Nitrogen-containing heterocyclic compounds and their preparation and use

Abstract

The present invention discloses nitrogen-containing heterocyclic compounds and their preparation and use. Specifically, the present invention discloses a compound represented by Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. This class of compounds can be used for the diagnosis and treatment of FAP-associated tumors, and is expected to have a wide range of applications due to its high tumor uptake and long retention time. JPEG2026508513000187.jpg3474

Description

[Technical Field]

[0001] The present invention relates to nitrogen-containing heterocyclic compounds and their preparation and use. [Background technology]

[0002] Chemotherapy remains widely used to treat cancer patients and other diseases. However, conventional anticancer chemotherapy drugs act on the basic mechanisms of cell survival and therefore cannot effectively distinguish between healthy and malignant cells. Furthermore, these drugs do not effectively reach and accumulate at disease sites after systemic administration. The nonspecific mechanism of action and low tumor localization efficiency are the causes of side effects and reduced therapeutic efficacy.

[0003] In recent years, the development of targeted drugs has attracted attention in new drug development to more effectively treat diseases. These drugs can selectively localize to disease sites and exert their effects after systemic administration. These drugs are composed of a typical therapeutic chemical (e.g., a cytotoxic drug or radionuclide) conjugated to a ligand with target cell specificity. Disease-specific monoclonal antibodies, peptides, and small molecule ligands are the ligands of choice for the development of targeted drug products. In targeted therapy applications, small molecule ligands have the advantages of more rapid and effective tumor penetration, lower immunogenicity, and lower manufacturing costs compared to macromolecules (e.g., peptides and antibodies).

[0004] Tumors are complex structures composed of tumor cells and their surrounding stromal cells and noncellular components. Tumor development and progression are dynamic processes in which tumor cells and their microenvironment (TME) mutually promote and co-evolve. The tumor microenvironment is composed of diverse heterogeneous cell types, including immune cells, endothelial cells, fibroblasts (cancer-associated fibroblasts, or CAFs), and their extracellular products. Among these, cancer-associated fibroblasts (CAFs) are the most dominant stromal cells in the tumor microenvironment, accounting for approximately 50% of the total number of tumor tissue cells. CAFs play important roles in tumor growth, metastasis, drug resistance, and therapy resistance, making them a focus of recent tumor diagnostic and therapeutic research.

[0005] A distinctive feature of CAFs is the high expression of seprase or fibroblast activation protein (FAP). Both are identical cell surface membrane serine proteases with dipeptidyl peptidase (DPP) and collagenase activities, capable of degrading dipeptides and type I collagen. FAP shares a similar domain and dipeptidyl peptidase activity with dipeptidyl peptidase IV (DPPIV), both of which belong to the serine protease family. However, FAP possesses specific endopeptidase activity, capable of cleaving gelatin, denatured type I collagen, and α2-antifibrin, whereas DPPIV lacks this function, distinguishing the two. FAP is selectively expressed on the surface of stromal fibroblasts in over 90% of epithelial malignancies, including breast, ovarian, lung, colorectal, gastric, pancreatic, and cutaneous melanoma. FAP is not typically expressed in benign and precancerous epithelial tumors, such as rectal adenomas, breast phyllodes tumors, and fibroadenomas. Furthermore, FAP is not generally expressed in normal human tissues; it is present only in the cervix and endometrium, where it is transiently expressed during embryonic development. Numerous studies have shown that high FAP expression in CAFs of epithelial tumors is associated with poor patient prognosis, and its activity is involved in cancer progression and cancer cell metastasis / spread.

[0006] Nuclear drugs are pharmaceutical preparations that combine radioisotopes with molecular reagents that target specific organs or tissues, and are radiopharmaceuticals used for diagnostic imaging and clinical treatment. Depending on their use, they are classified into diagnostic radiopharmaceuticals and therapeutic radiopharmaceuticals.

[0007] Diagnostic radiopharmaceuticals are divided into two types: organ imaging agents and functional measurement agents. When combined with SPECT or PET, it is possible to study in vivo pharmacokinetics and metabolic processes at the molecular level, achieving rapid, non-invasive, and real-time imaging of physiological and pathological processes, which is a means of enabling truly early diagnosis and timely treatment.

[0008] Therapeutic radiopharmaceuticals are radioactive drugs administered orally or by injection to patients that are highly selectively concentrated in diseased tissues, and utilize the local ionizing radiobiological effect of the radiation emitted by the radioisotope to suppress or destroy the diseased tissues, thereby achieving a therapeutic effect.

[0009] In recent years, the application of FAP as a target in oncology has attracted widespread attention. Compared with FDG imaging, FAP-targeted imaging has demonstrated low background and high tumor lesion detection rates in organs such as the brain and liver. However, to date, this type of probe has not demonstrated particularly effective therapeutic effects, primarily due to the generally low biological activity of these compounds and their low uptake at the lesion site. Furthermore, from the perspective of ligand selection, the one-to-one relationship between the monomer and the receptor results in low receptor binding stability and low uptake at the lesion site, significantly limiting the therapeutic efficacy. Therefore, utilizing FAP as a target in nuclear medicine imaging offers a promising strategy for the early diagnosis of malignant tumors, the assessment of tumor staging, and the diagnosis and therapeutic efficacy of tumor treatment. Summary of the Invention

[0010] This application claims priority to Chinese Patent Application No. 2023102011423, filed on March 3, 2023, and Chinese Patent Application No. 2023114214594, filed on October 27, 2023. This application cites the full text of the aforementioned Chinese patent applications.

[0011] The present invention aims to solve the existing problems in the art, such as low affinity of compounds to FAP, too short residence time at the target site, low uptake at the lesion site, etc. The present invention provides a nitrogen-containing heterocyclic compound and its preparation method and use, which has advantages such as simple preparation, good stability, high uptake in tumors, and long residence time, and is suitable for clinical application.

[0012] The present invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. [ka] However, R 1 and R 2 are independently hydrogen, halogen, C 1-6 Alkyl group, C 1-6 an alkoxy group or a hydroxyl group, and R 1 and R 2 At the same time, C 1-6 Alkyl group, C 1-6 rather than alkoxy or hydroxyl groups; A 1 is -CN, -B(OH)2, -CONH2, or -COOR a and; R a is hydrogen or C 1-6 is an alkyl group; W 1 is hydrogen or C 1-4 is an alkyl group; L 1 teeth [ka] and the a-terminus is attached to the carbonyl group in the left amide bond; X 1 and X 2 are independently N or CH; Y is O, S or NH; R b and R c are independently hydrogen, halogen, C 1-6 Alkyl group or C 1-6 is an alkoxy group; n1, n2, and n3 are independently 0, 1, or 2; m1, m2, and m3 are independently 0, 1, or 2; p is 1, 2, 3 or 4; R 3 is independently C1-6 is alkylene; V 1 is a chemical bond, -C(=O)-C 1-6 Alkylene NH- or -C(=O)-CH2-(OCH2CH2) s NH-, s is 1, 2, 3 or 4, and -C(=O)-C 1-6 Alkylenes NH- and -C(=O)-CH2-(OCH2CH2) s -NH- in NH- is U 1 binds to; U 1 is a group containing a radioactive metal ion or an optically imageable group.

[0013] In some embodiments, R 1 and R 2 are independently hydrogen or halogen. In some embodiments, Y is S. In some embodiments, A 1 is CN. In some embodiments, W 1 is hydrogen or C 1-4 It is an alkyl group. In some embodiments, R b and R c are independently hydrogen. In some embodiments, p is 1. In some embodiments, V 1 is a chemical bond or -C(=O)-C 1-6 It is alkylene NH-.

[0014] In some embodiments, the group containing a radioactive metal ion comprises a radioactive metal ion and a group having a function of chelating a metal ion, and the radioactive metal ion is chelated to the group having a function of chelating a metal ion.

[0015] In some embodiments, the group capable of chelating a metal ion is [ka] is.

[0016] In some embodiments, the radioactive metal ion has one or more of the following roles: (i) tracer; (ii) delivery; (iii) imaging (eg, PET imaging or SPECT imaging); (iv) therapeutic.

[0017] In some embodiments, the radioactive metal ion is 177 Lu 3+ , 68 Ga 3+ , 64 Cu 2+ , 225 Ac 3+ , 90 Y 3+ , 89 Zr 4+ , 212 Pb 2+ , 213 Bi 3+ or 227 Th 4+ For example, 177 Lu 3+ or 68 Ga 3+ is.

[0018] In some embodiments, the optically imageable group is a fluorescent group, such as cy3, cy5, or cy7.

[0019] In some embodiments, the compound of Formula I is a compound of Formula Ia. [ka]

[0020] In some embodiments, R 1 and R 2 are independently hydrogen or halogen; A 1 is CN; W 1 is hydrogen or C1-4 is an alkyl group; L 1 teeth [ka] and the a-terminus is attached to the carbonyl group in the left amide bond; X 1 and X 2 are independently N or CH; Y is S; R b and R c are independently hydrogen; n1, n2, and n3 are independently 0, 1, or 2; m1, m2, and m3 are independently 0, 1, or 2; p is 1; R 3 is C 1-6 is alkylene; V 1 is a chemical bond or -C(=O)-C 1-6 AlkyleneNH-, -C(=O)-C 1-6 -NH- in alkylene NH- is U 1 binds to; U 1 is a group containing a radioactive metal ion or an optically imageable group.

[0021] In some embodiments, R 1 and R 2 are independently hydrogen or fluorine. In some embodiments, W 1 is hydrogen or methyl.

[0022] In some embodiments, L 1 teeth [ka] where the a-terminus is attached to the carbonyl group in the amide bond on the left.

[0023] In some embodiments, R 3 is -CH2CH2-. In some embodiments, V 1 is a chemical bond or [ka] and [ka] -NH- in U 1 Combine with.

[0024] In some embodiments, U 1 teeth [ka] is.

[0025] In some embodiments, the compound of Formula I is a compound in which Compound A is chelated with the radioactive metal ion, and the structure of Compound A is any one of the following: [ka] [ka] [ka] [ka] [ka] [ka] .

[0026] In some embodiments, the compound of Formula I is selected from Compound A and Compound B. 177 Lu 3+ The compound A is a chelated compound of and, and the structure of the compound A is as shown above. In some embodiments, the compound of Formula I is selected from Compound A and Compound B. 68 Ga 3+ The structure of Compound A is as shown above.

[0027] The present invention also provides a method for preparing the compound of formula I, which comprises the step of chelating the radioactive metal ion with the compound of formula II. [ka] However, U 1a is a group having the function of chelating a metal ion.

[0028] In the compound represented by formula II, the definition of the group having the function of chelating a metal ion is as described above, and for example, [ka] is.

[0029] In the compound represented by formula II, the group having the function of chelating a metal ion did not chelate with a metal ion. The present invention provides a compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: [ka] However, U 1a , R 1, R 2 , A 1 , W 1 , L 1 ,p,R 3 and V 1 The definition is as above.

[0030] In some embodiments, the compound of Formula II is a compound of Formula IIa. [ka] In some embodiments, the compound of formula II is selected from any one of compounds A above.

[0031] The present invention provides a compound of formula III, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: [ka] However, R 4 and R 5 are independently hydrogen, halogen, C 1-6 Alkyl group, C 1-6 an alkoxy group or a hydroxyl group, and R 4 and R 5 At the same time, C 1-6 Alkyl group, C 1-6 alkoxy groups, or not hydroxyl groups; A 2 is -CN, -B(OH)2, -CONH2, or -COOR d and; R d is hydrogen or C 1-6 is an alkyl group; W 2 is hydrogen, C 1-4 Alkyl group or HO-C 1-4 alkyl-; L 2 is a phenyl group, one or more R e or a phenyl group substituted with [ka] and the b-terminus is V 2 binds to; R e and R f are independently hydrogen, halogen, C 1-6 Alkyl group, or C 1-6 is an alkoxy group; m4 and n4 are independently 0, 1 or 2; X 3 is CH or N; V 2 is a chemical bond, -C 1-6 Alkylene -NH- or -C(=O)-C 1-6 alkylene-C(=O)-5 to 10-membered heterocyclic alkyl group, 1-6 -NH- in alkylene-NH- is U 2 bonded to -C(=O)-C 1-6 The terminal of the 5- to 10-membered heterocyclic alkyl group in the alkylene-C(=O)-5- to 10-membered heterocyclic alkyl group is U. 2 binds to; U 2 is a group containing a radioactive metal ion or an optically imageable group.

[0032] In some embodiments, R 4 and R 5 are independently hydrogen. In some embodiments, A 2 is -B(OH)2. In some embodiments, R e and R f are independently hydrogen or halogen. In some embodiments, X 3 is CH. In some embodiments, m4 and n4 are independently 1.

[0033] In some embodiments, L 2 is a phenyl group, or one or more R eIf the phenyl group is substituted with V 2 Ha-C 1-6 alkylene-NH-, -C 1-6 -NH- in alkylene-NH- is U 2 Combine with.

[0034] In some embodiments, L 2 but [ka] If V 2 is a chemical bond or -C(=O)-C 1-6 alkylene-C(=O)-5 to 10-membered heterocyclic alkyl group, -C(=O)-C 1-6 The terminal of the 5- to 10-membered heterocyclic alkyl group in the alkylene-C(=O)-5- to 10-membered heterocyclic alkyl group is U. 2 Combine with.

[0035] In some embodiments, in the compound represented by formula III, the group containing a radioactive metal ion comprises a radioactive metal ion and a group having a function of chelating a metal ion, and the radioactive metal ion is chelated to the group having a function of chelating a metal ion.

[0036] In some embodiments, in the compound of Formula III, the group capable of chelating a metal ion is [ka] For example, [ka] is.

[0037] In some embodiments, in the compound of Formula III, the radiometal ion has one or more of the following roles: (i) tracer; (ii) delivery; (iii) imaging (e.g., PET imaging or SPECT imaging); or (iv) therapeutic.

[0038] In some embodiments, in the compound of Formula III, the radioactive metal ion is 177 Lu 3+ , 68 Ga 3+ , 64 Cu 2+ , 225 Ac 3+ , 90 Y 3+ , 89 Zr 4+ , 212 Pb 2+ , 213 Bi 3+ or 227 Th 4+ For example, 177 Lu 3+ or 68 Ga 3+ is.

[0039] In some embodiments, in the compound of Formula III, the optically imageable group is a fluorescent group, such as cy3, cy5, or cy7.

[0040] In some embodiments, the compound of Formula III is a compound of Formula IIIa: [ka] .

[0041] In some embodiments, R 4 and R 5 are independently hydrogen; A 2 is -B(OH)2; W 2 is hydrogen, C1-4 Alkyl group or HO-C 1-4 alkyl-; L 2 is a phenyl group, one or more R e or a phenyl group substituted with [ka] and the b-terminus is V 2 binds to; R e and R f are independently hydrogen or halogen; X 3 is CH; m4 and n4 are independently 1; V 2 is a chemical bond, -C 1-6 Alkylene -NH- or -C(=O)-C 1-6 alkylene-C(=O)-5 to 10-membered heterocyclic alkyl group, 1-6 -NH- in alkylene-NH- is U 2 bonded to -C(=O)-C 1-6 The terminal of the 5- to 10-membered heterocyclic alkyl group in the alkylene-C(=O)-5- to 10-membered heterocyclic alkyl group is U. 2 binds to; U 2 is a group containing a radioactive metal ion or an optically imageable group.

[0042] In some embodiments, W 2 is a methyl group, [ka] or [ka] is.

[0043] In some embodiments, L 2 teeth [ka] and the b-terminus is V 2 Combine with.

[0044] In some embodiments, V 2 is a chemical bond, -CH2-NH-, or [ka] and -NH- in -CH2-NH- is U 2 binds to [ka] The piperazine end in 2 Combine with.

[0045] In some embodiments, U 2 teeth [ka] is.

[0046] In some embodiments, the compound represented by Formula III is a compound in which Compound B is chelated with the radioactive metal ion, and Compound B has any one of the following structures: [ka] [ka]

[0047] In some embodiments, the compound of Formula III is 177 Lu 3+ The structure of Compound B is as described above. In some embodiments, the compound of Formula III is 68 Ga 3+ and the structure of Compound B is as shown above.

[0048] The present invention provides a method for preparing the compound of formula III, which comprises the step of chelating the radioactive metal ion with the compound of formula IV, [ka] However, U 2a is a group having the function of chelating a metal ion. In some embodiments, in the compound of formula IV, the metal ion-chelating group is [ka] For example, [ka] is.

[0049] In the compound represented by formula IV, the group having the function of chelating a metal ion did not chelate with a metal ion. The present invention provides a compound of formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: [ka] However, R 4 , R 5 , A 2 , W 2 , L 2 , V 2 and U 2a The definition is as described above. In some embodiments, the compound of formula IV is a compound of formula IVa: [ka] .

[0050] In some embodiments, the compound of formula IV is selected from any one of compounds B above. The present invention provides a compound of formula V, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: [ka] However, R 6 , R 7 , R 8 and R 9 are independently hydrogen, halogen, C 1-6 Alkyl group, C 1-6 an alkoxy group or a hydroxyl group, and R 6 and R 7 At the same time, C 1-6 Alkyl group, C 1-6 R is not an alkoxy or hydroxyl group 8 and R 9 At the same time, C 1-6 Alkyl group, C 1-6 rather than alkoxy or hydroxyl groups; A 3 and A 4 are independently -CN, -B(OH)2, -CONH2 or -COOR g and; R g is hydrogen or C 1-6 is an alkyl group; W 3 and W 4 are independently hydrogen or C 1-4 is an alkyl group; L 3 and L 8 are independently a phenyl group, one or more R h a phenyl group substituted with [ka] , [ka] ,or [ka] where the C-terminus is attached to a carbonyl group in an amide bond; R h , R i and R j are independently hydrogen, halogen, C 1-6 Alkyl group or C 1-6 is an alkoxy group; X 4 and X 5 are independently CH or N; m5, m6, n5 and n6 are independently 0, 1 or 2; L 4 and L 7 are independently chemical bonds or C 1-6 is an alkylene group; L 5 and L 6 is independently [ka] where the d-terminus is V 3 is bonded to; V 3 teeth [ka] where the e end is L 5 or L 6 binds to the f end of L 5 or L 6 binds to the g-terminus of U 3 is bound to; U 3 is a group containing a radioactive metal ion or an optically imageable group.

[0051] In some embodiments, R 6 , R 7 , R 8 and R 9 are independently hydrogen or halogen. In some embodiments, A 3 and A 4 are independently -CN or -B(OH)2.

[0052] In some embodiments, R i and R j are independently hydrogen. In some embodiments, X 4 and X 5 are independently CH. In some embodiments, m5, m6, n5 and n6 are independently 1. In some embodiments, L 3 and L 8 are independently phenylene, L 4 and L 7 is independently C 1-6 It is alkylene.

[0053] In some embodiments, L 3 and L 8 became independent [ka] If L 4 and L 7 are independently chemical bonds.

[0054] (7) When L2 is a phenyl group, V2 is a chemical bond or a -C(=O)-C1-6 alkylene-C(=O)-5-10 membered heterocyclic alkyl group, and the terminal of the 5-10 membered heterocyclic alkyl group in the -C(=O)-C1-6 alkylene-C(=O)-5-10 membered heterocyclic alkyl group is bonded to U2;

[0055] In some embodiments, in the compound of formula V, the metal ion-chelating group is [ka] For example, [ka] is.

[0056] In some embodiments, in the compound of Formula V, the radioactive metal ion has one or more of the following roles: (i) tracer; (ii) delivery; (iii) imaging (e.g., PET imaging or SPECT imaging); (iv) therapeutic. In some embodiments, in the compound of formula V, the radioactive metal ion is 177 Lu 3+ , 68 Ga 3+ , 64 Cu 2+ , 225 Ac 3+ , 90 Y 3+ , 89 Zr 4+ , 212 Pb 2+ , 213 Bi 3+ or 227 Th 4+ For example, 177 Lu 3+ or 68 Ga 3+ is. In some embodiments, in the compound of Formula V, the optically imageable group is a fluorescent group, such as cy3, cy5, or cy7.

[0057] In some embodiments, the compound of formula V is a compound of formula Va: [ka] . In some embodiments, R 6 , R 7 , R 8 and R 9 are independently hydrogen or halogen; A 3 and A 4 are independently -CN or -B(OH)2; W 3 and W 4 are independently hydrogen or C 1-4 is an alkyl group; L 3 and L 8 are independently a phenyl group, [ka] wherein the C-terminus is attached to a carbonyl group in an amide bond; R i and R j are independently hydrogen; X 4 and X 5 are independently CH; m5, m6, n5 and n6 are independently 1; L 4 and L 7 are independently chemical bonds or C 1-6 is an alkylene group; L 5 and L 6 is independently [ka] where the d-terminus is V 3 is bound to; V 3 teeth, [ka] where the e-terminus is L 5 or L 6binds to L 5 or L 6 The g-terminus binds to U 3 binds to; U 3 is a group containing a radioactive metal ion or an optically imageable group. In some embodiments, R 6 , R 7 , R 8 and R 9 are independently hydrogen or fluorine.

[0058] In some embodiments, W 3 and W 4 are independently hydrogen or methyl. In some embodiments, L 3 and L 8 is independently [ka] where the C-terminus is attached to the carbonyl group in the amide bond.

[0059] In some embodiments, -L 3 -L 4 -L 5 -teeth, [ka] where the C-terminus is attached to the carbonyl group in the amide bond.

[0060] In some embodiments, -L 6 -L 7 -L 8 -teeth, [ka] where the C-terminus is attached to the carbonyl group in the amide bond.

[0061] In some embodiments, U3 teeth, [ka] is.

[0062] In some embodiments, the compound represented by formula V is a compound in which compound C is chelated with the radioactive metal ion, and compound C has any one of the following structures: [ka] [ka] [ka] .

[0063] In some embodiments, the compound of formula V is 177 Lu 3+ and the structure of Compound C is as shown above. In some embodiments, the compound of formula V is 68 Ga 3+ and the structure of Compound C is as shown above.

[0064] The present invention provides a method for preparing the compound of formula V, which comprises the step of chelating the radioactive metal ion with a compound of formula VI, [ka] However, U 3a is a group having the function of chelating a metal ion.

[0065] In some embodiments, in the compound of Formula VI, the group capable of chelating a metal ion is [ka] For example, [ka] is.

[0066] In the compound represented by formula VI, the group having the function of chelating a metal ion did not chelate with a metal ion. The present invention provides a compound of formula VI, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: [ka] However, R 6 , R 7 , R 8 , R 9 , A 3 , W 3 , W 4 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , V 3 and U 3a The definition is as above.

[0067] In some embodiments, the compound of formula VI, the compound of formula VI is the compound of formula VIa. [ka] . In some embodiments, the compound of formula VI is selected from any one of compounds C above.

[0068] The present invention provides a compound of formula VII, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: [ka] However, L 9 teeth, [ka] and; R 1 , R 2 , A 1 , W 1 , X 1 , X 2 , Y, R b , R c , m1, m2, m3, n1, n2 and n3 are defined as above.

[0069] In some embodiments, the compound of Formula VII is a compound of Formula VIIa. [ka]

[0070] In some embodiments, L 9 teeth, [ka] is.

[0071] In some embodiments, the compound of Formula VII is selected from any one of the following compounds: [ka]

[0072] The present invention further provides a pharmaceutical composition comprising a substance X and a pharmaceutical auxiliary, wherein the substance X is a substance Y, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and the substance Y is a compound represented by formula I, formula III, or formula V.

[0073] In some embodiments, the pharmaceutical composition is a pharmaceutical composition for treating or diagnosing a tumor.

[0074] In some embodiments, the pharmaceutical composition is a pharmaceutical composition for imaging tumors. In some embodiments, the tumor is a FAP-associated tumor, such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, or cutaneous melanoma. In some embodiments, the tumor is a FAP-positive solid tumor, such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, or cutaneous melanoma.

[0075] In some embodiments, the substance X is a therapeutically effective amount of substance X. The present invention also provides use of a substance X in the manufacture of a medicament, wherein said substance X is a substance Y, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and said substance Y is a compound represented by formula I, formula III, or formula V; The medicament is a medicament for treating or diagnosing a tumor, or the medicament is a medicament for imaging a tumor.

[0076] In some embodiments, the medicament is a medicament for treating tumors and the radioactive metal ion is a beta-emitting radioactive metal ion. In some embodiments, when the medicament is a medicament for treating a tumor, the radioactive metal ion is 177 Lu 3+ is.

[0077] In some embodiments, when the pharmaceutical is a pharmaceutical for tumor diagnosis, the radioactive metal ion is 68 Ga 3+is. In some embodiments, the tumor is a FAP-associated tumor, such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, or cutaneous melanoma. In some embodiments, the tumor is a FAP-positive solid tumor, such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, or cutaneous melanoma.

[0078] Definition and explanation Unless otherwise specified, the following terms and phrases used herein shall have the following meanings: If a particular term or phrase is not specifically defined, it should not be considered indefinite or unclear, but should be understood in its ordinary sense. When a trade name is mentioned herein, it is intended to refer to the corresponding product or its active ingredient.

[0079] In the present invention, the term "substituted" or "substituent" means that a hydrogen atom in a group is replaced with a specified group. If the substitution position is not specified, the substitution can be performed at any position, but is only permitted if a stable or chemically feasible compound is formed. Illustrated in the following example: one or more R 3g The 5- to 12-membered heteroaromatic ring substituted with R 3g means that it is substituted with multiple R 3g If there is, then each R 3g are the same or different.

[0080] When any variable occurs more than one time in any composition or structure of a compound, its definition on each occurrence is independent. Thus, for example, a group may be defined as one or more R e In each situation, R is replaced by e are independent alternatives. Further, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0081] When the bonding direction of the linking group enumerated in the present invention is not specified, the bonding direction is arbitrary, and includes bonding from left to right and bonding from right to left. As exemplified below, when the linking group L in -ALB is -CD-, if the bonding direction of L is not specified, -ALB includes -ACDB and -ADCB.

[0082] When any variable is selected from a single bond, it indicates that the two groups it connects are directly bonded, for example, if L in ALZ represents a single bond, the structure is actually AZ.

[0083] In the present invention, the term "alkyl group" refers to a saturated, linear or branched monovalent hydrocarbon group. 1-6 The alkyl group refers to an alkyl group having 1 to 6 carbon atoms, specifically a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.

[0084] In the present invention, the term "alkylene group" refers to a saturated, linear or branched, divalent hydrocarbon group. A C1-6 alkylene group refers to an alkylene group having 1 to 6 carbon atoms, specifically a methylene group, an ethylene group (e.g., -CH2CH2-, -CH(CH3)-), a propylene group (e.g., -CH2CH2CH2-, -C(CH3)2-, -CH2CH(CH3)-), or a butylene group (e.g., -CH2CH2CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)CH2-).

[0085] In the present invention, halogen refers to F, Cl, Br or I. The term "alkoxy group" refers to the group R X -O-, where R X is an alkyl group as defined above. The term "heterocyclic alkyl group" refers to a saturated monocyclic ring structure having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). Heterocyclic alkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuryl, morpholinyl, piperidinyl, piperazinyl, and the like.

[0086] The "-" at the end of a group indicates that the group is bonded to another fragment within the molecule through this site. in structural fragments [ka] indicates that this structural fragment is connected to other fragments in the molecule through that position. For example, [ka] are carbonyl and amino groups, respectively. [ka] This refers to the fact that the fragment is linked to other fragments in the molecule via a

[0087] The term "plurality" refers to two, three, four or five. The term "solvate of a pharmaceutically acceptable salt" refers to a substance formed when a compound is combined with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base, a solvent (such as, but not limited to, water, methanol, ethanol, etc.), where the pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent may be stoichiometric or non-stoichiometric. Solvates of pharmaceutically acceptable salts include, but are not limited to, hydrochloride monohydrates, etc.

[0088] The term "therapeutically effective amount" refers to a sufficient amount of a compound administered to a patient to effectively treat the disease. The therapeutically effective amount varies depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art according to the situation. The term "pharmaceutical auxiliary material" refers to excipients and additives used in the manufacture and formulation of pharmaceuticals, and includes all substances contained in the formulation other than the active ingredient.

[0089] The term "treatment" refers to any one of the following situations: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that causes a disease; or (3) slowing the progression of one or more biological manifestations of a disease. The term "prevention" refers to reducing the risk of developing a disease.

[0090] The term "patient" refers to any animal that is receiving or about to receive treatment, preferably a mammal, and most preferably a human, including, but not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0091] Based on common knowledge in the art, each of the preferred embodiments of the present invention can be obtained by arbitrarily combining the above preferred conditions. All reagents and raw materials used in the present invention are commercially available. The positive effects of the present invention are as follows: the present invention provides nitrogen-containing heterocyclic compounds with high affinity for FAP, which can be used in the diagnosis and treatment of FAP-related tumors (e.g., solid tumors positive for FAP expression). Due to their high uptake and long retention time in tumors, they are expected to have a wide range of applications. [Brief explanation of the drawings]

[0092] [Figure 1] Figure 1 shows the oil-water partition coefficients (CLogP) of the 177Lu-JHH11 and 177Lu-JHDB4 compounds. [Figure 2]FIG. 2 shows the cellular competitive binding results of compounds JHH8, JHDB8 and JHH9 with the reference compound. [Figure 3] Figure 3 shows the cellular competitive binding results of compounds JHH5, JHH4, JHH10, JHH8, H4b, H5b, and H8b with the reference compound. [Figure 4] Figure 4 shows the tissue distribution results of compounds 177Lu-JHH3, 177Lu-JHH8, 177Lu-JHH9, 177Lu-JHDB7, 177Lu-JHDB8 and the reference compound in tumor-bearing mice 24 hours after injection. [Figure 5] FIG. 5 shows images of 68Ga-JHH7 compound in tumor-bearing mice. [Figure 6] FIG. 6 shows images of 68Ga-JHH11 compound in tumor-bearing mice. [Figure 7] FIG. 7 shows the tumor growth inhibitory effect of 177Lu-labeled compounds in a tumor-bearing mouse model. [Figure 8] FIG. 8 shows the effect of 177Lu-labeled compounds on body weight in a tumor-bearing mouse model. DETAILED DESCRIPTION OF THE INVENTION

[0093] The present invention will be further described through the following examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which specific conditions are not described are selected according to conventional methods and conditions or product instructions.

[0094] In the following examples, HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (CAS: 148893-10-1); DIPEA represents N,N-diisopropylethylamine (CAS: 7087-68-5); HOSu represents N-hydroxysuccinimide (CAS: 6066-82-6); and DOTA-NHS represents 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 1-(2,5-dioxo-1-pyrrolidinyl) ester (CAS: 170908-81-3).

[0095] The LCMS detection method in the embodiment of the present invention is Analysis Method 1 or Analysis Method 2 below. Analysis method 1: Column: SUNFIRE C18 (4.6 x 50 mm, 3.5 μm) Mobile phase: H2O (0.01% TFA) (A) / acetonitrile (0.01% TFA) (B) Elution program: Gradient from 5% to 95% B at a rate of 2.0 mL / min in 1.3 min Column temperature: 50℃ Detection: UV (214, 4 nm) and MS (ESI, positive mode, 110-1000 amu).

[0096] Analysis method 2: Column: Shim-pack VP-ODS (4.6 × 150 mm, 5 μm) Mobile phase: HO (0.01% TFA) (A) / acetonitrile (0.01% TFA) (B) Elution program: gradient from 10% to 40% B over 20 min at a flow rate of 1.0 mL / min, followed by a gradient from 40% to 70% B from 20 to 24 min, a gradient from 70% to 10% B from 24 to 24.1 min, and a hold at 10% B from 24.1 to 30 min. Column temperature: 30℃ Detection: UV (214, 4 nm) and MS (ESI, positive mode, 110-1000 amu).

[0097] Synthesis of DOTA-GA-NH2: [ka]

[0098] A 100 mL round-bottom flask equipped with a stir bar was charged with DOTA-GA(tBu)41 (1.5 g, 2.1 mmol), HBTU (1.03 g, 2.73 mmol), anhydrous MeCN (30 mL), and finally pyridine (10 mL). The reaction mixture was stirred at room temperature for 30 min, then aspirated into a syringe and transferred via a syringe pump at a rate of 0.5 mL / min over 1 h to a 100 mL round-bottom flask containing ethylenediamine (10 mL) and anhydrous MeCN (20 mL), stirred at room temperature. The reaction mixture was added to water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product tri-tert-butyl 2,2',2''-(10-(5-((2-aminoethyl)amino)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate 2 as a yellow oil (1.6 g). LCMS: m / z 743.5 [M+H] + , t R =1.014 minutes (Analysis method 1)

[0099] A reaction mixture of tri-tert-butyl 2,2',2''-(10-(5-((2-aminoethyl)amino)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate 2 (500 mg, 0.67 mmol) in TFA (10 mL) was stirred at room temperature overnight and then concentrated. The residue was purified by reverse-phase HPLC (silica gel, 40 g, Biotage, 0-5% MeCN in water) to give 2,2',2''-(10-(4-((2-aminoethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)DOTA-GA-NH2 (300 mg, 86.4% yield). LCMS: m / z 519.3 [M+H] + , t R =0.303 minutes (Analysis method 1)

[0100] Example 1: Synthesis of compounds JHMe1-JHMe10 Synthesis of compound JHMe1 (standard synthetic route 1) and use of analytical method 1: [ka]

[0101] Synthesis of M1a: A solution of 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylic acid (278 mg, 1.0 mmol), (S)-1-(D-alanyl)-4,4-difluoropyrrolidine-2-carbonitrile, 4-methylbenzenesulfonate (412 mg, 1.1 mmol), HATU (494 mg, 1.3 mmol), DIPEA (387 mg, 3.0 mmol), DMF (4 mL), and DCM (16 mL) was stirred at room temperature for 1 h. After concentration, the mixture was poured into water (100 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with water (30 mL × 2), brine (30 mL × 1), dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash chromatography (MeOH / DCM, 0% to 3%, 25 g, Biotage) to give 3-((R)-1-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (330 mg, 71.3%) as a pale yellow solid. LCMS: m / z 464.3 [M+H] + ;t R =1.01 minutes.

[0102] Synthesis of M1b: To a solution of tert-butyl 3-(((R)-1-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (330 mg, 0.71 mmol) in DCM (5 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 1 hour and then concentrated to give the crude product N-((R)-1-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide as a yellow oil. LCMS: m / z 364.2 [M+H] + ;t R =0.15 minutes.

[0103] Synthesis of M1c: A solution of N-(R)-1-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide (crude, 0.71 mmol), succinic anhydride (214 mg, 2.14 mmol), DMAP (43 mg, 0.36 mmol), and THF (10 mL) was stirred at 60° C. for 6 hours. The mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (gradient: MeOH / DCM, 0% to 5%, 25 g, Biotage) to afford 4-(3-(R)-1-(S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-4-oxobutyric acid (190 mg, 57.6%) as a yellow solid. LCMS: m / z 464.3 [M+H] + ;t R =0.86 minutes

[0104] Synthesis of M1d: A solution of 4-(3-((R)-1-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-4-oxobutanoic acid (190 mg, 0.41 mmol), HOSu (283 mg, 2.46 mmol), EDCI (236 mg, 1.23 mmol), and MeCN (5 mL) was stirred at room temperature for 6 hours. After concentration, the mixture was purified by silica gel flash column chromatography (gradient: MeOH / DCM, 0-2%, 25 g, Biotage) to give 2,5-dioxopyrrolidin-1-yl 4-(3-(((R)-1-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-4-oxobutyric acid ester (60 mg, 26.1%) as a white solid. LCMS: m / z 561.2 [M+H] + ;t R =0.88 minutes.

[0105] Synthesis of JHM1: A solution of DOTA-GA-NH (56 mg, 0.11 mmol) in PBS (1 mL) was neutralized with NaHCO, followed by the dropwise addition of a solution of 2,5-dioxopyrrolidin-1-yl 4-(3-(((R)-1-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-4-oxobutanoate (60 mg, 0.11 mmol) in MeCN (2 mL). The resulting reaction solution was stirred at room temperature for 1 hour. The mixture was purified by Prep-HPLC to give 2,2',2''-(10-(1-carboxy-4-((2-(4-(3-((R)-1-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-4-oxobutanamido)ethyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (18.2 mg, 17.6%) as a white solid. LCMS: m / z 965.3 [M+H] + ;t R =0.87 minutes.

[0106] Compounds JHM2 to JHM10 were synthesized according to analytical method 1 of conventional synthetic route 1. [ka]

[0107] JHM2: white solid (13.6 mg, 4.4%). LCMS: m / z 482.8 [M / 2+H] + ;t R= 0.94 minutes. [ka]

[0108] JHM3: White solid (22.2mg13.0%). LCMS: m / z 485.4 [M / 2+H] + ;t R= 0.90 minutes.

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[0109] JHM4: White solid (44.4 mg, 15.9%). LCMS: m / z 482.4 [M / 2+H] + ; t R= 0.90 points.

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[0110] JHM5: White solid (6.0 mg, 3.5%). LCMS: m / z 482.3 [M / 2+H] + ; t R= 0.94 points.

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[0111] JHM6: White solid (20.4 mg 13.2%). LCMS: m / z 482.4 [M / 2+H] + ; t R= 0.95 points.

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[0112] JHM7: White solid (13.6 mg 7.2%). LCMS: m / z 950.3 [M+H] + ; t R= 0.93 points.

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[0113] JHM8: White solid (17.5 mg 5.0%). LCMS: m / z 482.1 [M / 2+H] + ; t R= 1.24 points.

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[0114] JHM9: White solid (53.8mg27.7%). LCMS: m / z 991.0 [M+H] + ;t R= 0.84 minutes. [ka]

[0115] JHM10: White solid (8.6 mg 1.9%). LCMS: m / z 963.5 [M+H] + ;t R= 0.89 minutes.

[0116] Example 2: Synthesis of compounds JHH1-JHH14 Synthesis of compound JHH1 (Usual synthetic route 2) and use of analytical method 1: [ka]

[0117] Synthesis of H1a: To a solution of 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylic acid (385 mg, 1.38 mmol), (S)-4,4-difluoro-1-glycylpyrrolidine-2-carbonitrile benzenesulfonate (500 mg, 1.38 mmol), and HATU (632 mg, 1.66 mmol) in DCM (10 mL) and DMF (2 mL) was added DIEPA (537 mg, 4.15 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate (2 x 100 mL) and water (50 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by high-performance chromatography (silica gel, 10 g, Biotage, 0-25% methanol / dichloromethane solution) to give tert-butyl (S)-3-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate as a yellow oil (500 mg, 80% yield). LCMS: m / z 450.3 [M+H] + , t R =1.021 minutes.

[0118] Synthesis of H1b: To a solution of tert-butyl (S)-3-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (500 mg, 1.11 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 1 hour. The cooled mixture was then concentrated to give the crude product (S)—N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide as a yellow oil. LCMS: m / z 350.2 [M+H] + , t R =0.342 minutes.

[0119] Synthesis of H1c: A solution of (S)—N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxamide (500 mg, 1.11 mmol), succinic anhydride (666 mg, 6.66 mmol), and DMAP (67.8 mg, 0.55 mmol) in THF (10 mL) was stirred at 60° C. for 6 hours. The mixture was then purified by high-performance chromatography (silica gel, 10 g, Biotage, 0-25% methanol in dichloromethane) to give (S)-4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-4-oxobutyric acid as a yellow oil (300 mg, 60.2% yield). LCMS: m / z 450.2 [M+H] + , t R =0.803 minutes.

[0120] Synthesis of H1d: 2(S)-4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)aminocarbonyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-4-oxobutyric acid (250 mg, 0.55 mmol), EDCI (135 mg, 0.72 mmol), and HOSu (75 mg, 0.66 mmol) were dissolved in MeCN (5 mL) and stirred overnight at room temperature. The resulting solution was poured into water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude product 2,5-dioxopyrrolidin-1-yl (S)-4-(3-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-4-oxobutanoate (108 mg). LCMS: m / z 547.2 [M+H] + , t R =0.869 minutes.

[0121] Synthesis of JHH1: To a solution of 2,5-dioxopyrrolidin-1-yl (S)-4-(3-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-4-oxobutyric acid ester (100 mg, 0.18 mmol) in MeCN (2 mL) was added 2 mL of a PBS solution containing DOTA-GA-NH2 (139 mg, 0.27 mmol). The reaction mixture was stirred at room temperature for 30 min. The residue was purified by preparative high performance liquid chromatography to give 2,2',2''-(10-(1-carboxy-4-((2-(4-(3-((2-(S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-4-oxobutanamido)ethyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (25 mg, 14.6% yield). LCMS: m / z 950.3 [M+H] + , t R =0.739 minutes.

[0122] Compounds JHH2 to JHH10 were synthesized according to general synthetic route 2 and analytical method 1, and analytical method 2 was used for H2b, H3b, H4b, H5b, H6b, H7b, H8b, and H9b. [ka]

[0123] H2b: White solid (20.1mg, 34.1%). LCMS: m / z 350.4[M+H] + , t R= 8.501 minutes. [ka]

[0124] JHH2: White solid (42.3mg, 18.7%). LCMS: m / z 951.3[M+H] + , t R=0.899 points.

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[0125] H3b: White solid (20.4 mg, 32.7%). LCMS: m / z 354.6 [M+H] + t R= 9.270 points.

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[0126] JHH3: White solid (29 mg, 6.9%). LCMS: m / z 478.4 [M+H] + t R= 0.846 points.

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[0127] H4b: White solid (22.6 mg, 36.8%). LCMS: m / z 348.7 [M+H] + t R= 10.231 points.

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[0128] JHH4: White solid (44.4 mg, 18.7%). LCMS: m / z 475.3 [M+H] + t R= 0.841 points.

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[0129] H5b: White solid (18.62 mg, 18.02%). LCMS: m / z 348.91 [M+H] + t R= 11.54 points.

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[0130] JHH5: White solid (3 mg, 0.87%). LCMS: m / z 475.4 [M+H] + t R= 0.896 points.

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[0131] H6b: White solid (26.2 mg, 59.7%). LCMS: m / z 349.4 [M+H] + t R =9.184 points.

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[0132] JHH6: White solid (2 mg, 4.25%). LCMS: m / z 949.3 [M+H] + t R= 0.912 points.

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[0133] H7b: White solid (11.36 mg, 12.07%). LCMS: m / z 335.38 [M+H] + t R= 10.70 points.

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[0134] JHH7: White solid (59 mg, 17.1%). LCMS: m / z 935.3 [M+H] + t R= 0.888 points.

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[0135] H8b: White solid (12.09 mg, 30.04%). LCMS: m / z 371.28 [M+Na] + t R= 12.125 points.

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[0136] JHH8: White solid (10.4 mg, 2.34%). LCMS: m / z 950.3 [M+H] + t R= 0.923 points.

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[0137] H9b: White solid (8.13 mg, 20.5%). LCMS: m / z 376.76 [M+H] + t R= 11.87 points.

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[0138] JHH9: White solid (17.9 mg, 10.8%). LCMS: m / z = 489.3 [M+H] + t R= 0.957 points.

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[0139] JHH10: White solid (23.3 mg, 5.45%). LCMS: m / z = 950.3 [M+H] + t R= 0.768 points.

[0140] DOTA-NHS uses DOTAGA to replace it, and the usual synthesis route 2 and analysis method 1 are used to synthesize the following compounds JHH11~JHH14:

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[0141] JHH11: White solid (21.7 mg 14.2%). LCMS: m / z 954.0 [M+H] + ; t R= 0.78 points.

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[0142] JHH12: White solid (48.9 mg 28.1%). LCMS: m / z 948.3 [M+H] + ; t R= 0.92 points.

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[0143] JHH13: White solid (44.6 mg 28.1%). LCMS: m / z 948.1 [M+H] + ; t R= 0.79 points.

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[0144] JHH14: White solid (65.5 mg 26.9%). LCMS: m / z 948.0 [M+H] + ; t R= 0.77 points.

[0145] ●Example 3 Synthesis of Compounds JHB1~JHB5 Synthesis of compound JHB1

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[0146] Synthesis of B1a: 1 g of CTC resin (Xi'an Lanxiao New Materials Co., Ltd. (Sunresin)) (0.65 mmol) was added to a peptide synthesis tube, and DCM (20 mL) was added to swell for 20 minutes. After the solvent was removed, Fmoc-D-Ser(tBu)-OH (249 mg, 1.95 mmol) was dissolved in DCM (15 mL) and added to the peptide synthesis tube. DIEA (0.3 mL) was added and the reaction was continued for 2 hours. MeOH (1.5 mL) was added and the reaction was continued for 15 minutes. After the solvent was removed, the resin was washed five times with DMF (20 mL). 20% PIP / DMF (20 mL) was added and the reaction was continued for 10 minutes. This procedure was repeated once, and the resin was then washed six times with DMF (20 mL). Fmoc-Amb-OH (720 mg, 1.95 mmol) and DOTA-tBu (1.1 g, 1.98 mmol) were sequentially coupled to the resin using PyBOP and TBTU condensation reagents, respectively. The resin was cleaved five times with 1% TFA / DCM (20 mL). The cleavage solution was concentrated to dryness, and the crude product was purified to give 270 mg of product (B1a).

[0147] Synthesis of B1b: B1a (90 mg, 0.104 mmol), boronic acid ester (29 mg, 0.115 mmol), and HATU (43.7 mg, 0.115 mmol) were dissolved in DMF (0.5 mL). DIEA (39.6 mg, 0.3 mmol) was added and the mixture was stirred for 2 h. LCMS confirmed the reaction was complete, and the product (B1b) was directly purified to give 60 mg.

[0148] Synthesis of JHB1: B1b (60 mg, 0.056 mmol) was dissolved in DCM (2 mL), and BCl3 (2 mL) was added dropwise at -78 °C. The reaction was stirred for 1 hour. After confirming the completion of the reaction by LCMS, purification (ACN:H2O = 0 to 30%, 40 min) was carried out to obtain 30 mg of the product (JHB1). HPLC: 93.73%, t R= 10.717 min (Analysis method 2), MS: [M+H-H2O] += 704.79.

[0149] Compounds JHB2 to JHB5 were synthesized according to the synthetic route of JHB1.

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[0150] JHB2: HPLC: 91.94%, t R =8.864 points (Analysis Method 2), MS: [M+H-2H2O] + =700.73

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[0151] JHB3: HPLC: 97.84%, t R = 13.828 points (Analysis Method 2), MS: [M+H-H2O] + =706.47

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[0152] JHB4: HPLC: 96.1%, LCMS: m / z 715.3 [M+H-H2O] + ; t R= 0.77 points (Analysis Method 1)

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[0153] JHB5: HPLC: 100%, LCMS: m / z 883.4 [M+H-H2O] + ; t R= 0.88 points (Analysis Method 1) ●Example 4 Synthesis of Compound JHDB1 (Usual Synthesis Route 4) and Analysis Method 1 Use:

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[0154]

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[0155] 6-(2-(2-aminoethoxy)ethyl)amino-6-oxohexane-1,5-diyl)(S)-dicarbamate (2): To a 100 mL round-bottom flask equipped with a stir bar was added N-((benzyloxy)carbonyl)-N-(tert-butoxycarbonyl)-L-lysine (2 g, 5.25 mmol), HATU (2.6 g, 6.82 mmol), anhydrous MeCN (30 mL), and finally pyridine (10 mL). The reaction mixture was stirred at room temperature for 30 min, then drawn into a syringe and transferred via a syringe pump at a rate of 0.5 mL / min over 1 h to a 100 mL round-bottom flask containing 2,2'-oxybis(ethyl-1-amine) (3.28 g, 31.5 mmol) and anhydrous MeCN (20 mL), stirred at room temperature. The reaction mixture was added to water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product benzyl tert-butyl (6-((2-(2-aminoethoxy)ethyl)amino)-6-oxohexane-1,5-diyl)(S)-dicarbamate as a yellow oil (1.7 g). LCMS: m / z 467.3 [M+H] + , t R =1.06 minutes.

[0156] 2,2,2-(10-(9-((tert-butoxycarbonyl)amino)-3,10,18-trioxa-1-phenyl-2,14-dioxa-4,11,17-triazanonadecan-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl (S)-triacetate (3): 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (1.6 g, To a solution of 6-((2-(2-aminoethoxy)ethyl)amino)-6-oxohexane-1,5-diyl (S)-dicarbamate (1.7 g, 3.6 mmol), HATU (1.65 g, 4.32 mmol) in DMF (20 mL) was added DIEA (1.4 g, 10.8 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phase was washed with brine, dried over Na2SO4, and filtered. The residue was concentrated and purified by high-performance chromatography (silica gel 10 g, Biotage, 0-25% methanol in dichloromethane) to give 2,2',2''-(10-(9-((tert-butoxycarbonyl)amino)-3,10,18-trioxa-1-phenyl-2,14-dioxa-4,11,17-triazanonadecan-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(S)-triacetate as a yellow oil. LCMS: m / z 511.5 [1 / 2M+H] + , t R =1.17 minutes.

[0157] 2,2,2-(10-(6-(4-aminobutyl)-2,2-dimethyl-4,7,15-trioxa-3,11-dioxa-5,8,14-triazahexadecan-16-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(S)-triacetate (4-1): A solution of 2,2,2,2-(10-(9-((tert-butoxycarbonyl)amino)-3,10,18-trioxa-1-phenyl-2,14-dioxa-4,11,17-triazanonadecan-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(S)-triacetate (800 mg, 0.78 mmol) in MeOH (20 mL) was added to Pd / C (400 mg) was added. The mixture was stirred at room temperature under a hydrogen gas atmosphere for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated to give 2,2',2''-(10-(6-(4-aminobutyl)-2,2-dimethyl-4,7,15-trioxa-3,11-dioxa-5,8,14-triazahexadecan-16-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(S)-triacetate as a yellow oil (600 mg, 86.4% yield). LCMS: m / z 444.5 [1 / 2M+H] + , t R =1.04 minutes.

[0158] 2,2,2-(10-((12S)-12-(tert-butoxycarbonyl)amino)-3,6,13,21-tetraoxa-1-(4-((2R)-1-oxo-1-((2R)-2-((3aS,4S,6S)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)propan-2-yl)carbamoyl)phenyl)-17-oxa-2,7,14,20-tetraazadocosane-22-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (4-2): Compound (4-1) (300 mg, 0.33 mmol), 4-oxo-4-((2R)-1-oxo-1-((2R)-2-((3aS,4S,6S)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)propan-2-yl)amino)butanoic acid (187 mg, 0.33 mmol), HATU (155 mg, 0.40 mmol) in DMF (3 mL) was added DIEA (109 mg, 0.84 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic phase was washed with brine, dried over NaSO, filtered, concentrated, and purified by high-performance chromatography (silica gel 10 g, Biotage, 0-25% MeOH / DCM) to give compound (4-2) (80 mg, 16.6% yield). LCMS: m / z 712.0 [1 / 2M+H] + , t R =1.21 minutes.

[0159] 2,2,2-(10-((12S)-12-amino-3,6,13,21-tetraoxa-1-(4-((2R)-1-oxo-1-((2R)-2-((2R)-2-((3aS,4S,6S)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)propan-2-yl)carbamoyl)phenyl)-17-oxa-2,7,14,20-tetraazadocosan-22-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (4-3): A 1M solution of compound (4-2) (80 mg, 0.056 mmol) in DCM (2 mL) was added. HCl / EA (2 mL) was added. The reaction mixture was stirred at 0° C. for 30 minutes. The mixture was then evaporated to dryness under a stream of nitrogen to give crude compound (4-3) as a yellow oil. LCMS: m / z 662.0 [1 / 2M+H] + , t R =1.14 minutes.

[0160] 2,2,2-(10-(12S)-12-(4-(4-(2-(S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)amino)amino)-4-oxobutanamide)-3,6,13,21-tetraoxa-1-(4-((2R)-1-oxo-1-((2R)-2-((3aS,4S,6S)-3a,5,5- Trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)propan-2-yl)carbamoyl)phenyl)-17-oxa-2,7,14,20-tetraazadocosane-22-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (4-4): Compound (4-3) (46 mg, 0.03 mmol), 2,5-dioxopyrrolidin-1-yl (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoic acid ester (16 mg, 0.03 mmol), and HATU (16 mg, 0.04 mmol) were added to DMF (2 mL), and DIEA (13.4 mg, 0.09 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by high-performance chromatography (silica gel 10 g, Biotage, 0-25% methanol in dichloromethane) to give compound (4-4) as a yellow oil. LCMS: m / z 882.6 [1 / 2M+H] + , t R =1.21 minutes.

[0161] 2,2,2-(10-((R)-1-((R)-1-((R)-2-boronpyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)phenyl)-12-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-8-yl)amino)-4-oxobutanamido)-3,6,13,21-tetraoxa-17-oxa-2,7,14,20-tetraazadocosan-22-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) (JHDB1): Compound 4-4 (20 mg, 0.01 mmol) was dissolved in DCM (3 mL) and BC1 (1 mL) was added at −78 °C. The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added to the resulting solution, and the pH was adjusted to >7 with sodium bicarbonate. The mixture was purified by preparative high-performance liquid chromatography to give JHDB1 (2.0 mg, 12.5% ​​yield). LCMS: m / z 722.4 [1 / 2M+H] + , t R =0.78 minutes.

[0162] Example 5 Synthesis of compound JHDB2 (Usual synthetic route 5) and use of analytical method 1: [ka]

[0163] 2,2,2,10-(12S)-3,6,13,21-tetraoxa-1-(4-(2R)-1-oxo-1-(2R)-2-(3aS,4S,6S)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)propan-2-yl)carbamoyl)phenyl)-12-(4-oxo-4-(2R)-1-((2R)-2-( (2R)-2-((3aS,4S,6S)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)propan-2-yl)amino)amino)butanamido)-17-oxa-2,7,14,20-tetraazadocosane-22-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (5-2): 2,2',2''-(10-(2-(2-(2-(2,6-diaminohexanamido)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(S)-triacetate (125 mg, 0.159 mmol)-4-((4-((2R)-1-oxo-1-((2R)-2-((3aS,4S,6 S)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)propan-2-yl)aminoamino)benzyl)butanoate (175 mg, 0.318 mmol) was added to HATU (90 mg, 0.238 mmol) in DMF (2 mL) at room temperature, and DIEA (61.6 mg, 0.477 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by high-performance chromatography (silica gel 10 g, Biotage, 0-25% methanol in dichloromethane) to give compound (5-2) as a yellow oil. LCMS: m / z 929.6 [1 / 2 M+H] + , t R =1.28 minutes.

[0164] 2,2,2-(10-((S)-12-(4-(4-((R)-1-(R)-2-boronpyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)benzyl)amino)-4-oxobutanamido)-1-(4-((R)-1-(R)-2-boronpyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)phenyl)-3,6,13,21-tetraoxa-17-oxa-2,7,14,20-tetraazadocosane-22-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) (JHDB2): Compound (5-2) (70 mg, 0.037 mmol) was dissolved in DCM (3 mL) and BCl (2 mL) was added at -78 °C. The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added to the resulting solution, and the pH was adjusted to >7 with sodium bicarbonate. The mixture was purified by high-performance liquid chromatography to give JHDB2 (13.9 mg, 12.5% ​​yield). LCMS: m / z 462.5 [1 / 3 M+H] + , t R =0.921 minutes.

[0165] Compound JHDB3 was synthesized according to the synthetic route of JHDB2, and analytical method 2 was used for LCMS measurement. [ka]

[0166] JHDB3: (11 mg, 10.5% yield). LCMS: m / z 662.5 [M-3H2O]2H + , t R= 12.59 minutes.

[0167] Example 6: Synthesis of compound JHDB4 (Usual synthesis route 6) and use of analytical method 1 [ka]

[0168] [ka]

[0169] Synthesis of 1,1,1,5-triazinane-1,3,5-triyl)tris(3-((2-aminoethyl)thio)propan-1-one) (6-1): To a solution of 1,3,5-triacryloylhexahydro-1,3,5-triazine (5 g, 20 mmol) in methanol (50 mL) was added 2-mercaptoethanol (4.62 g, 60 mmol) and n-propylamine (5 drops). The mixture was stirred for 30 min and concentrated to give 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)tris(3-((2-aminoethyl)thio)propan-1-one) (9.8 g, quantitative yield) as a yellow solid. LCMS: m / z 481.4 [M+H]+; t R =0.21 minutes.

[0170] Synthesis of 2,2',2''-(10-(2-((2-(3-(3,5-bis(3-((2-aminoethyl)thio)propionyl)-1,3,5-triazin-1-yl)-3-oxopropyl)thio)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1,4,7-triyl)triacetate (6-2): 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (573 mg, 1.0 mmol), HBTU (417 mg, 1.1 mmol), and Py (7.11 g, 90 mmol) were dissolved in MeCN (20 mL) and stirred at room temperature for 0.5 hours. A solution of 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)tris(3-((2-aminoethyl)thio)propan-1-one) (1.44 g, 3.0 mmol) in MeCN (10 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. After concentration, the mixture was purified by prep-HPLC to obtain compound (6-2) (250 mg, 24.2%) as a white solid. LCMS: m / z 518.4 [m / 2+H] + ;t R =0.98 minutes.

[0171] Synthesis of 4,4'-((5-(3-(2-(2-(4,7,10-tris(2-tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)ethyl)thio)propanoyl)-1,3,5-triazinane-1,3-diyl)bis(3-oxopropane-3,1-diyl))bis(sulfondiyl))bis(ethane-2,1-diyl))bis(azadiyl))bis(4-oxobutanoic acid) (6-3): Compound (6-2) (250 mg, 0.24 mmol), succinic anhydride (48 mg, 0.48 mmol), and TEA (73 mg, 0.72 mmol) were stirred in MeCN (5 mL) for 1 hour. The mixture was concentrated under reduced pressure and purified by reverse-phase column chromatography (MeCN / H2O, 0% to 30%, 25 g, Biotage) to give compound (6-3) (80 mg, 26.8%) as a white solid. LCMS: m / z 618.5 [m / 2+H] + ;t R =1.07 minutes.

[0172] 2,2,2''-tri-tert-butyl-(10-(2-((2-(3-(3,5-bis(3-(2-(2-(4-oxo-4-(4-((2R)-1-oxo-1-((2R)-2-((3aS,4S,6S)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)propyl)amino)butanamido)ethyl)thio)propanoyl)-1,3,5-triazinan-1-yl)-3-oxopropyl)thio)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate Synthesis of (6-4): Compound (6-3) (80 mg, 0.06 mmol), 4-aminomethyl-N-((2R)-1-oxo-1-((2R)-2-((3aS,4S,6S)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)propan-2-yl)benzamide (59 mg, 0.13 mmol), HATU (62 mg, 0.16 mmol), and diisopropylethylamine (50 mg, 0.39 mmol) were stirred in DMF (2 mL) and DCM (8 mL) for 1 h. After concentration, the mixture was diluted with EtOAc (10 mL), washed with water (5 mL × 3), washed with brine (5 mL × 1), dried over NaSO, and concentrated. The residue was purified by preparative high performance liquid chromatography to give compound (6-4) (55 mg, 40.3%) as a white solid. LCMS: m / z 702.9 [M / 3+H] + ;t R =1.28 minutes.

[0173] 2,2,2-(10-(2-((3-(3,5-bis(3-(2-(4-(4-((R)-1-((R)-2-boronpyrrolidin-1-yl)-1-oxopropan-2-yl)amino)-4-oxobutanamido)ethyl)thio)propionyl)-1,3,5-triazinan-1-yl)-3-oxopropyl)thio)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (JHDB4): To a solution of compound 6-4 (55 mg, 0.03 mmol) in anhydrous DCM (5 mL) under a nitrogen atmosphere was added BCl (1.0 M in dichloromethane) (0.52 mL, 0.52 mmol) dropwise. The mixture was stirred at -78°C for 0.5 hours and then at room temperature for 3 hours. The mixture was concentrated under reduced pressure at room temperature. The residue was diluted with water (3 mL) and neutralized. The mixture was purified by prep-HPLC to give JHDB4 (10.0 mg, 22.9%) as a white solid. LCMS: m / z 545.3 [(M-34) / 3+H] + ;t R =0.75 minutes.

[0174] Example 7: Synthesis of compound JHDB5 (Usual synthesis route 7) and use of analytical method 2 [ka]

[0175] Intermediate 7-1 was prepared from SM4 and OncoFAP (synthesis reference for OncoFAP: PNAS2021, 118, 16 e2101852118 or Eur J Nucl Med Mol Imaging, 2022, 49(6):1822-1832) via standard synthetic route 2, followed by coupling with DOTA. It was purified by preparative HPLC to give compound JHDB5 (15.2 mg, 25%) as a white solid. LCMS: 1528.68 [M+H + ] + , t R =10.75 minutes.

[0176] The following compounds JHDB6 and JHDB7 were prepared using the general synthetic route 7 (analytical method 2) by coupling different intermediates with SM4 followed by coupling with DOTA.

[0177] JHDB6 [ka] White solid (10.2mg, 24%), LCMS: 754.06[M / 2+H + ] + , t R =11.41 minutes.

[0178] JHDB7 [ka] White solid (28.6mg, 42%), LCMS: 782.12[M / 2+H + ] + , t R =13.06 minutes.

[0179] Example 8: Synthesis of compound JHDB8 (standard synthesis route 8) [ka]

[0180] 8-1 was coupled with OncoFAP to give compound 8-2, which was deprotected to give compound 8-3. Compound 8-3 was reacted with DOTA-NHS (CAS: 170908-81-3) to give crude JHDB8, which was purified by preparative liquid chromatography to give pure JHDB8 as a white solid (435 mg, 100%). LCMS: 1592.60 [M+H + ] + , t R =11.68 minutes (Analysis method 2)

[0181] Biological experiments: 1. In vitro activity test Ligand binding of FAP protein (Sinobiological) was detected using a Biacore 8K (Cytiva) instrument. FAP protein was captured on an SA chip. Prior to ligand immobilization (flow paths 1 and 2, flow rate 10 μL / min), FAP protein (10 μg / mL, flow rate 5 μL / min, injection time 600 s) was immobilized in flow path 2 using flow buffer. The sensor surface was conditioned by three consecutive injections of 1 M NaCl in 50 mM NaOH. After each ligand injection, additional washes were performed with 1 M NaCl and isopropanol in 50 mM NaOH (flow paths 1 and 2, flow rate 10 μL / min, injection time 60 s).

[0182] Test compounds were dissolved in 100% dimethyl sulfoxide and diluted to 10 mM. The appropriate maximum concentration was then added to the analysis buffer (PBS, pH 7.4, 1 mM TCEP (tris(2-carboxyethyl)phosphine), 0.05% P20, 2% dimethyl sulfoxide). The analysis was performed under the following conditions: analysis temperature 15°C, analysis step = all set to LMW kinetics; cycle type = single cycle (contact time 90 s, separation time 1800 s, flow rate 30 μL / min, flow cell 1, 2); flow cell detection = 2-1). Data were evaluated using Biacore Insight software, and the data were fitted to a 1:1 binding model.

[0183] The Biacore results are shown in Table 1: pK D =-LogK D where K D is the binding affinity of the compound to the FAP protein as measured by Biacore. D (M)=K d (1 / s) / K a (1 / Ms), where A: pK D >8, B: 7 <pK D <8, C: 6 <pK D <7, D: pK D <6.

[0184] Table 1. Biacore test results [Table 1]

[0185] ●2.Selective experiment The specificity of synthetic compounds for recombinant human dipeptidyl peptidase IV (DPPIV), fibroblast activation protein (FAP), or prolyl oligopeptidase (PREP) is determined by the half-maximal inhibitory concentration (IC) of protease inhibition. 50 The specific steps are as follows:

[0186] 1) The synthesized compounds were dissolved in DMSO to a final concentration of 100 mM. a) For FAP testing: Test compounds were diluted to a 1 mM solution using 50 mM Tris, 140 mM NaCl buffer, pH 7.5. b) For DPPIV testing: Test compounds were diluted to a 1 mM solution using 25 mM Tris, 250 mM NaCl buffer at pH 7.5. c) For PREP testing: Test compounds were diluted to a 1 mM solution using 140 mM NaCl buffer at pH 8.0. 2) The 1 mM test compound solution prepared above was serially diluted (1:10) with the corresponding buffer solution and dispensed into one row of a 96-well plate. 3) Substrates were prepared as DMSO stock solutions (FAP and PREP: 2.5 mM Z-Gly-Pro-AMC (VWR, Cat. No. I-1145.0050BA) in DMSO; DPPIV: 100 mM Gly-Pro-AMC (VWR, Cat. No. 100042-646) in DMSO), and then the substrate stock solutions were diluted 20-fold with the corresponding buffers listed above. 4) The enzyme was diluted in the appropriate assay buffer. The final enzyme concentrations for DPPIV, FAP, and PREP were 0.1 nM, 1.2 nM, and 0.6 nM, respectively. 180 μL was added to each well in columns 2 through 10, as needed. Column 1 (A, B, C) was prepared as a control using 200 μL of the appropriate assay buffer. Column 1 (D, E, F, G, H) was prepared as a no-inhibitor control using 20 μL of the appropriate assay buffer and 180 μL of enzyme. 5) If appropriate, add 20 μL of test compound from the dilution plate prepared in step 2 to columns 2–10 of the assay plate. Each sample was tested in triplicate. Incubate at room temperature for 10 minutes, shaking the plate for the first 2 minutes. 6) Add 10 μL of the 20x substrate prepared in step 3 to each well and incubate at room temperature for 15 minutes, shaking the plate for the first 2 minutes. 7) Fluorescence was measured at λex: 380 and λem: 460. As a result of the above test, the synthesized compounds showed good selectivity against FAP. A: pIC50>8, B: 7 <pIC50<8、C: 6<pIC50<7、D: pIC50<6

[0187] Table 2. Compound selectivity [Table 2]

[0188] ●3. ClogP measurement 177 Lu-JHH11 and 177 Lu-JHDB4 is described below as "7. General Purpose" 177 Lu labeling experiment method 177 Lu labeling was performed, and a certain amount was taken from the labeled compound solution and mixed uniformly with ultrapure water. After mixing, the radioactivity was measured.

[0189] Add 100 μL of saturated n-octanol solution and 80 μL of pure water to each of two EP tubes. 17720 μL of Lu-labeled compound solution was added, and the mixture was shaken for 2 hours. After centrifugation at 2000 rpm / min for 5 minutes at room temperature, 20 μL of the mixture was taken from the upper layer (lipid layer) and the lower layer (aqueous layer) of each tube, and the gamma count was measured. See Figure 1 for the results.

[0190] ●4. Cell competitive binding test (1) Prepare a cell suspension using HT1080 8# cells in the logarithmic growth phase at a cell density of 1 × 10 4 After adjusting the concentration to 1 mL / mL, 1 mL of the solution was seeded onto a 24-well cell culture plate and cultured overnight in a 37°C incubator. (2) The cell culture medium was removed, the cells were washed once with PBS, and then 975 μL of additive-free medium was added. (3) In each well, a fixed concentration of 177 Twenty-five μL of Lu-radiolabeled FAPi-46 (Nanchang Probe Needle Biotechnology Co., Ltd., CAS: 2374782-04-2) (final concentration in culture medium: 1.35 μCi / ml) and unlabeled test compounds JHH8, JHDB8, and JHH9 were added at different concentrations (final concentrations in culture medium: 1000 ng / mL, 100 ng / mL, 10 ng / mL, 1 ng / mL, 0.1 ng / mL, 0.01 ng / mL, 0.001 ng / mL, and 0 ng / mL). (4) Incubated on ice for 2 hours. (5) The cells were washed three times with chilled PBS. (6) The cells were lysed with 0.5 mL of 1 M sodium hydroxide and washed twice with 0.5 mL of PBS. The sodium hydroxide solution (0.5 mL) and PBS (0.5 mL x 2) solutions were collected, and the uptake counts were measured.

[0191] The control compound was OncoFAP-DOTAGA (structural formula: [ka] For synthesis, see literature PNAS2021, 118, 16 e2101852118 or Eur J Nucl Med Mol Imaging, 2022, 49(6):1822-1832), and for results, see Figure 2.

[0192] Using the above method, the cell competitive binding of compounds JHH5, JHH4, JHH10, JHH8, H4b, H5b and H8b in the same batch was measured, and the experimental results are shown in Table 3 and Figure 3.

[0193] Table 3. Competitive binding of compounds [Table 3]

[0194] ●5.Tissue distribution Tissue distribution in FAP-positive tumor-bearing mice: 2×10 6 HT1080 2# FAP cells (50% Matrigel, Corning) were inoculated subcutaneously into the right shoulder of 6- to 9-week-old mice (Balb / c nude, Louisiana River). Tumors grew to approximately 150-350 mm. 3 Once it has grown to this size, please refer to "7. General Purpose" below. 177 The JHH3, JHH8, JHH9, JHDB7, and JHDB8 compounds were labeled using the "Lu labeling experimental method" 177 Lu-JHH3, 177 Lu-JHH8, 177 Lu-JHH9, 177 Lu-JHDB7, 177 Lu-JHDB8 and 177 The Lu-OncoFAP DOTAGA radiolabeled compound was injected into the tail vein of mice (approximately 3.7 MBq / mouse). 24 hours after administration, the animals were euthanized by carbon dioxide inhalation, and blood and organs (liver, kidney, and muscle tumor) were collected.

[0195] Blood was collected from the inferior vena cava, and immediately after collection, 100 μL was dispensed into designated centrifuge tubes (weight measurement). After organ collection, the organs were washed twice with deionized water, dried, and then placed in pre-weighed test tubes, which were then weighed again to calculate the sample weight. The samples were measured on the day of collection. All blood and tissue samples were measured for radioactivity using a gamma counter. See Figure 4 for the results. The results showed that after intravenous injection of the labeled compound into the animal's body, it was distributed to all organs in the animal's body and excreted from the body mainly through renal metabolism, and compared with the reference compound, 177 It was confirmed that Lu-JHH3 was taken up at a high level in tumor tissues and at a low level in other organs.

[0196] ●6. 68 Ga labeling and animal imaging experiments A. 1.0 mg of JHH7 precursor was weighed and dissolved in 0.1 M sodium acetate buffer to prepare a 1.0 mg / mL precursor solution. B. The germanium-gallium generator was fractionally eluted using 5 mL of 0.1 M HCl. The most radioactive portion (0.5 mL) was collected, and 0.5 mL of a metal-free 0.1 M sodium acetate buffer solution (pH 4.5) was added. A 1.5 mL centrifuge tube was used as a reaction vessel, and a fixed amount of precursor (1000 (molecular weight) / 14.94 μL (precursor solution) / mCi (nuclide)) was added. The mixture was vortex-mixed for 10 seconds and then heated at 95°C, 800 rpm for 15 minutes. C. The C18 cartridge was activated with absolute ethanol, then washed with pure water and dried. D. After the reaction was completed, the solution was passed through a C18 cartridge, washed with pure water, dried, and then eluted with 3 drops of ethanol each time, and approximately 10 fractions were collected. E. The final formulation was a clear solution and was used on the same day after preparation. PCT / CT scan 1) According to the PET / CT operating regulations, the power was turned on, the scanning software was started, and daily calibration was performed. 2) To prepare the animals for anesthesia, tumor-bearing mice (provided by Shanghai Alamo Pharmaceutical Technology Co., Ltd., FAP-high-expressing HT1080 cell line) were anesthetized using isoflurane. 3) After the tumor-bearing mice lost their righting reflex, the imaging agent was administered via the tail vein. 4) A 10-minute dynamic scan was performed 1 hour after administration and a 10-minute static scan was performed 3 hours later. 5) During the process, the animal's weight, injection amount, injection time, and residual amount were recorded according to the record sheet, and the injection amount measurement time and residual amount measurement time were recorded respectively. 6) Using PMOD software, the incorporation of animal organs such as tumors and muscles was performed. 68 The imaging results of Ga-labeled compounds JHH7 and JHH11 in tumor-bearing mice are shown in Figures 5 and 6, and image data are shown in Tables 4 and 5.

[0197] Table 4. 68 Image data of Ga-JHH7 tumor-bearing mice [Table 4]

[0198] Table 5. 68 Image data of Ga-JHH11 tumor-bearing mice [Table 5]

[0199] The above results indicate that after the labeled compound was injected into tumor-bearing mice via the tail vein, it was rapidly distributed to each organ of the mouse and rapidly excreted from the body over time. Renal metabolism was the main metabolic pathway, and the uptake of the labeled compound into FAP-positive tumors gradually increased over time. 68 Ga-JHH7 reached its peak uptake in the tumor 1.5 hours after administration to mice, and the uptake gradually decreased thereafter, but a certain amount of uptake remained in the tumor even 3 hours after administration. 68The Ga-JHH11 compound reached its peak uptake into the tumor 30 minutes after administration to the mouse body, and was then rapidly metabolized and excreted from the mouse body. However, uptake into the tumor was still observed 3 hours later.

[0200] ●7. General-purpose 177 Lu labeling experimental method: JHH5 is used as an example. 1) The precursor compound JHH5 (1 mg) was weighed and dissolved in 0.5 M pH 4.0 ascorbic acid buffer to form a 0.1 mg / mL solution. 2) Depending on the nuclide: Precursor = 1:7-10 (molar ratio) Labeling was performed: 2 mCi 177 LuCl3 was added to the labeling buffer (0.5 M pH 4.0 ascorbic acid buffer) system with the precursor amount calculated based on the real-time specific radioactivity, and the reaction volume was adjusted to 0.15 mL. 3) The reaction was carried out at 95°C on a constant temperature heater for 30 minutes, and after the reaction was completed, the product was subjected to iTLC and Radio-HPLC. 4) iTLC developing solvent: 1% EDTA, stationary phase: silica gel 254, developed to 1 cm from the top of the stationary phase, lasted for about 20 minutes, spot volume was 0.5 μl. 5) The labeled product was considered acceptable when the results of iTLC and Radio-HPLC reached 95%. 6) The reaction solution was transferred to a syringe bottle, and the reaction tube was washed with 0.15 mL of physiological saline, and the washing solution was also added to the syringe bottle. 7) 6.7 μL of DTPA solution (2.5 mM) was added, mixed uniformly, and prepared for use. 1 mg of DTPA was added to 1 mL of saline to prepare a DTPA stock solution (concentration 2.5 mM), which was mixed uniformly and prepared for use.

[0201] The final preparation was a clear solution, which was used on the same day after preparation and was then discarded. The radiochemical purity and labeling rate were calculated from the peak area.

[0202] As shown in Table 6, 177The LuCl3 solution was spread in the developer to the top of a silica gel plate, and iTLC showed the purity of the labeled compound to be >99.9%.

[0203] Table 6 [Table 6]

[0204] ●8. 177 Therapeutic experiments using Lu-labeled compounds Mice aged 6-8 weeks (Balb / c nude tumor-bearing mice supplied by Shanghai Alhamo Pharmaceutical Technology Co., Ltd., FAP-high expression HT1080 cell line) were randomly divided into 13 experimental groups based on tumor volume, with 5 mice per group. Animal weights and tumor sizes were measured, and treatment began on the day of group allocation, starting with the control group (saline). After the start of the experiment, general health and appearance were observed daily, and animal weights and tumor sizes were measured before each sample collection. Any abnormal observations observed during the study were recorded in the raw data.

[0205] Synthetic compounds 177 After Lu labeling, it was used in a mouse tumor model treatment experiment, and the results are shown in Figure 7 and Table 7. 177 Lu-labeled compounds such as JHH1, JHH5, JHH9, and JHH14 showed dose-dependent therapeutic effects in this model, suppressing tumor growth. 177 The excellent inhibitory effect of the Lu-labeled compound was confirmed, and furthermore, the body weight of the mice (FIG. 8) did not show any significant change throughout the experimental period.

[0206] Table 7 [Table 7]

[0207] T.G.I. TV : Relative tumor inhibition rate (TGI TV ):TGI TV (%)=[1-(Ti-T0) / (Vi-V0)]×100%; (Ti: mean tumor volume on day i of administration in the treatment group; T0: mean tumor volume on day 0 of administration in the treatment group; Vi: mean tumor volume on day i of administration in the vehicle control group; V0: mean tumor volume on day 0 of administration in the vehicle control group) T / C: T / C% is one of the most common indicators of tumor treatment response: T / C%=T / C * 100%; (T refers to the mean tumor volume at a particular time point in the treatment group, and C refers to the mean tumor volume at a particular time point in the control group.)

[0208] The tumor volumes of the treatment groups (groups 2, 3, 4, and 5) and the control group (group 1) were analyzed using two-way ANOVA with Fisher's LSD test, as were the tumor volumes of groups 1, 3, 4, and 5 and group 2. P values ​​less than 0.05 were considered significant. Both statistical and biological significance were considered in the analysis of the results.

Claims

1. A compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (However, R １ and R ２ are independently hydrogen, halogen, C １－６ Alkyl group, C １－６ is an alkoxy group or a hydroxyl group, and R １ and R ２ At the same time, C １－６ Alkyl group, C １－６ not an alkoxy or hydroxyl group; A １ -CN, -B(OH) ２ , -CONH ２ , or -COOR ａ and R ａ is hydrogen or C １－６ is an alkyl group; W １ is hydrogen or C １－４ is an alkyl group; L １ teeth 【Chemistry 2】 where the a-terminus is attached to the carbonyl group in the left amide bond; X １ and X ２ are independently N or CH; Y is O, S or NH; R ｂ and R ｃ are independently hydrogen, halogen, C １－６ Alkyl group or C １－６ is an alkoxy group; n １ , n ２ and n ３ is independently 0, 1 or 2; m １ , m ２ and m ３ is independently 0, 1 or 2; p is 1, 2, 3 or 4; R ３ is independently C １－６ an alkylene group; V １ is a chemical bond, -C(=O)-C １－６ Alkylene NH— or —C(═O)—CH ２ -(OCH ２ CH ２ ) ｓ NH—, s is 1, 2, 3 or 4, and —C(═O)—C １－６ Alkylenes NH— and —C(═O)—CH ２ -(OCH ２ CH ２ ) ｓ -NH- in NH- is U １ binds to; U １ is a group containing a radioactive metal ion or an optically imageable group.

2. The compound of formula I, its pharmaceutically acceptable salt, its solvate, or its solvate of a pharmaceutically acceptable salt according to claim 1, characterized in that the compound of formula I satisfies one or more of the following conditions: (1) R １ and R ２ are independently hydrogen or halogen; (2) A １ is a condition that CN; (3) W １ is hydrogen or C １－４ The condition that it is an alkyl group; (4) R ｂ and R ｃ are independently hydrogen; (5) p is 1; (6) Y is S; (7) V １ is a chemical bond or -C(=O)-C １－６ alkylene NH-; (8) The group containing a radioactive metal ion is composed of a radioactive metal ion and a group having a function of chelating a metal ion, and the radioactive metal ion chelates with the group having a function of chelating a metal ion; (9) The optically imageable group is a group having fluorescent properties.

3. The compound of formula I, its pharmaceutically acceptable salt, its solvate, or its solvate of a pharmaceutically acceptable salt according to claim 2, characterized in that the compound of formula I satisfies one or more of the following conditions: (1) The group having the function of chelating a metal ion is 【Transformation 3】 the condition that (2) Conditions in which the radioactive metal ion has one or more of the following roles: (i) tracer; (ii) delivery; (iii) imaging; (iv) therapeutic; (3) The radioactive metal ion is １７７ Lu ３＋ , ６８ Ga ３＋ , ６４ Cu ２＋ , ２２５ A.C. ３＋ , ９０ Y ３＋ , ８９ Zr ４＋ , ２１２ Pb ２＋ , ２１３ Bi ３＋ or ２２７ Th ４＋ the condition that (4) The optically imageable group is cy3, cy5, or cy7; (5) The compound represented by formula I is a compound represented by formula Ia. 【Chemistry 4】

4. R １ and R ２ are independently hydrogen or halogen; A １ is CN; W １ is hydrogen or C １－４ is an alkyl group; L １ teeth 【Transformation 5】 where the a-terminus is attached to the carbonyl group in the left amide bond; X １ and X ２ are independently N or CH; Y is S; R ｂ and R ｃ are independently hydrogen; n １ , n ２ and n ３ is independently 0, 1 or 2; m １ , m ２ and m ３ is independently 0, 1 or 2; p is 1; R ３ is C １－６ alkylene; V １ is a chemical bond or -C(=O)-C １－６ alkyleneNH—, —C(═O)—C １－６ -NH- in alkylene NH- is U １ binds to; U １ The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate, or its solvate of a pharmaceutically acceptable salt, characterized in that: is a group containing a radioactive metal ion or an optically imageable group.

5. The compound of formula I, its pharmaceutically acceptable salt, its solvate, or its solvate of a pharmaceutically acceptable salt according to claim 1, characterized in that the compound of formula I satisfies one or more of the following conditions: (1) R １ and R ２ are independently hydrogen or fluorine; (2) W １ is hydrogen or a methyl group; (3) L １ teeth 【Transformation 6】 provided that the a-terminus is bonded to the carbonyl group in the left amide bond; (4) R ３ Ha-CH ２ CH ２ - the condition that (5) V １ is a chemical bond or 【Transformation 7】 and 【Transformation 8】 -NH- in U １ Conditions for binding to (6) U １ teeth 【Chemistry 9】 The condition is:

6. The compound represented by formula I is a compound obtained by chelating compound A with the radioactive metal ion according to claim 3, and the structure of compound A is represented by any one of the following: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 Preferably, the compound of formula I is a compound of formula I and compound A. １７７ Lu ３＋ and a chelated compound of Preferably, the compound of formula I is a compound of formula I and compound A. ６８ Ga ３＋ 2. The compound of formula I according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that it is a chelated compound of

7. A method for preparing a compound of formula I according to any one of claims 1 to 6, comprising the step of chelating a radioactive metal ion according to claim 3 with a compound of formula II. 【Chemistry 16】 (However, U １ａ is a group having a function of chelating a metal ion, and the group having a function of chelating a metal ion is as defined in claim 3.

8. A compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Chemistry 17】 (However, U １ａ is defined as in claim 7, and R １ , R ２ , A １ , W １ , L １ , p, R ３ and V １ The definitions are as set forth in any one of claims 1 to 5.

9. The compound of formula II is a compound of formula IIa, [Chemistry 18] Preferably, the compound represented by formula II is selected from any one of compounds A, wherein compound A is as defined in claim 6. A compound represented by formula II, its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt, according to claim 8.

10. A compound of formula III, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Chemistry 19】 (However, R ４ and R ５ are independently hydrogen, halogen, C １－６ Alkyl group, C １－６ an alkoxy group or a hydroxyl group, and R ４ and R ５ At the same time, C １－６ Alkyl group, C １－６ not an alkoxy group or a hydroxyl group; A ２ -CN, -B(OH) ２ , -CONH ２ , or -COOR ｄ and R ｄ is hydrogen or C １－６ is an alkyl group; W ２ is hydrogen, C １－４ Alkyl group or HO—C １－４ alkyl-; L ２ is a phenyl group, one or more R ｅ or a phenyl group substituted with 【Chemistry 20】 and the b-terminus is V ２ binds to; R ｅ and R ｆ are independently hydrogen, halogen, C １－６ alkyl group, or C １－６ is an alkoxy group; m ４ and n ４ is independently 0, 1 or 2; X ３ is CH or N; V ２ is a chemical bond, -C １－６ Alkylene -NH- or -C(=O)-C １－６ alkylene-C(═O)-5 to 10-membered heterocyclic alkyl group, １－６ -NH- in alkylene-NH- is U ２ is bonded to —C(═O)—C １－６ The terminal of the 5- to 10-membered heterocyclic alkyl group in the alkylene-C(═O)-5- to 10-membered heterocyclic alkyl group is U ２ binds to; U ２ is a group containing a radioactive metal ion or an optically imageable group.

11. The compound of formula III, its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt according to claim 10, characterized in that the compound of formula III satisfies one or more of the following conditions: (1) R ４ and R ５ are independently hydrogen; (2) A ２ Ha-B(OH) ２ the condition that (3) R ｅ and R ｆ are independently hydrogen or halogen; (4) X ３ is CH; (5) m ４ and n ４ are independently 1; (6) L ２ is a phenyl group, one or more R ｅ When V is a phenyl group substituted with ２ Ha-C １－６ alkylene -NH-, -C １－６ -NH- in alkylene -NH- is U ２ Conditions for binding to (7) L ２ but 【Chemistry 21】 If V ２ is a chemical bond or -C(=O)-C １－６ alkylene-C(═O)-5 to 10-membered heterocyclic alkyl group, —C(═O)—C １－６ The terminal of the 5- to 10-membered heterocyclic alkyl group in the alkylene-C(═O)-5- to 10-membered heterocyclic alkyl group is U ２ Conditions for binding to (8) The radioactive metal ion-containing group is as defined in claim 2; (9) The optically imageable group is as defined in claim 2 or 3; (10) The condition that the compound represented by formula III is a compound represented by formula IIIa. 【Chemistry 22】

12. R ４ and R ５ are independently hydrogen; A ２ Ha-B(OH) ２ and W ２ is hydrogen, C １－４ Alkyl group or HO—C １－４ alkyl-; L ２ is a phenyl group, one or more R ｅ or a phenyl group substituted with 【Chemistry 23】 and the b-terminus is V ２ binds to; R ｅ and R ｆ are independently hydrogen or halogen; X ３ is CH; m ４ and n ４ are independently 1; V ２ is a chemical bond, -C １－６ Alkylene -NH- or -C(=O)-C １－６ alkylene-C(═O)-5 to 10-membered heterocyclic alkyl group, １－６ -NH- in alkylene-NH- is U ２ is bonded to —C(═O)—C １－６ The terminal of the 5- to 10-membered heterocyclic alkyl group in the alkylene-C(═O)-5- to 10-membered heterocyclic alkyl group is U ２ binds to; U ２ is a group containing a radioactive metal ion or an optically imageable group, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, according to claim 10.

13. The compound of formula III, its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt according to claim 10, characterized in that the compound of formula III satisfies one or more of the following conditions: (1) W ２ is a methyl group, 【Chemistry 24】 the condition that (2) L ２ teeth 【Chemistry 25】 and the b-terminus is V ２ Conditions for binding to (3) V ２ is a chemical bond, -CH ２ -NH- or 【Chemistry 26】 and -CH ２ -NH- in -NH- is U ２ binds to 【Chemistry 27】 The piperazine end in ２ Conditions for binding to (4) U ２ teeth 【Chemistry 28】 The condition is:

14. The compound represented by formula III is a compound obtained by chelating compound B with the radioactive metal ion according to claim 3, and the structure of compound B is represented by any one of the following: 【Chemistry 29】 【Transformation 30】 Preferably, the compound of formula III is a compound of formula B and １７７ Lu ３＋ and a chelated compound of Preferably, the compound of formula III is a compound of formula B and ６８ Ga ３＋ 11. The compound of formula III according to claim 10, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that it is a chelated compound of

15. A method for preparing a compound of formula III according to any one of claims 10 to 14, comprising the step of chelating a radioactive metal ion according to claim 3 with a compound of formula IV. 【Chemistry 31】 (However, U ２ａ is a group having a function of chelating a metal ion, and the group having a function of chelating a metal ion is as defined in claim 3.

16. A compound of formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Chemistry 32】 (However, R ４ , R ５ , A ２ , W ２ , L ２ and V ２ is defined as claimed in any one of claims 10 to 13, and U ２ａ is defined as in claim 15.

17. The compound of formula IV is a compound of formula IVa, 【Transformation 33】 Preferably, the compound represented by formula IV is selected from any one of compounds B, wherein compound B is as defined in claim 14. The compound represented by formula IV, its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt according to claim 16.

18. A compound of formula V, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Transformation 34】 (However, R ６ , R ７ , R ８ and R ９ are independently hydrogen, halogen, C １－６ Alkyl group, C １－６ is an alkoxy group or a hydroxyl group, and R ６ and R ７ At the same time, C １－６ Alkyl group, C １－６ R is not an alkoxy or hydroxyl group. ８ and R ９ At the same time, C １－６ Alkyl group, C １－６ not an alkoxy or hydroxyl group; A ３ and A ４ are independently -CN, -B(OH) ２ , -CONH ２ or -COOR ｇ and R ｇ is hydrogen or C １－６ is an alkyl group; W ３ and W ４ are independently hydrogen or C １－４ is an alkyl group; L ３ and L ８ are independently a phenyl group, one or more R ｈ a phenyl group substituted with 【Chemistry 35】 、 【Transformation 36】 ,or 【Chemistry 37】 wherein the C-terminus is attached to the carbonyl group in an amide bond; R ｈ , R ｉ and R ｊ are independently hydrogen, halogen, C １－６ Alkyl group or C １－６ is an alkoxy group; X ４ and X ５ is independently CH or N; m ５ , m ６ , n ５ and n ６ is independently 0, 1 or 2; L ４ and L ７ are independently a chemical bond or C １－６ an alkylene group; L ５ and L ６ is independently 【Transformation 38】 where the d-terminus is V ３ binds to; V ３ teeth, 【Chemistry 39】 where the e-terminus is L ５ or L ６ The f end binds to L ５ or L ６ The g-terminus binds to U ３ binds to; U ３ is a group containing a radioactive metal ion or an optically imageable group.

19. The compound of formula V according to claim 18, its pharmaceutically acceptable salt, its solvate or a solvate of its pharmaceutically acceptable salt, characterized in that the compound of formula V satisfies one or more of the following conditions: (1) R ６ , R ７ , R ８ and R ９ are independently hydrogen or halogen; (2) A ３ and A ４ are independently -CN or -B(OH) ２ the condition that (3) R ｉ and R ｊ are independently hydrogen; (4) X ４ and X ５ are independently CH; (5) m ５ , m ６ , n ５ and n ６ are independently 1; (6) L ３ and L ８ are independently a phenyl group, L ４ and L ７ is independently C １－６ The condition that it is an alkylene group; (7) L ３ and L ８ became independent 【Chemistry 40】 If L ４ and L ７ are independently chemical bonds; (8) In the compound represented by formula V, the group containing the radioactive metal ion is as defined in claim 2; (9) In the compound of formula V, the optically imageable group is as defined in claim 2 or 3; (10) The condition that the compound represented by formula V is a compound represented by formula Va. 【Chemistry 41】

20. R ６ , R ７ , R ８ , and R ９ are independently hydrogen or halogen; A ３ and A ４ are independently -CN or -B(OH) ２ and W ３ and W ４ are independently hydrogen or C １－４ is an alkyl group; L ３ and L ８ are independently a phenyl group, 【Chemistry 42】 wherein the C-terminus is attached to a carbonyl group in an amide bond; R ｉ and R ｊ are independently hydrogen; X ４ and X ５ is independently CH; m ５ , m ６ , n ５ and n ６ are independently 1; L ４ and L ７ are independently a chemical bond or C １－６ an alkylene group; L ５ and L ６ is independently 【Chemistry 43】 where the d-terminus is V ３ binds to; V ３ teeth, 【Chemistry 44】 where the e-terminus is L ５ or L ６ The f end binds to L ５ or L ６ The g-terminus binds to U ３ binds to; U ３ 19. The compound of formula V according to claim 18, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein: is a group containing a radioactive metal ion or an optically imageable group.

21. The compound of formula V according to claim 18, its pharmaceutically acceptable salt, its solvate or a solvate of its pharmaceutically acceptable salt, characterized in that the compound of formula V satisfies one or more of the following conditions: (1) R ６ , R ７ , R ８ and R ９ are independently hydrogen or fluorine; (2) W ３ and W ４ are independently hydrogen or a methyl group; (3) L ３ and L ８ is independently 【Chemistry 45】 provided that the C-terminus is linked to the carbonyl group in the amide bond; (4) U ３ teeth 【Chemistry 46】 The condition is:

22. The compound represented by formula V is a compound obtained by chelating compound C with the radioactive metal ion according to claim 3, and the structure of compound C is represented by any one of the following: 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 Preferably, the compound represented by formula V is a compound represented by formula V, １７７ Lu ３＋ and a chelated compound of Preferably, the compound represented by formula V is a compound represented by formula V, ６８ Ga ３＋ 19. The compound of formula V according to claim 18, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that it is a chelated compound of

23. A method for preparing a compound of formula V according to any one of claims 18 to 22, comprising the step of chelating a radiometal ion according to claim 3 with a compound of formula VI: [Transformation 50] (However, U ３ａ is a group having a function of chelating a metal ion, and the group having a function of chelating a metal ion is as defined in claim 3.

24. A compound of formula VI, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Chemistry 51】 (However, R ６ , R ７ , R ８ , R ９ , A ３ , W ３ , W ４ , L ３ , L ４ , L ５ , L ６ , L ７ , L ８ and V ３ is defined as in any one of claims 18 to 21, and U ３ａ is defined as in claim 23.

25. The compound of formula VI is a compound of formula VIa, 【Chemistry 52】 Preferably, the compound represented by formula VI is selected from any one of compounds C, wherein compound C is as defined in claim 22. A compound represented by formula VI, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, as defined in claim 24.

26. A compound of formula VII, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Chemistry 53】 (However, L ９ teeth, 【Chemistry 54】 and R １ , R ２ , A １ , W １ , X １ , X ２ , Y., R. ｂ , R ｃ , m １ , m ２ , m ３ , n １ , n ２ and n ３ are defined as in any one of claims 1 to 5; Preferably, L ９ teeth 【Transformation 55】 It is.)

27. The compound of formula VII is a compound of formula VIIa, 【Transformation 56】 Preferably, the compound of formula VII is selected from any one of the following compounds: 【Chemistry 57】 27. A compound of formula VII according to claim 26, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a substance X and a pharmaceutical auxiliary, wherein the substance X is a substance Y, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and the substance Y is a compound of formula I according to any one of claims 1 to 6, a compound of formula III according to any one of claims 10 to 14, or a compound of formula V according to any one of claims 18 to 22.

29. Use of substance X in the manufacture of a medicament, wherein said substance X is substance Y, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and said substance Y is a compound of formula I according to any one of claims 1 to 6, a compound of formula III according to any one of claims 10 to 14, or a compound of formula V according to any one of claims 18 to 22; The pharmaceutical is a pharmaceutical for treating or diagnosing a tumor, or the pharmaceutical is a pharmaceutical for imaging a tumor.

30. 30. The use according to claim 29, characterized in that said use satisfies one or more of the following conditions: (1) When the pharmaceutical is a pharmaceutical for tumor diagnosis, the radioactive metal ion is ６８ Ga ３＋ the condition that (2) When the medicine is a medicine for treating tumors, the radioactive metal ion is １７７ Lu ３＋ the condition that (3) The condition that the tumor is breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, or skin melanoma.

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