(4-carboxybutyryl)glutamic acid, glutamic acid residues, pyroglutamic acid residues, citrulline residues, or aspartic acid residues; preferably. (Preferred) )、 (Preferred) )、 (Preferred) )、 (Preferred) )、 Among them, *4, *5, *6 and *7 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; preferably (S) configuration; preferably (R) configuration; Z is selected from DOTA、 USE、 NODAGA, DOTAGA, HBED-CC、 p-SCN-Bn-CHX-A"-DTPA、 p-SCN-Bn-NOTA and p-SCN-Bn-DOTA; Preferred DOTA or NOTA; Preferred DOTA; Preferably, L2 is selected from: (preferred) Preferred )、 (preferred) )、 (preferred) )、 (preferred) )、 (preferred) )、 (preferred) )、 (preferred) )、 (preferred) )and (preferred) )。 11. The compound of any one of claims 1-10, wherein, V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne and Preferred chemical bonds, C 1-6 Alkylene (preferably C) 1-4 Alkylene, preferably C 1-2 alkylene) and Preferred chemical bonds and Preferably, Ring B is a 3-7 membered heterocyclic group; preferably a 4-6 membered heterocyclic group; preferably a 5 membered heterocyclic group, for example... Wherein, *8 is a chiral center, independently selected from (S) or (R) configurations, or racemic form; preferably (S) configuration; preferably (R) configuration; The remaining variables are defined as described in any one of claims 1-10.

12. The compound of any one of claims 1-11, wherein, W3 is selected from -NR-, -O- and -C(O)-, preferably -NR- and -C(O)-; the remaining variables are defined as claimed in any one of claims 1-11.

13. The compound of any one of claims 1-12, wherein, Ab is selected from: Preferred Preferred Wherein, *8 is a chiral center, independently selected from (S) or (R) configurations, or racemic form; preferably (S) configuration; preferably (R) configuration; The remaining variables are defined as described in any one of claims 1-12.

14. The compound of any one of claims 3-12, wherein, L1 is -W1-V1-W4-V2-W2-; W1 is selected from -NR-, -C(O)-, -C(O)O- and -C(O)NR-; preferably -NR- or -C(O)-; Preferably, R 1s Independently selected from H, -OR a -NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H or -OR a and -NR b R c H and -NR are preferred. b R c ; The remaining variables are as described in any one of claims 1-13; Preferably, L1 is selected from: (preferred) )、 (preferred) )and (preferred) )； Among them, *1, *2, *3 and *9 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; preferably (S) configuration; preferably (R) configuration; The remaining variables are as described in any one of claims 1-13.

15. The compound of any one of claims 1-14, having the structure shown in formula (III-1) or (IV-1), in, V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group; L1 is -W1-V1-W4-V2-W2-; W1 is selected from -C(O)-, -C(O)O- and -C(O)NR-; preferably -C(O)-; W2 is selected from -C(O)-, -OC(O)- and -NRC(O)-; preferably -C(O)-; V1 is selected from C 1-8 Alkylene, C 2-6 imide and C 2-6 Alynyl group, preferably C 1-8 Alkylene (e.g., -(CH2)) m -), which is optionally divided by 1, 2, 3, 4, 5 or 6 R 1s replace; m is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 1s Independently selected from H, D, -OR a -NR b R c Halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H, D, or -OR a and -NR b R c Preferably, R 1s It can be independently of the (S) or (R) configuration, or in a racemic form; V2 is a chemical bond or -(CR'R”). 1-6 -;Preferred-(CR'R”) 1-6 -; R' is independently selected from H, D, or -C. 1-4 Alkylene-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form; "R" is independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Ar is independently selected from C 6-14 Aryl and 5-14 quinone heteroaryl groups; C is preferred. 6-14 Aryl; W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O-, and -C(O)NR-; R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-7 membered heterocyclic groups; A1, A2, A3, and A4 are selected from glycine residues, alanine residues, phenylalanine residues, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, or arginine residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, phenylalanine residues, or arginine residues, optionally marked with 1, 2, 3, or 4 R's. L replace; R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably C 1-6 Acyl group; Z is as defined in claim 1 or 5.

16. The compound of claim 15, wherein, V3 is selected from chemical bonds and C. 1-6 Alkylene (preferably C) 1-4 Alkylene, preferably C 1-2 Alkylene); preferably chemical bond; L1 is -W1-V1-W4-V2-W2-; W1 is -C(O)-; W2 is -C(O)-; V1 is selected from C 1-6 Alkylene, C 2-6 imide and C 2-6 Alynyl group, preferably C 1-6 Alkylene (e.g., -(CH2)) m -), C is preferred 1-4 Alkylene (e.g., -(CH2)) m -), which is optionally divided by 1, 2, 3, 4, 5 or 6 R 1s replace; m is independently selected from 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4; R 1s Independently selected from H, D, -OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H and -OR a Preferred selections are from H and D; V2 is a chemical bond or -(CR'R”). 1-4 -; preferably a chemical bond or -(CR'R”) 1-2 -(preferably -CHR'-); preferably -(CR'R”) 1-2 -(preferably -CHR'-); R' is independently selected from H or -C 1-4 Alkylene-Ar, preferably H or -CH2-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form; preferably in (S) configuration; "R" is independently selected from H, D, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D; Ar independently for C 6-14 Aryl, such as phenyl, naphthyl, anthraceneyl or phenanthrene; preferably C 6-10 Aryl, such as phenyl or naphthyl, preferably naphthyl, preferably 2-naphthyl; W4 is selected from chemical bonds or -C(O)NR-; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R a Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; A1 is a lysine residue; A2 is a tyrosine residue; A3 is a lysine residue; A4 is a glutamic acid residue or an N-acetylglutamic acid residue, preferably a glutamic acid residue; Z is selected from DOTA、 USE、 NODAGA, DOTAGA, p-SCN-Bn-NOTA and p-SCN-Bn-DOTA; Preferred DOTA or NOTA; Preferred DOTA; Preferably, for Preferred Among them, *4, *5, *6 and *7 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; the (R) configuration is preferred; Preferably, L1 is (preferred) ), preferably (preferred) )； Among them, *3 is a chiral center, which is independently selected from the (S) or (R) configuration, or is a racemic form; the (S) configuration is preferred.

17. The compound of any one of claims 1-14, having the structure shown in formula (II-4), in, V3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne and Ring B is a 3-7 membered heterocyclic group; W3 is selected from -NR- and -C(O)-; preferably -C(O)-; L1 is -W1-V1-W4-V2-W2-; W1 is selected from -NR-, -C(O)-, -C(O)O- and -C(O)NR-; preferably -NR- or -C(O)-; W2 is selected from -C(O)-, -OC(O)- and -NRC(O)-; preferably -C(O)-; V1 is selected from C 1-8 Alkylene, C 2-6 imide and C 2-6 Alynyl group, preferably C 1-8 Alkylene (e.g., -(CH2)) m -), which is optionally divided by 1, 2, 3, 4, 5 or 6 R 1s replace; m is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 1s Independently selected from H, D, -OR a -NR b R c Halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H, D, or -OR a and -NR b R c Preferably, R 1s It can be independently of the (S) or (R) configuration, or in a racemic form; V2 is a chemical bond or -(CR'R”). 1-6 -;Preferred-(CR'R”) 1-6 -; R' is independently selected from H, D, or -C. 1-4 Alkylene-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form; "R" is independently selected from H, D, halogen, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Ar is independently selected from C 6-14 Aryl and 5-14 quinone heteroaryl groups; C is preferred. 6-14 Aryl; W4 is selected from chemical bonds, -OC(O)-, -NRC(O)-, -C(O)O-, and -C(O)NR-; R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R b R c Together with the atoms they connect, they form 3-7 membered heterocyclic groups; L2 is A1, A2, A3, and A4 are selected from glycine residues, alanine residues, phenylalanine residues, lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, or arginine residues; preferably selected from lysine residues, tyrosine residues, aspartic acid residues, serine residues, glutamic acid residues, pyroglutamic acid residues, citrulline residues, phenylalanine residues, or arginine residues, optionally marked with 1, 2, 3, or 4 R's. L replace; R L Independently selected from halogens, -OR a -NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, urea, C 1-6 Acyl group and -C(O)-C 1-6 Alkylene-COOH; preferably C 1-6 Acyl group; Z is as defined in claim 1 or 5.

18. The compound of claim 17, wherein, V3 is selected from chemical bonds, C 1-6 Alkylene (preferably C) 1-4 Alkylene, preferably C 1-2 alkylene) and Preferred chemical bonds and Ring B is a 4-6 membered heterocyclic group; preferably a 5-membered heterocyclic group, for example... W3 is selected from -NR- and -C(O)-; preferably -C(O)-; L1 is -W1-V1-W4-V2-W2-; W1 is -NR-; preferably -NH-; W2 is -C(O)-; V1 is selected from C 1-6 Alkylene, C 2-6 imide and C 2-6 Alynyl group, preferably C 1-6 Alkylene (e.g., -(CH2)) m -), C is preferred 1-4 Alkylene (e.g., -(CH2)) m -), which is optionally divided by 1, 2, 3, 4, 5 or 6 R 1s replace; m is independently selected from 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4; R 1s Independently selected from H, D, -OR a -NR b R c C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H, -OR a and -NR b R c Preferred selections are H and -NR. b R c ; V2 is a chemical bond or -(CR'R”). 1-4 -; preferably a chemical bond or -(CR'R”) 1-2 -(preferably -CHR'-); preferably -(CR'R”) 1-2 -(preferably -CHR'-); R' is independently selected from H or -C 1-4 Alkylene-Ar, preferably H or -CH2-Ar; preferably, R' is independently in (S) or (R) configuration, or in racemic form; preferably in (S) configuration; "R" is independently selected from H, D, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably H or D; Ar independently for C 6-14 Aryl, such as phenyl, naphthyl, anthraceneyl or phenanthrene; preferably C 6-10 Aryl, such as phenyl or naphthyl, preferably naphthyl, preferably 2-naphthyl; W4 is selected from chemical bonds or -C(O)NR-; preferably -C(O)NR-; R is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably H; L2 is A1 is a lysine residue; A2 is a tyrosine residue; A3 is a lysine residue; A4 is a glutamic acid residue or an N-acetylglutamic acid residue, preferably a glutamic acid residue; Z is selected from DOTA、 USE、 NODAGA, DOTAGA, p-SCN-Bn-NOTA and p-SCN-Bn-DOTA; Preferred DOTA or NOTA; Preferred DOTA; Preferably, for Preferred Among them, *4, *5, *6, *7 and *8 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; the (R) configuration is preferred; Preferably, L1 is (preferred) )or (preferred) )； Among them, *3 and *9 are chiral centers, independently selected from (S) or (R) configurations, or racemic forms; the (S) configuration is preferred.

19. The compound of any one of claims 1-14, wherein, The compound is selected from:

20. A compound comprising a compound of formula (I), 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. in, Compound (I) is defined as claimed in any one of claims 1-19; M is selected from at least one of radioactive nuclides or non-radioactive elements (preferably radioactive nuclides); Preferably, the 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, or 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; Preferably, the radionuclide is selected from... 68 Ga、 18 F, 64 Cu、 161 Tb or 177 Lu; Preferably, the radionuclide 18 F is through 18 FAl forms by complexation with a compound of formula (I); Preferably, M is selected from... 68 Ga、 18 F, 161 Tb or 177 Lu; Preferred 68 Ga or 177 Lu.

21. A compound of formula (V), or an isotopic variant, hydrate, ester or solvate thereof, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, Ab, L1 and L2 are as defined in any one of claims 1-19; Z' is a coordinating group formed by the complexation of a chelating group Z derived from a chelating agent and M, wherein Z is defined as in any one of claims 1-19; M is selected from at least one of radioactive nuclides or non-radioactive elements (preferably radioactive nuclides); Preferably, the 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, or 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; Preferably, the radionuclide is selected from... 68 Ga、 18 F, 64 Cu、 161 Tb or 177 Lu; Preferably, the radionuclide 18 F is through 18 Formed by FAl complexation; Preferably, M is selected from... 68 Ga、 18 F, 161 Tb or 177 Lu; Preferred 68 Ga or 177 Lu.

22. A pharmaceutical composition comprising the compound of claims 1-21, 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.

23. Use of the compound of claims 1-21, or an isotopic variant, hydrate, ester or solvate, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, in the preparation of a medicament for inhibiting the expression of carbonic anhydrase IX.

24. The compound of claims 1-21, or an isotopic variant, hydrate, ester or solvate, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, for inhibiting the expression of carbonic anhydrase IX.

25. A method for inhibiting the expression of carbonic anhydrase IX, the method comprising administering to a subject the compound of claims 1-21, 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 22.

26. Use of the compound of claims 1-21, or an isotopic variant, hydrate, ester or solvate, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, in the preparation of reagents and / or medicaments for the diagnosis and / or treatment of one or more tumors, cancers or cells expressing carbonic anhydrase IX.

27. The compound of claims 1-21, or an isotopic variant, hydrate, ester or solvate, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, for the diagnosis and / or treatment of one or more tumors, cancers or cells expressing carbonic anhydrase IX.

28. A method for diagnosing and / or treating one or more tumors, cancers, or cells expressing carbonic anhydrase IX, the method comprising administering to a subject the compound of claims 1-21, 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 22.

29. The use of claim 26, the compound or pharmaceutical composition of claim 27, or the method of claim 28, wherein, 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. Preferably, the treatment is selected from radiotherapy and / or fluorescent surgical navigation to assist in surgery.

30. The use, compound, pharmaceutical composition, or method of claim 29, wherein, The diseases associated with carbonic anhydrase IX expression were selected from tumors; Preferably, the diseases associated with carbonic anhydrase IX expression are selected from renal cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, melanoma, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head and neck cancer, astrocytoma, and oral cancer.

31. A method for imaging tissues expressing carbonic anhydrase IX, wherein, This includes administering the compound of claims 1-21, or isotopic variants, hydrates, esters or solvates, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 22, 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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