Bone-targeting radiopharmaceutical and use thereof

Abstract

The present application discloses a bone-targeting radiopharmaceutical or imaging agent and a use thereof. The bone-targeting radiopharmaceutical or imaging agent can be used for the treatment or diagnosis of bone diseases, such as bone metastasis from a tumor.

Description

Bone-targeting radiopharmaceuticals and their uses Technical Field

[0001] This invention belongs to the field of nuclear medicine technology, specifically relating to radiopharmaceuticals and their uses. Background Technology

[0002] Bone metastasis is a type of cancer metastasis caused by tumor invasion of the bone, and it is a common symptom in the late stages of many malignant tumors. Bone-related events caused by bone metastasis, such as bone pain, spinal cord compression, pathological fractures, and hypercalcemia, are major factors affecting patients' ability to move independently and their quality of life. The relative incidence of bone metastasis is 65-75% in breast cancer, 65-75% in prostate cancer, 60% in thyroid cancer, 30-40% in lung cancer, 40% in bladder cancer, 20-25% in renal cell carcinoma, and 14-45% in melanoma. Furthermore, the median survival time for patients with bone metastasis is: 19-25 months for breast cancer, 12-53 months for prostate cancer, 28 months for thyroid cancer, 6 months for lung cancer, 6 months for bladder cancer, 12 months for renal cancer, and 6 months for melanoma.

[0003] Currently marketed drugs for bone metastases include strontium chloride. 89 Drugs such as [Sr], pamidronate disodium, and denosumab (a human monoclonal antinuclear factor KB ligand receptor activator) have been used, but these drugs all have varying degrees of side effects, such as myelosuppression, which may cause increased pain within the first week of treatment; or effects on the musculoskeletal system, such as transient bone pain, myalgia, joint pain, and myoclonus. Denosumab is also expensive. Furthermore, these drugs have ultimately failed to improve the overall survival of patients with bone metastases. Therefore, the development of drugs to treat bone metastases is of great significance.

[0004] Radioligand therapy utilizes tumor-targeting carriers to deliver radioactive isotopes to lesions, precisely killing cancer cells. It typically consists of a targeting compound (ligand) and a therapeutic radioactive isotope (radioactive particle). Pluvicto, developed by Novartis, is a radiopharmaceutical that targets prostate-specific membrane antigen (PSMA) for the treatment of PSMA-positive metastatic castration-resistant prostate cancer. It binds to PSMA-expressing prostate cancer cells, delivered by a radionuclide... 177 The beta rays emitted during the decay of Lu can damage tumor cells, causing cell death. Pluvicto's radiation only works over a very short distance, thus limiting the drug's damage to surrounding healthy cells. Lutathera is also a drug developed by Novartis. 177Lu-labeled somatostatin analogues are used to treat adult patients with unresectable or metastatic somatostatin receptor-positive gastrointestinal and pancreatic neuroendocrine tumors. They act by binding to the somatostatin receptor in cells, which may be present on some tumors. After binding to the receptor, the drug enters the cell and releases radiation to damage tumor cells. Lutathera has effectively prolonged progression-free survival in patients.

[0005] Radioligand therapy boasts advantages such as high efficacy and safety, but currently, very few drugs are available on the market, and no bone-targeting radioligand drugs are yet available. Therefore, there is a significant demand for radioligand drugs to treat bone metastases, representing a vast market potential. Summary of the Invention

[0006] One or more embodiments of this application provide a compound of Formula I or a pharmaceutically acceptable salt, crystal, eutectic, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate thereof.

[0007] in

[0008] CL is a chelating agent;

[0009] BP is R4 can be H, OH, amino, or halogen;

[0010] Each LK is independently either LK1 or LK2;

[0011] The LK1 is a C1-C6 alkyl, C3-C10 cycloalkyl, 5- to 10-membered heterocyclic alkyl, C4-C10 aryl, 5- to 10-membered heteroaryl.

[0012] The LK2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or amino acid residues or dipeptides formed from amino acids;

[0013] R1 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkyl-C3-C10 cycloalkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or acyl;

[0014] R2 and R3 are each independently hydrogen or C1-C6 alkyl; or R2 and R3 together form a carbonyl group;

[0015] m1, m2, and m3 are each independently 0, 1, 2, 3, 4, or 5;

[0016] n1, n2, and n3 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0017] o can be 0, 1, or 2;

[0018] p is 0, 1, or 2;

[0019] When m1, m2, m3, n1, n2, n3, o, or p is greater than 1, each of -NR1-, -CR2R3-, and -LK- is independently the same or different.

[0020] In one or more embodiments, the chelating agent is

[0021] In one or more embodiments, BP is

[0022] In one or more embodiments, R1 is methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, methylcyclopropyl, cyclobutylmethyl, methylcyclobutyl, cyclopentylmethyl, methylcyclopentyl, cyclohexylmethyl, methylcyclohexyl, formyl, or acetyl.

[0023] In one or more embodiments, R2 and R3 are each independently methyl, ethyl, propyl, or butyl.

[0024] In one or more embodiments, the C1-C6 alkyl group is methyl, ethyl, or propyl.

[0025] In one or more embodiments, the C2-C6 alkenyl group is vinyl or propylene.

[0026] In one or more embodiments, the C2-C6 ynyl group is acetylene or propynyl.

[0027] In one or more embodiments, the C3-C10 cycloalkyl group is

[0028] In one or more embodiments, the C3-C10 cycloalkyl group is The * end is connected to the side containing the right end of Equation I.

[0029] In one or more embodiments, the C1-C6 alkyl group in the C1-C6 alkyl-C3-10 cycloalkyl or C3-10 cycloalkyl-C1-C6 alkyl group is methyl, ethyl, or propyl, and the C3-10 cycloalkyl group in the C1-C6 alkyl-C3-10 cycloalkyl or C3-10 cycloalkyl-C1-C6 alkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0030] In one or more embodiments, the 5- to 10-membered heterocyclic alkyl group is

[0031] In one or more embodiments, the 5- to 10-membered heterocyclic alkyl group is

[0032] In one or more embodiments, the 5- to 10-membered heterocyclic alkyl group is

[0033] In one or more embodiments, the C4-C10 aryl group is

[0034] In one or more embodiments, the C4-C10 aryl group is

[0035] In one or more embodiments, the 5- to 10-membered heteroaryl group is pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, triazinyl, tetraazinyl, quinolinyl, or indoleyl.

[0036] In one or more embodiments, the 5- to 10-membered heteroaryl group is

[0037] In one or more embodiments, the 5- to 10-membered heteroaryl group is

[0038] In one or more embodiments, R1 is methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, methylcyclopropyl, cyclobutylmethyl, methylcyclobutyl, cyclopentylmethyl, methylcyclopentyl, cyclohexylmethyl, methylcyclohexyl, formyl, or acetyl.

[0039] In one or more embodiments, the amino acid residue or dipeptide formed from the amino acid residue is a hydrophilic amino acid residue or a dipeptide formed from the hydrophilic amino acid residue.

[0040] In one or more embodiments, the amino acid residues or dipeptides formed from amino acid residues are

[0041] In one or more embodiments, the amino terminus of the amino acid residue or the dipeptide formed from the amino acid residue is attached to the side containing the left end of Formula I.

[0042] In one or more embodiments, when m is greater than 1, each -NR1- is independently -NH-, -NCH3-,

[0043] In one or more embodiments, when n is greater than 1, each -CR2R3- is independently methylene or carbonyl.

[0044] In one or more embodiments, formula I is formula I-1 or I'-1.

[0045] in

[0046] LK1 is a C1-C6 alkyl, C3-C10 cycloalkyl, 5- to 10-membered heterocyclic alkyl, C4-C10 aryl, 5- to 10-membered heteroaryl, or Or LK1 does not exist;

[0047] The LK2 is

[0048] R4 is selected from H, OH, amino, or halogen;

[0049] n3 can be 1, 2, 3, 4, or 5.

[0050] In one or more embodiments, LK1 is methyl, ethyl, propyl,

[0051] In one or more embodiments, LK1 is The * end is connected to the side containing the right end of formula I-1 or formula I'-1.

[0052] In one or more embodiments, LK1 is

[0053] In one or more embodiments, LK1 is

[0054] In one or more embodiments, LK1 is

[0055] In one or more embodiments, LK1 is

[0056] In one or more embodiments, LK1 is

[0057] In one or more embodiments, LK1 is pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, triazinyl, tetraazinyl, quinolinyl, or indoleyl.

[0058] In one or more embodiments, LK1 is

[0059] In one or more embodiments, LK1 is

[0060] In one or more embodiments, formula I is formula I-2.

[0061] in

[0062] LK1 is a C1-C6 alkyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl group, or...

[0063] LK2 is Triazolyl or

[0064] R4 is selected from H, OH, amino, or halogen;

[0065] n3 can be 1, 2, 3, 4, or 5.

[0066] In one or more embodiments, LK1 is methyl, ethyl, propyl,

[0067] In one or more embodiments, LK1 is The * end is connected to the side containing the right end of Equation I-2.

[0068] In one or more embodiments, LK1 is

[0069] In one or more embodiments, LK1 is

[0070] In one or more embodiments, LK1 is

[0071] In one or more embodiments, LK1 is

[0072] In one or more embodiments, LK1 is

[0073] In one or more embodiments, LK1 is pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, triazinyl, tetraazinyl, quinolinyl, or indoleyl.

[0074] In one or more embodiments, LK1 is

[0075] In one or more embodiments, LK1 is

[0076] In one or more embodiments, LK1 is a 5-membered heteroaryl group.

[0077] In one or more embodiments, the 5-membered heteroaryl group has one or two N heteroatoms.

[0078] In one or more embodiments, the 5-membered heteroaryl group is

[0079] In one or more embodiments, LK2 is

[0080] In one or more embodiments, n3 is 1.

[0081] In one or more embodiments, R4 is OH.

[0082] In one or more embodiments, formula I is formula I-3.

[0083]

[0084] in

[0085] R1 is hydrogen, C1-C6 alkyl, C3-10 cycloalkyl, C1-C6 alkyl-C3-10 cycloalkyl, C3-10 cycloalkyl-C1-C6 alkyl, or acyl;

[0086] R2 and R3 are each independently hydrogen or C1-C6 alkyl, specifically methyl, ethyl, propyl, or butyl; or R2 and R3 together form a carbonyl group;

[0087] R4 is H, OH, amino, or halogen; n2 and n3 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10:

[0088] n1, m1, and o are independently 0 and 1.

[0089] In one or more embodiments, R1 is methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, methylcyclopropyl, cyclobutylmethyl, methylcyclobutyl, cyclopentylmethyl, methylcyclopentyl, cyclohexylmethyl, methylcyclohexyl, formyl, or acetyl.

[0090] In one or more embodiments, LK is an amino acid residue or a dipeptide formed from an amino acid residue.

[0091] In one or more embodiments, LK is

[0092] In one or more embodiments, LK is

[0093] In one or more embodiments, LK is The * end is connected to the side where the right end of Equation I-3 is located.

[0094] In one or more embodiments, the LK is

[0095] In one or more embodiments, the LK is

[0096] In one or more embodiments, the LK is

[0097] In one or more embodiments, the LK is

[0098] In one or more embodiments, the LK is

[0099] In one or more embodiments, the LK is pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, triazinyl, tetraazinyl, quinolinyl, or indoleyl.

[0100] In one or more embodiments, the LK is

[0101] In one or more embodiments, the LK is

[0102] In one or more embodiments, formula I is formula I-4.

[0103] in

[0104] LK is an amino acid residue or a dipeptide formed from amino acid residues;

[0105] R2 and R3 are each independently hydrogen or C1-C6 alkyl, specifically methyl, ethyl, propyl, or butyl; or R2 and R3 together form a carbonyl group;

[0106] R4 can be H, OH, amino, or halogen;

[0107] n2 and n3 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0108] m1, o, and n1 are each independently 0 or 1.

[0109] In one or more embodiments, LK is

[0110] In one or more embodiments, LK is

[0111] In one or more embodiments, LK is The * end is connected to the side where the right end of Equation I-4 is located.

[0112] In one or more embodiments, the LK is

[0113] In one or more embodiments, the LK is

[0114] In one or more embodiments, the LK is

[0115] In one or more embodiments, the LK is

[0116] In one or more embodiments, the LK is

[0117] In one or more embodiments, the LK is pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, triazinyl, tetraazinyl, quinolinyl, or indoleyl.

[0118] In one or more embodiments, the LK is

[0119] In one or more embodiments, the LK is

[0120] In one or more embodiments, Formula I is Formula I-5.

[0121] in

[0122] LK1 is

[0123] R1 is independently hydrogen, C1-C6 alkyl, C3-10 cycloalkyl, C1-C6 alkyl-C3-10 cycloalkyl, C3-10 cycloalkyl-C1-C6 alkyl, or acyl;

[0124] R2 and R3 are each independently hydrogen or C1-C6 alkyl, specifically methyl, ethyl, propyl, or butyl, or R2 and R3 together form a carbonyl group;

[0125] R4 can be H, OH, amino, or halogen;

[0126] n2 and n3 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0127] n1, m1, and o are each independently 0 or 1.

[0128] In one or more embodiments, R1 is methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, methylcyclopropyl, cyclobutylmethyl, methylcyclobutyl, cyclopentylmethyl, methylcyclopentyl, cyclohexylmethyl, methylcyclohexyl, formyl, or acetyl.

[0129] In one or more embodiments, LK1 is The * end is connected to the side where the right end of Equation I-5 is located.

[0130] In one or more embodiments, LK1 is

[0131] In one or more embodiments, LK1 is

[0132] In one or more embodiments, LK1 is

[0133] In one or more embodiments, LK1 is

[0134] In one or more embodiments, LK1 is

[0135] In one or more embodiments, LK1 is pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, triazinyl, tetraazinyl, quinolinyl, or indoleyl.

[0136] In one or more embodiments, LK1 is

[0137] In one or more embodiments, LK1 is

[0138] In one or more embodiments, Formula I is Formula I-6.

[0139] in

[0140] R1 is hydrogen, C1-C6 alkyl, C3-10 cycloalkyl, C1-C6 alkyl-C3-10 cycloalkyl, C3-10 cycloalkyl-C1-C6 alkyl, or acyl;

[0141] R4 can be H, OH, amino, or halogen;

[0142] LK for Pyrrole, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, triazinyl, tetraazinyl, quinolinyl, or indoleyl;

[0143] n1 is 0, 1, 2, 3, 4 or 5;

[0144] n2 is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0145] n3 can be 1, 2, 3, 4, or 5.

[0146] In one or more embodiments, R1 is methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, methylcyclopropyl, cyclobutylmethyl, methylcyclobutyl, cyclopentylmethyl, methylcyclopentyl, cyclohexylmethyl, methylcyclohexyl, formyl, or acetyl.

[0147] In one or more embodiments, Formula I is Formula I-7.

[0148] in

[0149] R4 can be H, OH, amino, or halogen;

[0150] LK2 is an amino acid residue;

[0151] LK1 is a C1-C6 alkyl, C3-C10 cycloalkyl, pyrrolyl, imidazole, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, triazinyl, tetraazinyl, quinolinyl, indoleyl, or

[0152] n2 and n3 are each independently 1, 2, 3, 4 or 5.

[0153] In one or more embodiments, LK2 is a hydrophilic amino acid residue.

[0154] In one or more embodiments, LK1 is methyl, ethyl, propyl,

[0155] In one or more embodiments, LK1 is The * end is connected to the side where the right end of Equation I-7 is located.

[0156] In one or more embodiments, Formula I is Formula I-8.

[0157] in

[0158] R4 can be H, OH, amino, or halogen;

[0159] LK2 is an amino acid residue, specifically a hydrophilic amino acid residue;

[0160] LK1 is a C1-C6 alkyl, C3-C10 cycloalkyl, pyrrolyl, imidazole, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, triazinyl, tetraazinyl, quinolinyl, indoleyl, or

[0161] n2 and n3 are each independently 0, 1, 2, 3, 4, and 5.

[0162] In one or more embodiments, LK2 is a hydrophilic amino acid residue.

[0163] In one or more embodiments, LK1 is methyl, ethyl, propyl,

[0164] In one or more embodiments, LK1 is The * end is connected to the side where the right end of formula I-8 or formula I'-8 is located.

[0165] One or more embodiments of this application provide a compound or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, said compound being

[0166] One or more embodiments of this application provide radiolabels comprising complexes formed by coordination of a compound of the application or its pharmaceutically acceptable salt, crystal, eutectic, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate with a radionuclide.

[0167] In one or more embodiments, the radionuclide is selected from... 18 F-Al, 90 Y、 153 Sm、 166 Ho、 186 Re、 188 Re、 46 Sc、 177 Lu、 89 Sr、 223 Ra、 225 Ac、 67 Ga、 68 Ga、 99m Tc, 111 In、 159 Gd, 149 Tb, 161 Tb, 212 Pb, 43 Sc、 47 Sc、 67 Cu, and 64 Cu.

[0168] In one or more embodiments, the radionuclide is 177 Lu.

[0169] One or more embodiments of this application provide radioactive markers, which are

[0170] One or more embodiments of this application provide pharmaceutical compositions comprising the compounds of this application or their pharmaceutically acceptable salts, crystals, cocrystals, stereoisomers, enantiomers, diastereomers, prodrugs, deuterated derivatives, metabolites, hydrates, or solvates, or the radiolabels of this application, as well as pharmaceutically acceptable carriers, excipients, or excipients.

[0171] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, crystal, eutectic, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or the radiolabeled product of this application, in the preparation of a medicament for the treatment / prevention of bone diseases.

[0172] One or more embodiments of this application provide compounds, pharmaceutical compositions, and pharmaceutical preparations of this application, which are used as pharmaceuticals.

[0173] One or more embodiments of this application provide compounds, pharmaceutical compositions, and pharmaceutical formulations of this application, which are used as bone-targeting drugs.

[0174] One or more embodiments of this application provide compounds, pharmaceutical compositions, and pharmaceutical preparations of this application, which are used as medicines for treating / preventing bone diseases.

[0175] One or more embodiments of this application provide compounds, pharmaceutical compositions, and pharmaceutical preparations of this application, which are used as medicines for diagnostic and / or therapeutic methods in nuclear medicine.

[0176] One or more embodiments of this application provide a method for treating / preventing bone diseases, comprising administering the compounds, pharmaceutical compositions, or pharmaceutical preparations of this application to a subject in need of such treatment.

[0177] One or more embodiments of this application provide diagnostic and / or therapeutic methods for nuclear medicine, including administering the compounds, pharmaceutical compositions, or pharmaceutical preparations of this application to a subject in need of such treatment.

[0178] In one or more embodiments, the drug is a bone-targeting drug.

[0179] In one or more embodiments, the bone disease is bone cancer, osteosarcoma, bone metastasis of tumors, or diseases caused by them.

[0180] In one or more embodiments, the tumor bone metastasis is a bone metastasis of breast cancer, prostate cancer, thyroid cancer, lung cancer, bladder cancer, renal cell carcinoma, or melanoma.

[0181] In one or more embodiments, the tumor bone metastasis is osteolytic bone metastasis or osteoblastic bone metastasis.

[0182] In one or more embodiments, the bone cancer, osteosarcoma, or diseases caused by bone metastases are bone pain, spinal cord compression, pathological fractures, or hypercalcemia.

[0183] In one or more embodiments, the drug, bone-targeting drug, drug for treating / preventing bone diseases, or medicine for diagnostic and / or therapeutic methods in nuclear medicine is also used as an imaging agent.

[0184] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, crystal, eutectic, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or the radiolabeled product of this application, in the preparation of pharmaceutical products for diagnostic and / or therapeutic methods in nuclear medicine.

[0185] In one or more embodiments, the diagnostic and / or therapeutic methods of nuclear medicine are for positron emission tomography (PET) and single-photon emission computed tomography (SPECT).

[0186] In one or more embodiments, the medicine used for diagnosis and / or treatment of nuclear medicine is also used for the treatment / prevention of bone diseases.

[0187] In one or more embodiments, formula I is formula I-9 or formula I'-9.

[0188] LK, R1, R2, R3, R4, m1, m2, m3, n1, n2, n3, o, p are as described above.

[0189] One or more embodiments of this application provide compounds of this application for use in positron emission tomography (PET) and single-photon emission computed tomography (SPECT).

[0190] One or more embodiments of this application provide the use of the compounds of this application in the preparation of medicaments that combine imaging and treatment of metastatic bone tumors.

[0191] The terminology used in the technical solutions of this application is explained below. As used in the specification and appended claims, unless specifically stated otherwise, the terminology of this application has the following meanings. Undefined groups have their common meaning in the art.

[0192] "Chlorinating agent" refers to a ligand compound that can complex a central atom or ion. For example, chelating agents can be cyclic compounds that provide one or more side chains, such as DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTAGA (dodecano-1-glutaric acid-1,4,7,10-tetraamine-triacetic acid), or other DOTA derivatives, NOTA (nonano-1,4,7-triamine-triacetic acid), NOTA-GA (1,4,7-triazacyclononane, 1-glutaric acid-4,7-acetic acid), and other NOTA derivatives.

[0193] In one or more embodiments, the chelating agent may be, for example,

[0194] "Radioactive nuclides" refer to unstable atomic nuclei that spontaneously emit radiation (such as alpha rays, beta rays, etc.) and decay into stable nuclides. Non-limiting examples of radioactive nuclides include... 18 F-Al, 90 Y、 153 Sm、 166 Ho、 186 Re、 188 Re、 46 Sc、 177 Lu、 89 Sr、 223 Ra、 225 Ac、 67 Ga、 68 Ga、 99m Tc, 111 In、 159 Gd, 149 Tb, and 161 Tb, 212 Pb, 43 Sc、 47 Sc、 67 Cu、 64 Cu.

[0195] A "complex" also refers to a coordination compound, which consists of a central atom or ion and ligands surrounding it, linked by complete or partial coordinate bonds. Non-limiting examples of complexes include... A represents a radioactive nuclide.

[0196] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, 6), more preferably an alkyl group with 1 to 6 carbon atoms, and even more preferably an alkyl group with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; when the alkyl group is substituented, it may optionally be further substituted by one or more substituents.

[0197] "Alkenyl" refers to an aliphatic hydrocarbon group consisting of a straight or branched chain of 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms containing one or more double bonds, preferably an alkenyl group consisting of 2 to 4 carbon atoms.

[0198] "Alkyne" refers to an aliphatic hydrocarbon group consisting of a straight or branched chain of 2 to 6 carbon atoms (e.g., 2, 3, 4, 5, 6) containing one or more triple bonds, preferably an alkyne group consisting of 2 to 4 carbon atoms.

[0199] "Amino acid residue" refers to the part of an amino acid after it loses a molecule of water in the formation of a peptide bond. In other words, it is the part remaining after an amino acid linked by a peptide bond loses water, such as the part of an amino group that is missing a hydrogen atom or a carboxyl group.

[0200] "Cycloalkyl" refers to a cyclic saturated aliphatic hydrocarbon group with 3 to 10 carbon atoms, which can be a monocyclic ring with 3 to 10 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10) or a bicyclic ring with 4 to 10 carbon atoms (e.g., 4, 5, 6, 7, 8, 9, 10), preferably with 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. When the cycloalkyl group is substituted, it may optionally be further substituted by one or more substituents.

[0201] "Heterocyclic alkyl" refers to a saturated heterocycle in which one to four heteroatoms (e.g., one, two, three, or four heteroatoms) selected from N, O, and S are substituted for carbon atoms in the ring skeleton. It can be a 5- to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered) monocyclic or bicyclic ring. The 1 to four (e.g., one, two, three, or four) N and S atoms selectively substituted in the ring of the "heterocyclic alkyl" can be oxidized to various oxidation states; the "heterocyclic alkyl" can be attached to a heteroatom or a carbon atom; the "heterocyclic alkyl" can be a bridged ring or a spirocyclic ring. Non-limiting examples of "heterocyclic alkyl" include epoxide ethyl, epoxide propyl, aziroxide propyl, oxacyclobutyl, aziroxide butyl, thioheroxide, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexacycloyl, aziroxide heptyl, oxacycloheptyl, thioheptyl, oxazaphenyl, diazaphenyl, thioazaphenyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, thiaxyl, 1,3-dithiaalkyl, dithiapentyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiaranyl, tetrahydropyrroleyl, tetrahydroimidazoyl, tetrahydrothiazoyl, tetrahydropyranyl, 2-pyrroleyl The compounds include 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl. The "heterocyclic alkyl" may optionally be further substituted with one or more substituents.

[0202] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a monocyclic or bicyclic ring with 4 to 10 carbons (e.g., 4, 5, 6, 7, 8, 9, or 10 carbons), and can be a bridged or spirocyclic ring. Non-limiting examples include phenyl and naphthyl groups. The aryl group may optionally be further substituted by one or more substituents.

[0203] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 10-membered (e.g., 5, 6, 7, 8, 9, 10-membered) monocyclic or bicyclic ring, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, such as 5- to 8-membered heteroaryls. The 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms selectively substituted in the ring of the heteroaryl can be oxidized to various oxidation states. The heteroaryl can be attached to a heteroatom or a carbon atom, and can be a bridged ring, spirocyclic, or fused ring. Non-limiting examples include cyclopyridyl, furanyl, thiophene, pyranyl, pyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, and pyrrolopyridyl. The heteroaryl can optionally be further substituted by one or more substituents.

[0204] Unless otherwise stated, the term "optionally substituted" means that a hydrogen atom is not substituted, or one or more hydrogen atoms are substituted by one or more groups independently selected from the following groups: alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxyl, O-carboxyl, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, trihalosulfonyl.

[0205] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0206] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0207] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0208] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0209] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0210] "Optional" or "optionally" or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group.

[0211] The term "compound" includes all stereoisomers, geometric isomers, and tautomers. A "compound" as used herein can be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, individual enantiomers and diastereomers or other stereoisomeric forms, or mixtures thereof. Compounds containing asymmetric carbon atoms as used herein can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. A "compound" as used herein also includes geometric isomers, which are chiral forms of compounds where the substituents on the double bonds or rings have different cis-trans isomers. A "compound" as used herein also includes tautomers. Tautomers can arise from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton.

[0212] The compounds described herein, whether intermediates or compounds of formula (I), may also be isotopically labeled by replacing one or more atoms therein with atoms having different atomic masses or mass numbers. Such isotopically labeled (i.e., radiolabeled) compounds are considered to be within the scope of this document. Examples of isotopes in the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, each having the same number of protons but different mass numbers.

[0213] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, and transdermal penetration enhancers.

[0214] The term "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products. These are all substances included in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0215] "Pharmaceutically acceptable excipients" refers to inert substances added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants. Attached Figure Description

[0216] Figure 1 is 177 SPECT images after Lu-DOTA-ZOL administration (n=3).

[0217] Figure 2 is 177 SPECT images after Lu-S18 administration (n=3).

[0218] Figure 3 shows the distribution of radioactivity in various tissues 7 days after compound administration (n=3 for each group).

[0219] Figure 4 shows 177 Distribution of Lu-DOTA-ZOL organizations at different time points.

[0220] Figure 5 shows 177 Distribution of Lu-S18 tissues at different time points.

[0221] Figure 6 shows 177Distribution of Lu-S31 tissues at different time points.

[0222] Figure 7 shows 177 Distribution of Lu-S38 tissues at different time points.

[0223] Figure 8 shows the tumor signal on day 34 after administration in a mouse model of breast cancer bone metastasis.

[0224] Figure 9 shows 177 Bone condition of Lu-S18 on day 34 after administration to a mouse model of breast cancer bone metastasis. Example

[0225] The following embodiments are merely illustrative descriptions of this application and are not intended to explain the scope of protection of this application. All reagents used are commercially available.

[0226] Preparation Examples

[0227] Example 1: Synthetic route of compound DOTA-ZOL (positive reference)

[0228] Synthesis of compound S2:

[0229] Weigh histamine dihydrochloride (16.0 g, 86.9 mmol, 1.0 eq.) and K₂CO₃ (36.0 g, 261 mmol, 3.0 eq.) into a round-bottom flask, add 200 mL of water, and add Ac₂O (8.2 mL, 86.9 mmol, 1.0 eq.) dropwise under ice bath conditions. After the addition is complete, bring the mixture to room temperature and allow it to react. After 3 h, monitor the reaction of the starting material by TLC until it is complete. Wash once with CH₂Cl₂, freeze-dry the aqueous phase to obtain a white solid, disperse the white solid in a CH₂Cl₂ / MeOH (5:1) mixed solvent, stir for 30 min, filter to remove insoluble matter, and concentrate the filtrate under reduced pressure to obtain 25.0 g (containing inorganic salts) of white solid compound S1, which can be directly used for the next step.

[0230] The 25.0 g white solid obtained in the previous step and Cs₂CO₃ (56.7 g, 174 mmol, 2.0 eq.) were placed in a round-bottom flask, and 300 mL of DMF was added. Then, a DMF solution of benzyl bromoacetate (27.6 mL, 174 mmol, 2.0 eq.) (100 mL) was added under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and stirred. After 20 h, the reaction mixture was monitored by TLC to ensure complete reaction. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography (CH₂Cl₂:MeOH = 15:1) to finally obtain 11.0 g of compound S₂, with a two-step yield of 42%. 1H NMR (400MHz, CD3OD) δ7.59 (s, 1H), 7.41-7.30 (m, 5H), 6.91 (s, 1H), 5.21 (s, 2H), 4.92 (s, 2H), 3.41 (t, J=7.2Hz, 2H), 2.72 (t, J=7.2Hz, 2H), 1.91 (s, 3H).

[0231] Synthesis of compound S4:

[0232] 10.0 g of compound S2 and 1.0 g of palladium on carbon were weighed into a round-bottom flask, 100 mL of MeOH was added, and the mixture was purged with hydrogen and stirred at room temperature. After 3 h, the reaction was monitored by TLC to ensure the starting material was completely reacted, and the product peak was clearly visible by LC-MS. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 6.24 g of white solid, namely compound S3, with a yield of 89%. 1 H NMR (400MHz, CD3OD) δ 8.63 (s, 1H), 7.27 (s, 1H), 4.74 (s, 2H), 3.45 (t, J = 6.8Hz, 2H), 2.85 (t, J = 6.8Hz, 2H), 1.92 (s, 3H).

[0233] Compound S3 (5.00 g, 23.7 mmol, 1.0 eq.) and H3PO3 (4.28 g, 52.1 mmol, 2.2 eq.) were weighed into a three-necked flask. After purging with nitrogen, 25 mL of sulfolane was added, and the flask was heated and stirred in a 75 °C oil bath. After 30 min, PCl3 (5.4 mL, 61.6 mmol, 2.6 eq.) was added dropwise, and the reaction was continued at this temperature overnight. After 15 h, the reaction solution was cooled to room temperature, 25 mL of water was added, and the temperature was raised to reflux. The reaction was stopped after reflux for 5 h. The pH was adjusted to approximately 2.5 with 30% NaOH aqueous solution, and 60 mL of MeOH was added, resulting in the precipitation of a white solid. The solid was obtained by filtration and dissolved in 35 mL of 30% NaOH. The solution was then heated to 100 °C and refluxed. After 6 hours, the reaction was cooled to room temperature, the pH was adjusted to about 2.5 with hydrochloric acid, 55 mL of MeOH was added, a white solid precipitated, and 3.15 g of solid compound S4 (70% purity) was obtained by filtration.

[0234] Synthesis of compound S5:

[0235] S4 (70% purity, 1.06 g, 2.35 mmol, 1.0 eq.) was weighed into a round-bottom flask, 2.5 mL of water was added, and Et3N was added at room temperature to adjust the pH to approximately 9. After stirring for 5 min, a MeCN solution of DOTA-tri-tert-butyl ester-succinimide ester (1.57 g, 2.35 mmol, 1.0 eq.) (5 mL) was added. After the addition was complete, the mixture was heated to 55 °C in an oil bath for reaction. The reaction was stopped after 15 h, and LC-MS was used to monitor the complete disappearance of the starting material and the distinct peak of the product. The reaction solution was concentrated under reduced pressure to remove some of the MeCN, and then purified by reverse-phase preparative HPLC. After lyophilization, 562 mg of a white solid compound S5 was obtained.

[0236] Synthesis of compound DOTA-ZOL:

[0237] The 562 mg of compound S5 obtained in the previous step was dissolved in 3 mL of TFA and 3 mL of CH2Cl2 and stirred at room temperature for 24 h. After the reaction of the starting material was completed by LC-MS, the mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase preparative liquid chromatography (A: 0.05% TFA in H2O; B: MeCN) to finally obtain 326 mg of compound DOTA-ZOL as a white powder. 1 ¹H NMR (800MHz, D₂O): δ 8.63 (s, 1H), 7.36 (s, 1H), 4.65 (t, J = 9.6Hz, 2H), 4.35–2.77 (m, 28H). LC-MS: Theoretical exact mass: 701.2, measured value: [M+H] + :702.1.

[0238] Example 2 Synthetic route of compound S11

[0239] Synthesis of compound S6:

[0240] Weigh 10.0 g (133 mmol, 1.0 eq.) and 24.0 g (293 mmol, 2.2 eq.) of H3PO3 into a three-necked flask. After purging with nitrogen, add 70 mL of sulfolane and heat in an 80 °C oil bath with stirring. After 30 min, add 30.3 mL (347 mmol, 2.6 eq.) of PCl3 dropwise. Continue the reaction at this temperature overnight. After 17 h, cool the reaction solution to room temperature, add water, and then heat the solution to reflux. Reflux for 3 h and then cool the system to room temperature. Adjust the pH to approximately 3.5 with a 30% NaOH aqueous solution, add 200 mL of MeOH, and filter out a yellow solid. Dissolve the yellow solid in 200 mL of water, add 30% NaOH aqueous solution to adjust the pH to about 11, filter to remove the insoluble solid, adjust the pH of the filtrate to about 3.5 again with 10% HCl aqueous solution, add 200 mL of MeOH, and the solid gradually precipitates out. Filter to obtain 15.0 g of solid compound S6.

[0241] Synthesis of compound S8:

[0242] Commercially available N-tert-butoxycarbonyl-1,4-trans-diaminomethylcyclohexane (1.50 g, 6.19 mmol, 1.0 eq.) was weighed into a round-bottom flask. After purging with nitrogen, 20 mL of dry CH2Cl2 was added to dissolve the compound. DIPEA (1.18 mL, 6.80 mmol, 1.1 eq.) and phenyl chloroformate (0.78 mL, 6.19 mmol, 1.0 eq.) were added sequentially under ice bath conditions. The mixture was stirred under ice bath conditions until the reaction was complete after 1 h, as monitored by LC-MS. The reaction was stopped and brought to room temperature. CH2Cl2 was added to dissolve the compound until clear. The solution was washed twice with 1 M / L potassium hydrogen sulfate aqueous solution. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give 1.81 g (81% yield) of a white solid, crude compound S7.

[0243] Weigh 1.10 g (4.97 mmol, 1.0 eq.) of crude compound S7 into a round-bottom flask, dissolve it in 15 mL of water, adjust the pH to approximately 9 with triethylamine, then add 15 mL of MeCN solution of compound 301-2 (1.80 g, 4.97 mmol, 1.0 eq.). After the addition is complete, heat the mixture to a 50°C oil bath and stir. Monitor the pH of the reaction solution during the reaction, maintaining it at approximately 9. After 6 hours, LC-MS monitoring showed that the starting material reaction was complete and the product peak was obvious. Cool the reaction solution to room temperature, adjust the pH to approximately 10 with 10% NaOH aqueous solution, extract three times with CH2Cl2, and then adjust the pH of the aqueous phase to approximately 3.5 with 1 M / L hydrochloric acid solution. Concentrate the aqueous phase under reduced pressure to obtain crude compound S8, which can be directly used for the next step.

[0244] Synthesis of compound S9:

[0245] 5 mL of TFA and 10 mL of CH2Cl2 were added to the crude compound S8 obtained in the previous step to dissolve it. After stirring at room temperature for 1 h, the reaction was monitored by LC-MS to ensure the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain 938 mg of a pale yellow solid, which is the crude compound S9.

[0246] Synthesis of compound S10:

[0247] S9 (900 mg, 2.31 mmol, 1.0 eq.) was weighed into a round-bottom flask, dissolved in 12 mL of water, and the pH was adjusted to approximately 9 with triethylamine. Then, a MeCN solution (12 mL) of compound DOTA-tri-tert-butyl ester-succinimide (1.70 g, 2.54 mmol, 1.1 eq.) was added. After the addition was complete, the mixture was heated to 60 °C in an oil bath and stirred. The pH of the reaction solution was monitored during the reaction and maintained at approximately 9. After 4 h, LC-MS showed that the reaction of the starting material was complete and the product peak was obvious. The reaction solution was cooled to room temperature, and the pH was adjusted to approximately 4 with 1 M / L hydrochloric acid solution. The mixture was extracted three times with EA. The aqueous phase was purified by preparative HPLC under medium and low pressure (A: 0.05% TFA in H2O; B: MeCN) to obtain 1.40 g of white solid compound S10.

[0248] Synthesis of compound S11:

[0249] 500 mg of compound S10 was weighed into a round-bottom flask, and 4.0 mL of CH2Cl2 and 2.0 mL of TFA were added to dissolve it. The mixture was stirred at room temperature. After 24 h, LC-MS monitoring showed that the reaction of the starting material was complete and the product peak was obvious. The mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase preparative liquid chromatography (A: 0.05% TFA in H2O; B: MeCN) to finally obtain 228 mg of white solid compound S11. 1 ¹H NMR (800MHz, D₂O): δ 4.34–2.83 (m, 30H), 1.79–1.68 (m, 4H), 1.49–1.34 (m, 2H), 0.99–0.85 (m, 4H). LC-MS: Theoretical exact mass: 775.3, measured value: [M+H] + : 776.2.

[0250] Example 3 Synthetic route of compound S18

[0251] Synthesis of compound S13:

[0252] N6-Cbz-L-lysine (20.0 g, 71.3 mmol, 1.0 eq.) and KBr (14.8 g, 124.8 mmol, 1.75 eq.) were weighed into a 500 mL three-necked flask, and 160 mL of 1 M / L hydrobromic acid aqueous solution was added. The mixture was stirred in an ice bath until clear. Then, a 20 mL aqueous solution of NaNO2 (5.90 g, 85.6 mmol, 1.2 eq.) was slowly added dropwise over 1.5 h. After the addition was complete, the mixture was stirred in an ice bath. After 3.5 hours, 10 mL of concentrated sulfuric acid was added to the reaction solution under ice bath conditions. After stirring for 5 minutes, the mixture was brought to room temperature. After another 5 minutes, 100 mL of Et2O was added. After stirring, the mixture was allowed to stand and separate into layers. The Et2O was extracted three times. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (CH2Cl2:MeOH = 50:1 to 20:1) to obtain 15.8 g (64% yield) of product S12, which was a pale yellow oily liquid.

[0253] Compound S12 (15.8 g, 45.9 mmol, 1.0 eq.) was weighed into a 500 mL round-bottom flask. After purging with nitrogen, 130 mL of dry CH2Cl2 was added to dissolve it. A solution of tert-butyltrichloroacetylimide ester (TBTA, 20.1 g, 91.8 mmol, 2.0 eq.) in 28 mL of dry CH2Cl2 was added at room temperature. Then, 0.3 mL of BF3·Et2O solution was added under ice bath conditions, and the mixture was stirred at room temperature. After 3 h, the reaction mixture was monitored by TLC to ensure complete reaction. The reaction solution was poured into 150 mL of 2 M / L NaOH aqueous solution under ice bath conditions. After stirring for 10 min, the mixture was extracted three times with CH2Cl2. The combined organic phases were washed once with water and once with saturated NaCl solution. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 20:1 to 5:1) to obtain 15.0 g (81.6% yield) of product S13. 1 H NMR (400MHz, CDCl3) δ7.39-7.27 (m, 5H), 5.08 (s, 2H), 4.09 (t, J=7.2Hz, 1H), 3.19 (q, J=6.4Hz, 2H), 2.09-1.86 (m, 2H), 1.47 (s, 13H).

[0254] Synthesis of compound S15:

[0255] The following compounds were weighed into a round-bottom flask: tri-tert-butyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate hydrobromide (3.1 g, 5.20 mmol, 1.0 eq.), S13 (2.50 g, 6.24 mmol, 1.2 eq.), and K2CO3 (1.80 g, 13.0 mmol, 2.5 eq.). 26 mL of MeCN was added, and the mixture was heated to 60 °C in an oil bath with stirring. The reaction was stopped after 24 h. After concentrating most of the MeCN under reduced pressure, water and EtOAc were added, and the mixture was co-extracted twice with EtOAc. The organic phases were combined, washed once with water and once with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain 4.8 g of compound S14 (characterization data of the racemic S14 synthesized from the N6-Cbz-lysine racemic compound confirmed that S14 in this example was a racemic compound). The crude product was directly used for the next step.

[0256] The 4.8 g crude compound S14 obtained in the previous step was placed in a round-bottom flask, 480 mg of Pd(OH)2 was weighed in, and then 30 mL of MeOH was added. After purging with hydrogen, the mixture was stirred at room temperature. After 4 h, the reaction was monitored by TLC (CH2Cl2:MeOH = 10:1, R0). f =0.4) After the reactants reacted completely, Pd(OH)2 was filtered off with diatomaceous earth and washed with MeOH. The filtrate was concentrated under reduced pressure to obtain a black oily substance. The oily substance was dissolved in 16 mL of MeCN, and then 5.6 g of mercaptosilica was added. After stirring at room temperature for 2 h, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was pulped with methyl tert-butyl ether to finally obtain 2.80 g of light black solid, namely compound S15, which was directly used for the next step.

[0257] Synthesis of compound S17:

[0258] The S15 obtained in the previous step (1.80 g, 2.57 mmol, 1.0 eq.) was placed in a round-bottom flask, purged with nitrogen, and 15 mL of dry CH2Cl2 was added. After sonication to dissolve, N,N-diisopropylethylamine (0.67 mL, 3.86 mmol, 1.5 eq.) and phenyl chloroformate (0.48 mL, 3.86 mmol, 1.5 eq.) were added sequentially at room temperature. After the addition was complete, the reaction was continued at room temperature. After 2 h, the reaction of the starting material was monitored by TLC until it was complete. 6 mL of 1 M / L potassium hydrogen sulfate aqueous solution was added to the reaction solution, followed by a small amount of water. The mixture was extracted three times with CH2Cl2. The organic phases were combined, concentrated under reduced pressure, and crude S16 was obtained, which was directly used for the next step.

[0259] S4 (70% purity, 1.16 g, 2.57 mmol, 1.0 eq.) was weighed into a round-bottom flask, 12 mL of water was added, and 2.1 mL of Et3N was added at room temperature. After stirring for 5 min, a MeCN solution (12 mL) of the crude S16 obtained in the previous step was added. After the addition was complete, the mixture was heated to 55 °C in an oil bath for reaction. The reaction was stopped after 20 h. LC-MS monitoring showed that the starting material had completely disappeared and the product peak was obvious. The reaction solution was filtered to remove insoluble matter with filter paper. The filtrate was concentrated under reduced pressure to remove some MeCN and then purified by reverse-phase preparative liquid chromatography (A: 0.05% TFA in H2O; B: MeCN) to finally obtain 1.6 g of compound S17 as a white solid.

[0260] Synthesis of compound S18:

[0261] 0.9 g of compound S17 was weighed into a round-bottom flask, and 4.5 mL of CH2Cl2 and 4.5 mL of TFA were added. The flask was then placed in an oil bath at 40 °C and stirred. After 24 h, LC-MS monitoring showed that the reaction of the starting material was complete and the product peak was obvious. The mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase preparative liquid chromatography (A: 0.05% TFA in H2O; B: MeCN) to finally obtain 480 mg of compound S18, which was a white solid. 1 ¹H NMR (600MHz, D₂O): δ 8.63 (s, 1H), 7.31 (s, 1H), 4.70–4.58 (m, 2H), 4.30–2.81 (m, 29H), 1.91–1.37 (m, 6H). LC-MS: Theoretical exact mass: 816.3, measured value: [M+H] + :817.3.

[0262] Example 4 Synthetic route of compound S25

[0263] Synthesis of compound S19:

[0264] Cyclopropylamine (5.00 g, 87.6 mmol, 1.0 eq.) was weighed into a round-bottom flask, and tert-butyl acrylate (25.6 mL, 175 mmol, 2.0 eq.) was added. The mixture was then stirred at room temperature. After 4 h, the reaction was monitored by TLC until complete. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (CH2Cl2:MeOH = 50:1 to 10:1) to give 8.0 g (49% yield) of a colorless oily compound S19. 1H NMR (400MHz, CDCl3) δ2.88 (t, J=6.4Hz, 2H), 2.39 (t, J=6.4Hz, 2H), 2.09 (tt, J=6.4, 3.2Hz, 1H), 1.41 (s, 9H), 0.42-0.36 (m, 2H), 0.31-0.26 (m, 2H).

[0265] Synthesis of compound S20:

[0266] 9.01 g (39.3 mmol, 1.0 eq.) of trans-(4-hydroxymethyl)cyclohexylcarbamate tert-butyl ester was weighed into a three-necked flask. After purging with nitrogen, 120 mL of dry CH2Cl2 was added to dissolve the ester. Then, under ice bath conditions, Et3N (13.6 mL, 98.2 mmol, 2.5 eq.) and MsCl (3.65 mL, 47.1 mmol, 1.2 eq.) were added sequentially. After stirring for 5 min, the mixture was brought to room temperature. After 4 h, the reaction was monitored by TLC until complete. The reaction was quenched with water, and the mixture was extracted three times with CH2Cl2. The combined organic phases were washed once with water and once with saturated NaCl aqueous solution, then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 10.0 g of white solid, compound S20, with a yield of 83%.

[0267] Synthesis of compound S21:

[0268] Compounds S19 (6.00 g, 32.4 mmol, 1.0 eq.), S20 (9.96 g, 32.4 mmol, 1.0 eq.), and NaI (243 mg, 1.62 mmol, 0.05 eq.) were weighed into round-bottom flasks. After purging with nitrogen, 70 mL of dry DMF was added, followed by Et3N (5.40 mL, 38.9 mmol, 1.2 eq.). The reaction flasks were then placed in an oil bath at 80 °C and stirred. After overnight reaction, the reaction mixture was monitored by TLC until the reactants were completely reacted. The insoluble matter was filtered off, and then water and EtOAc were added. The mixture was extracted three times with EtOAc. The organic phases were combined and washed once with water and once with saturated NaCl aqueous solution. The mixture was then dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 7.0 g of a yellow oily substance, namely S21 (54% yield).

[0269] Synthesis of compound S23:

[0270] The 7.0 g of compound S21 obtained in the previous step was placed in a round-bottom flask, and 70 mL of ethyl acetate hydrochloride solution (4 M / L) was added. The mixture was then stirred overnight at room temperature. After 16 h, the starting material was monitored by TLC until it disappeared completely. The mixture was then concentrated under reduced pressure, and the crude product was pulped with MeCN to finally obtain 4.0 g of white solid compound S22, which was then directly proceeded to the next step.

[0271] Compound S22 (2.00 g, 8.33 mmol, 1.0 eq.) and H3PO3 (1.50 g, 18.3 mmol, 2.2 eq.) were weighed into a three-necked round-bottom flask. After purging with nitrogen, 14 mL of sulfolane was added. The reaction mixture was transferred to a 75 °C oil bath and stirred. PCl3 (1.89 mL, 21.6 mmol, 2.6 eq.) was slowly added dropwise, and the mixture was stirred overnight at the same temperature. After 17 h, 14 mL of water was added to the reaction mixture, and the temperature was raised to reflux. After stirring under reflux for 4 h, the reaction mixture was cooled to room temperature, and the pH was adjusted to approximately 3 with a 30% NaOH aqueous solution. MeOH was added, and a yellow solid gradually precipitated. The solid was filtered to obtain 1.50 g of a pale yellow solid, namely compound S23. The yield of the two steps was calculated to be 44%.

[0272] Synthesis of compound S24:

[0273] The compound S23 obtained in the previous step (1.50 g, 3.88 mmol, 1.0 eq.) was placed in a round-bottom flask, and 19 mL of water was added. Et3N was added and the pH was adjusted to approximately 9 under stirring at room temperature until the solution became clear. Then, a MeCN solution (19 mL) of compound DOTA-tri-tert-butyl ester-succinimide ester (2.60 g, 3.88 mmol, 1.0 eq.) was added. After the addition was complete, the mixture was heated to 60°C in an oil bath and stirred, with Et3N used to maintain the pH of the reaction solution at approximately 9. After reacting at this temperature for 15 h, LC-MS monitoring showed that the reaction of the starting material was complete and the product peak was distinct. The product was purified by medium-low pressure reversed-phase preparative HPLC (A: 0.05% TFA in H2O; B: MeCN), finally yielding 800 mg of a white solid, namely compound S24.

[0274] Synthesis of compound S25:

[0275] The 800 mg of compound S24 obtained in the previous step was dissolved in 2 mL of TFA and 2 mL of CH2Cl2 and reacted at room temperature. After 12 h, the reaction of the starting material was monitored by LC-MS to be complete. After concentration under reduced pressure, the mixture was purified by high pressure reversed-phase preparative liquid chromatography (A: 0.05% TFA in H2O; B: MeCN) to finally obtain 150 mg of compound S25 as a white solid. 1¹H NMR (800MHz, D₂O): δ 4.30–2.96 (m, 29H), 2.81–2.76 (m, 1H), 2.50–2.40 (m, 2H), 2.03–1.92 (m, 3H), 1.91–1.83 (m, 2H), 1.36–1.25 (m, 2H), 1.24–1.11 (m, 3H), 1.08–0.92 (m, 3H). LC-MS: Theoretical exact mass: 772.3, measured value: [M+H] + : 773.3.

[0276] Synthetic route of compound S31 in Example 5

[0277] Synthesis of compound S26:

[0278] Weigh 10.2 g (49.7 mmol, 1.0 eq.) of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthylidine hydrochloride and 17.2 g (124 mmol, 2.5 eq.) of K₂CO₃ into a 500 mL three-necked round-bottom flask. Add 200 mL of MeCN and, with stirring at room temperature, add 12.0 mL (64.6 mmol, 1.3 eq.) of N-Boc-3-aminopropyl bromide. After the addition is complete, heat the flask to 50 °C and stir overnight in an oil bath. After 16 h, monitor the reaction of the starting material by TLC until it is complete. Stop the reaction, filter the reaction solution, concentrate the filtrate under reduced pressure, and then add EA and H₂O. Extract the solution three times with EA. Combine the organic phases, wash once with water and once with saturated NaCl solution, dry the solution with anhydrous Na₂SO₄, filter and concentrate the solution. The resulting crude oily product is slurried with methyl tert-butyl ether and filtered to give 9.18 g of white solid, namely compound S26 (57% yield). Synthesis of compound S27:

[0279] Compound S26 (8.02 g, 24.6 mmol, 1.0 eq.), Cs₂CO₃ (16.0 g, 49.2 mmol, 2.0 eq.), Pd₂(dba)₃ (1.13 g, 1.23 mmol, 0.05 eq.), and XantPhos (1.42 g, 2.46 mmol, 0.1 eq.) were weighed into a three-necked flask. After purging with nitrogen, 160 mL of PhMe was added, followed by diethyl malonate (14.9 mL, 98.4 mmol, 4.0 eq.). The mixture was then heated to 100 °C in an oil bath and stirred. After 3 h, the reaction mixture was monitored by TLC to ensure complete reaction. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. CH₂Cl₂ and water were added, and the layers were extracted. The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 8.07 g of the target product S27 (73% yield).

[0280] Synthesis of compound S28:

[0281] 8.00 g of compound S27 was placed in a round-bottom flask, and 36 mL of concentrated hydrochloric acid was added. The flask was then placed in an oil bath at 100 °C and stirred. After 3 h of reaction, LC-MS monitoring showed that the starting material had reacted completely, and the product peak was obvious. The reaction solution was concentrated under reduced pressure and then purified by medium-low pressure reverse-phase preparative HPLC to obtain 4.17 g of a pale yellow viscous solid. This solid was pulped by EA and filtered to obtain 3.90 g of solid compound S28.

[0282] Synthesis of compound S29:

[0283] Compound S28 (2.1 g, 8.42 mmol, 1.0 eq.) and H3PO3 (1.52 g, 18.5 mmol, 2.2 eq.) were weighed into a three-necked flask. After purging with nitrogen, 20 mL of sulfolane was added, and the mixture was transferred to a 75 °C oil bath and stirred. After 30 min, PCl3 (1.9 mL, 21.9 mmol, 2.6 eq.) was added dropwise, and the reaction continued at the same temperature. After 15 h, the reaction was cooled to room temperature, 20 mL of water was added, and the mixture was heated to reflux. After reflux for 3 h, the reaction mixture was monitored by LC-MS to ensure the starting material was completely reacted. The reaction solution was cooled to room temperature, and the pH was adjusted to approximately 3 with 30% NaOH aqueous solution in an ice bath. A small amount of solid precipitated. The solution was filtered, and 40 mL of MeOH was added to the filtrate. A pale yellow solid precipitated. The filtrate was filtered to obtain a white solid compound S29, which was dried and weighed to 2.12 g.

[0284] Synthesis of compound S30:

[0285] Compound S29 (1.00 g, 2.53 mmol, 1.0 eq.) was weighed into a round-bottom flask, 10 mL of water was added, and Et3N was added with stirring at room temperature to adjust the pH to approximately 9. Then, a MeCN solution of DOTA-tri-tert-butyl ester-succinimide ester (1.69 g, 2.53 mmol, 1.0 eq.) (10 mL) was added. After the addition was complete, the mixture was heated to 60 °C and stirred overnight in an oil bath. After 16 h, LC-MS monitoring showed that the reaction of the starting material was complete and the product peak was obvious. After cooling the reaction to room temperature, the mixture was purified by reverse-phase preparative liquid chromatography (A: 0.05% TFA in H2O; B: MeCN) to obtain 600 mg of white solid compound S30.

[0286] Synthesis of compound S31:

[0287] The 600 mg of compound S30 obtained in the previous step was dissolved in 6 mL of TFA and 6 mL of CH2Cl2 and reacted at room temperature. After 20 h, the reaction of the starting material was monitored by LC-MS to ensure complete reaction. After concentration under reduced pressure, the mixture was purified by high pressure reversed-phase preparative liquid chromatography (A: 0.05% TFA in H2O; B: MeCN) to finally obtain 220 mg of white solid compound S31. 1 ¹H NMR (800MHz, D₂O): δ 8.26 (d, J = 8.0Hz, 1H), 7.90 (d, J = 8.0Hz, 1H), 4.64–2.81 (m, 36H), 2.19–2.03 (m, 2H). LC-MS: Theoretical accurate mass: 781.3, measured value: [M+H] + : 782.3.

[0288] Synthetic route of compound S38 in Example 6

[0289] Synthesis of compound S32:

[0290] Weigh 10.0 g (50.5 mmol, 1.0 eq.) of 6-bromo-3H-imidazo[4,5-B]pyridine and 8.38 g (60.6 mmol, 1.2 eq.) of K₂CO₃ into a round-bottom flask. Add 100 mL of MeCN and 7.36 mL (50.5 mmol, 1.0 eq.) of tert-butyl bromoacetate sequentially. After addition, stir at room temperature. After 16 h, monitor the reaction of the starting materials by TLC until complete. Filter off the insoluble matter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 4:1 to 1:1.5) to obtain 8.8 g of compound S32 as a yellow solid.

[0291] Synthesis of compound S33:

[0292] Compound S32 (8.10 g, 25.9 mmol, 1.0 eq.), N-tert-butoxycarbonyl-1,4-trans-diaminomethylcyclohexane (9.87 g, 40.7 mmol, 1.57 eq.), Cs2CO3 (12.7 g, 38.9 mmol, 1.5 eq.), Pd2(dba)3 (2.37 g, 2.59 mmol, 0.1 eq.), and BrettPhos (1.39 g, 2.59 mmol, 0.1 eq.) were weighed into a round-bottom flask. After purging with nitrogen, 104 mL of dry 1,4-dioxane was added. The reaction mixture was then stirred in an oil bath at 100 °C. After 3 h, the reaction mixture was stopped, cooled, filtered, and the filtrate was concentrated under reduced pressure. Water and CH2Cl2 were added, and the mixture was extracted four times with CH2Cl2. The organic phases were combined, washed once with water and once with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated, and then purified by silica gel column chromatography (CH2Cl2:MeOH = 100:1 to 20:1) to finally obtain 2.90 g of compound S33.

[0293] Synthesis of compound S34:

[0294] Compound S33 (2.90 g, 6.12 mmol, 1.0 eq.) and paraformaldehyde (736 mg, 24.5 mmol, 4.0 eq.) were weighed into a round-bottom flask. 30 mL of MeOH was added, followed by the sequential addition of TFA (45 μL, 0.612 mmol, 0.1 eq.) and NaBH3CN (1.54 g, 24.5 mmol, 4.0 eq.) under stirring at room temperature. The reaction was continued at room temperature until the starting material was completely dissolved, as monitored by TLC. The reaction was quenched by adding saturated NH4Cl solution, and then the MeOH was concentrated under reduced pressure. The mixture was then extracted three times with CH2Cl2. The organic phases were combined, washed once with water and once with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (CH2Cl2:MeOH = 70:1 to 40:1), yielding 2.75 g (92% yield) of a pale yellow, foamy solid, which was compound S34. 1¹H NMR (400MHz, DMSO-d⁶) δ 8.22 (s, 1H), 7.94 (d, J = 2.4Hz, 1H), 7.30 (d, J = 2.4Hz, 1H), 6.77 (t, J = 6.0Hz, 1H), 4.97 (s, 2H), 3.18 (d, J = 6.8Hz, 2H), 2.93 (s, 3H), 2.73 (t, J = 6.4Hz, 2H), 1.74–1.61 (m, 5H), 1.41 (s, 9H), 1.36 (s, 9H), 1.32–1.22 (m, 1H), 1.00–0.73 (m, 4H). Synthesis of compound S35:

[0295] 2.70 g of compound S34 was dissolved in 9 mL of TFA and 9 mL of CH2Cl2. After stirring at room temperature for 36 h, the reaction was monitored by TLC until the starting material was completely reacted, and the product peak was clearly observed by LC-MS. The reaction solution was concentrated under reduced pressure, slurried with EA, and filtered to obtain 1.75 g of white solid compound S35.

[0296] Synthesis of compound S36:

[0297] Compound S35 (1.75 g, 5.28 mmol, 1.0 eq.) and H3PO3 (952 mg, 11.6 mmol, 2.2 eq.) were weighed into a three-necked flask. After purging with nitrogen, 20 mL of sulfolane was added, and the reaction mixture was transferred to a 75 °C oil bath and stirred. After heating for 30 min, PCl3 (1.20 mL, 13.7 mmol, 2.6 eq.) was added dropwise, and the reaction continued at the same temperature. After 15 h, the reaction mixture was cooled to room temperature, 20 mL of water was added, and the mixture was heated to reflux. After reflux for 5 h, stirring was stopped, and the mixture was cooled to room temperature. The pH was adjusted to approximately 3 with a 30% NaOH aqueous solution, and 40 mL of MeOH was added. A large amount of white solid precipitated out. After filtration, the solid was slurried with a MeOH / H2O (3:1) mixed solvent and filtered again to obtain 900 mg of white solid, which is compound S36.

[0298] Synthesis of compound S37:

[0299] Compound S36 (600 mg, 1.26 mmol, 1.0 eq.) was weighed into a round-bottom flask, 6 mL of water was added, and the pH was adjusted to approximately 9 with Et3N. Then, a MeCN solution (6 mL) of compound DOTA-tri-tert-butyl ester-succinimide ester (842 mg, 1.26 mmol, 1.0 eq.) was added. The reaction solution was transferred to a 50°C oil bath and stirred overnight, maintaining the pH at approximately 9. After 16 h, the reaction was stopped, and the mixture was purified by reverse-phase preparative liquid chromatography to obtain 480 mg of a pale yellow solid, namely compound S37 (37% yield).

[0300] Synthesis of compound S38:

[0301] The 480 mg of compound S37 obtained in the previous step was dissolved in 4 mL of TFA and 4 mL of CH2Cl2 and stirred overnight at room temperature. After 16 h, the reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse-phase preparative liquid chromatography to finally obtain 218 mg of compound S38 as a pale yellow solid. 1 ¹H NMR (800MHz, D₂O) δ 9.29 (s, 1H), 8.57 (s, 1H), 8.03 (s, 1H), 5.10–4.99 (m, 2H), 4.26–2.84 (m, 31H), 1.76–1.65 (m, 4H), 1.58–1.40 (m, 2H), 1.05 (q, J = 12.8 Hz, 2H), 0.82 (q, J = 12.8 Hz, 2H). LC-MS: Theoretical exact value (Exact Mass): 863.3, Measured value: [M+H] + :864.3.

[0302] Synthetic route of compound S41 in Example 7

[0303] The specific synthesis method for compound S41 can be referred to that for compound S11. LC-MS: Theoretical exact mass: 693.2, measured value: [M+H] + :694.3.

[0304] Synthetic route of compound S45 in Example 8

[0305] The detailed synthesis method of compound S45 is the same as that of compound S38 in Example 6. LC-MS: Theoretical exact mass: 781.2, measured value: [M+H] + : 782.3.

[0306] Synthetic routes of compounds S46, S47, and S48 in Example 9

[0307] The detailed synthetic procedures for compounds S46, S47, and S48 can be found in the synthetic method for compound S11 in Example 2. N-tert-butyloxycarbonyl-1,2-ethylenediamine and S4 are linked via urea, guanidinium, and thiourea functional groups, respectively, and then reacted with the chelating agent DOTA-tri-tert-butyl ester-succinimide ester. Finally, tert-butyl ester is hydrolyzed to obtain S46 (LC-MS: Theoretical Exact Mass: 787.3, Test Value: [M+H]). + S47 (LC-MS: Theoretical Exact Mass: 786.3, Tested Mass: [M+H]) + S48 (LC-MS: Theoretical Exact Mass: 803.2, Tested Mass: [M+H]) + :803.3).

[0308] Synthetic routes of compounds S49 and S50 in Example 10

[0309] The synthesis of compounds S49 and S50 is shown in the figure above. The chelating agent active ester (DOTA-tert-butyl ester-succinimide ester) reacts with tranexamic acid and 4-(aminomethyl)benzoic acid, respectively, to form amide bonds. Then, the terminal carboxylic acid is reacted under HBTU / Et3N / PFP conditions to generate a pentafluorophenol active ester. This active ester reacts directly with S4, and finally, the tert-butyl ester on the chelating agent is hydrolyzed to obtain S49. (LC-MS: Theoretical Exact Mass: 840.3, Test Value: [M+H]) + S50 (LC-MS: Theoretical Exact Mass: 834.3, Tested Mass: [M+H]) and S50 (LC-MS: Theoretical Exact Mass: 841.3) and S50 (LC-MS: Theoretical Exact Mass: 834.3, Tested Mass: [M+H]) + :834.2).

[0310] Synthetic routes of compounds S51, S52, and S53 in Example 11

[0311] The synthesis methods for compounds S51, S52, and S53 can be the same as those for S18. Intermediate S16 is first reacted with diethyl squaric acid, protecting phenylalanine, and glutamic acid, respectively, and then linked to S4. After removing the protecting group, S51 is obtained (LC-MS: Theoretical Exact Mass: 868.3, Test Value: [M+H]). + S52 (LC-MS: Theoretical Exact Mass: 963.4, Tested Mass: [M+H]) +S53 (LC-MS: Theoretical Exact Mass: 964.3, Tested Mass: [M+H]) + :946.3).

[0312] Active Examples

[0313] 1. In vitro activity test

[0314] 1.1 177 Lu radiolabeling method

[0315] Pipette 1 nmol of the ultrapure aqueous solution of the labeled precursor (1 mg / mL) into 95 μL of 0.25 M sodium acetate buffer (pH = 5.0), then add approximately 1.3 mCi. 177 LuCl3 solution was heated in a constant temperature metal bath at 95℃ for 30 min. The radiochemical purity of the sample was monitored by radio-TLC and radio-HPLC and was >92%.

[0316] 1.2 Study on the bonding of hydroxyapatite

[0317] Weigh the required amount of hydroxyapatite powder into a suitable container, add physiological saline to the required volume, and mix by vortexing to obtain a hydroxyapatite suspension of 1.5 mg / mL.

[0318] Weigh the required amount of the labeled precursor, prepare the mother liquor, and take an appropriate amount of the mother liquor and each 177 Lu-labeled solution was placed in a suitable container, and physiological saline was added sequentially to the desired volume. After mixing thoroughly, the desired concentrations of different substances were obtained. 177 Lu-labeled solutions (0.026 nmol / mL, 0.255 nmol / mL, 2.55 nmol / mL, 25.5 nmol / mL, 100.5 nmol / mL, 250.5 nmol / mL, based on the labeled precursor). After preparation, a gamma counter is needed to detect the different concentrations of the substances. 177 The actual radioactivity concentration of the Lu-labeled solution.

[0319] Take six 1.5 mL release tubes and add 0.2 mL of hydroxyapatite suspension (1.5 mg / mL) to each. Incubate at 37 °C with shaking for 24 h. Then add 0.2 mL of the above-mentioned different concentrations of the substance. 177 The Lu-labeled solution was incubated with shaking at 37°C for 0.5 h. After incubation, the sample was centrifuged at 4500 rpm for 10 min. The supernatant was separated and collected, and the precipitate was washed twice with physiological saline, and the eluent was collected. The radioactivity content in the supernatant, eluent, and precipitate was detected using a gamma counter. [Further details needed for accurate translation.] 177The degree of in vitro binding between Lu-labeled substances and hydroxyapatite. Each sample was incubated in triplicate.

[0320] Formula for calculating binding rate:

[0321] Binding rate (%) = Radioactivity of precipitated sample / (Radioactivity of supernatant + Radioactivity of eluent + Radioactivity of precipitated sample) × 100.

[0322] The half-maximal effect concentration (EC50) was calculated using SofiMax Pro7 Gxp software. 50 (and 95% confidence interval).

[0323] Table A. In vitro binding results of 177Lu-labeled compounds with hydroxyapatite

[0324] Add 0.017–167 nmol of [amount] per milligram of hydroxyapatite. 177 Lu-markers (based on marker precursors), 177 The binding rates of Lu-labeled compounds to hydroxyapatite ranged from 5% to 95%, indicating that these compounds bind to hydroxyapatite in vitro. Most of the molecules showed similarities to the positive reference compound. 177 Lu-DOTA-ZOL (EC50 = 14.26 nmol / mg) has a considerable binding affinity (e.g., 177 Lu-S41(EC 50 =10.23 nmol / mg), 177 Lu-S11(EC 50 =11.12 nmol / mg), 177 Lu-S45 (EC) 50 =14.23 nmol / mg), 177 Lu-S38 (EC50=13.30nmol / mg), 177 Lu-S18(EC 50 =13.23 nmol / mg), 177 Lu-S53 (EC50=12.03nmol / mg).

[0325] 2. In vivo experiments in mice

[0326] Main instruments

[0327] Table 1. Main Instrument Systems

[0328] Preparation of radioactive markers:

[0329] Pipettes of 30 nmol aqueous solutions of S11, S18, S25, S31, S38, and DOTA-ZOL (1 mg / mL) were respectively added to 0.25 M sodium ascorbate buffer (pH = 5.02, 145 μL), and 3.5 μL of each was added. 177 LuCl3 solution (approximately 2 mCi) was prepared, with pH ranging from 4.5 to 5.0. The sample was heated in a 95°C metal bath for 30 min. Radiochemical purity was monitored by radio-TLC and radio-HPLC, and the result was >99%.

[0330] 2.1 microSPECT / CT imaging

[0331] 2.1.1 SPECT Imaging Study

[0332] Twelve healthy Kunming mice (6-8 weeks old, male, 37-46g) were randomly divided into four groups of three. Approximately 500 μCi of a pre-labeled solution diluted with physiological saline was injected via the tail vein. Specific groupings are shown in the table below. Each animal was anesthetized with 2% isoflurane-oxygen at the corresponding imaging time points after drug administration, and InliView-3000B small animal PET / CT imaging was performed. Signals were acquired at 1h, 24h, 72h, and 168h post-administration; CT scans were used to confirm tissue and organ involvement.

[0333] Table 2. Grouping Information

[0334] The results showed that clear imaging of bone and joints was visible 1 hour after administration, and significant radioactive enrichment was observed in the bladder. This indicates that the compound in this application and the positive control were cleared more quickly in soft tissues, had higher uptake in bones, and had the same metabolic pathway, mainly excreted through the kidneys in urine. Clear imaging of bone and joints was still visible 168 hours later, indicating that the compound in this application had a long retention time in bone. The imaging results are shown in Figures 1-2.

[0335] 2.2 Tissue distribution 7 days after drug administration

[0336] After 7 days of SPECT / CT imaging, the above-mentioned animals underwent enucleation and bloodletting (blood samples were retained). Heart, liver, spleen, kidneys, lungs, stomach (emptied contents), intestines (emptied contents), pancreas, femur, muscles, thymus, and remaining cadaver samples were harvested. After weighing, the radioactivity count was determined using a gamma counter. After time decay correction, the percentage injection dose rate per gram of tissue (%ID / g) was calculated. The results are shown in the table below.

[0337] Data Processing and Analysis: %ID / g = A tissue / [(A0-A residue )*M tissue ]×100%

[0338] A0: Total radioactivity count (CPM) of the syringe before drug administration.

[0339] A residue Post-administration syringe residual radioactivity count (CPM)

[0340] A tissue Organ radioactivity count (CPM)

[0341] M tissue : Detect the weight (g) of the tissue sample.

[0342] Physical attenuation correction:

[0343] 177 Lu physical decay: Activity dose at time T = 0.5^(T / 160.08)

[0344] Table 3. Biodistribution data of each compound in mice 7 days after administration.

[0345] Conclusion: Seven days after administration, experimental animals were sacrificed and dissected to analyze the distribution of the compound in tissues. The compound of this application showed the lowest radioactive uptake in the blood and the highest radioactive uptake in the femur. 177 Lu-S11, 177 Lu-S18 radioactive uptake in the femur is higher than that in the femur. 177 Lu-DOTA-ZOL (see Figure 3 for details).

[0346] 2.3 Tissue distribution at different time points after drug administration

[0347] Experimental Procedure: Forty-eight healthy Kunming mice (6-8 weeks old, male, 37-42g) were randomly divided into 16 groups of 3 mice each. Approximately 80 μCi of a labeled solution diluted with physiological saline was injected via the tail vein. Specific groupings are shown in the table below. Following administration, at different time points (0.5h, 2h, 24h, 168h), the mice were anesthetized, enucleated, and blood samples were collected. The heart, liver, spleen, lungs, kidneys, stomach (with contents removed), intestines (including large and small intestines), pancreas, femur (hind limb), muscles, brain, salivary glands, testes, prostate, vertebrae, and remaining carcass were harvested. After weighing, the radioactivity count was measured using a gamma counter. After time decay correction, the percentage dose rate per gram of tissue (%ID / g) was calculated.

[0348] Table 4. Summary of Trial Groups and Dosages

[0349] Data Processing and Analysis: CPM / g = Atissue / Mtissue × 100% %ID / g = Atissue / [(A0 - Aresidue) * Mtissue] × 100%

[0350] A0: Total radioactivity count (CPM) of the syringe before drug administration.

[0351] Aresidue: Residual radioactivity count in the syringe after drug administration (CPM)

[0352] Atissue: Organ Radioactivity Count (CPM)

[0353] Mtissue: Detects tissue sample weight (g)

[0354] 177 Lu physical attenuation correction: Activity dose attenuation coefficient at time T = 0.5^(T / 160.8).

[0355] Multiply the administered dose (A0-Aresidue) by the decay factor over the corresponding time to obtain the corrected CPM value, and calculate %ID / g.

[0356] Establish lutetium [ 177 The calibration curve of the activity meter detection value (μCi) and the gamma counter detection value (CPM) is used for the conversion of activity and CPM values ​​(Lu[177Lu] activity meter (μCi) and gamma counter (CPM).

[0357] %ID / g was calculated for the main exposed tissues and blood at each time point, expressed as mean ± standard deviation.

[0358] Distribution results:

[0359] Table 5. 177 Lu-DOTA-ZOL Organizational Distribution Data at Different Time Points

[0360] Table 6. 177 Lu-S18 tissue distribution data at different time points

[0361] Table 7. 177 Lu-S31 tissue distribution data at different time points

[0362] Table 8. 177 Lu-S38 tissue distribution data at different time points

[0363] Conclusion: The compounds in this application are absorbed in very low amounts in normal tissues, but the uptake rate in bone is relatively high, and the uptake in the femur is even higher than that in the positive control, for example... 177 Lu-S18 177 Lu-S38. Seven days after administration, bone uptake remained high, significantly higher than in other organs and tissues. This indicates that the compound in this application has strong targeting and a long residence time in bone. Distribution diagrams for each tissue are shown in Figures 4-7.

[0364] 0.5 hours after administration, 177 Lu-DOTA-ZOL 177 Lu-S18 177 Lu-S31, 177 The bone / organ ratio of Lu-S38 in mice is shown in Table 9.

[0365] Table 9

[0366] Conclusion: The compounds in this application exhibit high bone / organ ratios for different organs, indicating that they have good bone targeting properties and low toxicity to normal organs and tissues.

[0367] 3. Biodistribution and efficacy of drugs in mouse models of breast cancer bone metastasis

[0368] 3.1 Model Mouse Establishment

[0369] When human breast cancer cells MDA-MB-231-Luc reached a confluence of over 80%, cells were collected for seeding at a seeding density of 1×10⁶ cells / year. 6 Tumor cells per animal. Several healthy 5-6 week old BALB / c nude female mice were selected and acclimatized for one week beforehand. The mice were anesthetized, and the left knee joint was disinfected with povidone-iodine. A hole was made in the distal femur, and tumor cells were injected using a microsyringe. The injection volume was 10 μL per animal. After injection, the hole was sealed with bone wax, sutured, and disinfected. The PerkinElmer small animal in vivo optical imaging system was used to measure the tumor fluorescence signal intensity using bioluminescence imaging technology to assess tumor growth. The signal intensity unit was p / s / cm² / sr.

[0370] 3.2 Biodistribution of tissues in a mouse model of breast cancer bone metastasis

[0371] 3.2.1 Experimental Methods

[0372] The animals were randomly assigned to five groups (groups 1-5) based on their body weight using a randomized controlled trial. The 30 selected BALB / c Nude mice with MDA-MB-231-luc tumor models were divided into these groups. The difference in body weight between groups was limited to ±20% of the mean body weight for the same sex. After grouping, there was no statistically significant difference in mean body weight among the groups at the 5.0% significance level. The dosage design for this experiment is shown in Table 10.

[0373] Table 10. Biodistribution of Model Mice and Dosing Regimens

[0374] 177 Lu-S18 labeled solution was diluted with physiological saline, and the corresponding activity was injected via tail vein. Animals were sacrificed at 0.5h, 2h, 24h, 120h, and 240h after administration. Whole blood, plasma, urine, brain, eyeballs, salivary glands, thyroid gland, heart, lungs, liver, stomach, small intestine, large intestine, spleen, pancreas, adrenal glands, kidneys, bladder, urethra, ovaries, uterus, femur (tumor-inoculated side), femur (contralateral side), knee joint (tumor-inoculated side), knee joint (contralateral side), tibia (tumor-inoculated side), tibia (contralateral side), bone marrow, muscle, fat, and tumor were collected. Tissue samples were weighed and their radioactivity was measured. For both the femur (tumor-inoculated side) and femur (contralateral side), the bone marrow was removed by centrifugation, and the samples were weighed before radioactivity measurement. Each sample was measured once using a gamma counter for 30 seconds, and all data were attenuated to the attenuation-corrected time point.

[0375] 3.2.2 Conclusion

[0376] For the MDA-MB-231-luc tumor model in female BALB / c Nude mice, a single intravenous injection of 20 mCi / kg was administered. 177 After Lu-S18, the radioactive material is mainly concentrated in bone tissues such as the knee joint, femur and tibia, and its elimination is slow, while the radioactivity distribution in other organs is relatively low.

[0377] Table 11. Biodistribution data of model mouse tissues at different time points

[0378] Note: NC: Samples with fewer than 3 samples were not included in the statistics. Radioactive material content in non-body fluid tissues is expressed as %ID / g, and radioactive material content in body fluids is expressed as %ID / mL.

[0379] This demonstrates that the compounds of this invention can rapidly target bone tissue in vivo, exhibiting high uptake and slow elimination. They also show low uptake and rapid clearance from blood and non-target organs, indicating good safety.

[0380] 3.3 Drug efficacy in a mouse model of breast cancer bone metastasis

[0381] 3.3.1 Tumor-suppressing effect

[0382] The experiment consisted of three groups. Mice were weighed and in vivo images were performed before grouping. Groups were formed based on animal weight and tumor fluorescence signal intensity. The groups were: a model control group (saline), a control group (model control group), and a control group (model control group). 177 Lu-DOTA-ZOL injection at a dose of 1 mCi / vial 177 In the Lu-S18 1mCi / animal dose group, the administration route was a single intravenous injection. The results showed that the tumor signal intensity in the control group continued to increase, and by day 34 after administration, the average tumor signal intensity in the group was 4.26E+06p / s / cm2 / sr. 177 On day 34 after administration of Lu-DOTA-ZOL, the mean intensity of tumor signal in the animals was 3.20E+05p / s / cm2 / sr; 177 The mean tumor signal intensity in the Lu-S18-treated group was 4.95E+04 p / s / cm² / sr on day 34. Compared with the control group, 177 Lu-DOTA-ZOL and 177 Lu-S18 significantly inhibited tumor cell growth and proliferation, and 177 The average tumor signal intensity after Lu-S18 administration was significantly lower than that of the positive control compound, indicating that the anti-cancer effect of the compound in this application is significantly superior to that of the positive control compound. 177 Lu-DOTA-ZOL (see Figure 8 for details). Furthermore, the compound... 177 The tumor-bearing mice tolerated Lu-S18 well during the observation period after administration, indicating that the compound of this application has good drug safety.

[0383] 3.3.2 Bone protection effect

[0384] Six mice were used to establish a breast cancer bone metastasis model using the experimental methods described in section 3.1. They were divided into a model control group and a drug administration group (single intravenous injection). 177 Lu-S180.2 mCi / mouse, 3 mice / group. After administration, femoral bone from the tumor side was harvested for micro-CT scanning. At the end of the experiment, micro-CT scans showed severe femoral bone damage on the inoculated side in the model control mice, mainly manifested as perforation, defects, and fractures. These injuries were caused by the erosive effect of tumor cell growth on the inoculated femur. Administration 177 Following Lu-S18 treatment, bone damage to the femur on the injection side was significantly reduced, with no severe defects or fractures observed, indicating that the compound... 177 Lu-S18 inhibited tumor cell growth and reduced the erosion of the femur on the inoculated side. Compared with the control group, it significantly reduced femoral bone damage on the inoculated side (see Figure 9), indicating a significant inhibitory effect on breast cancer bone metastasis.

Claims

1. A compound of formula I-2 or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate. in LK1 is a C1-C6 alkyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl group, or... LK2 is Triazolyl or R4 is selected from H, OH, amino, or halogen; n3 can be 1, 2, 3, 4, or 5.

2. The compound of claim 1 or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, wherein LK1 is methyl, ethyl, propyl, 3. The compound of claim 1 or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, wherein LK1 is The * end is connected to the side containing the right end of Equation I-2.

4. The compound of claim 1 or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, wherein LK1 is More specifically for More specifically 5. The compound of claim 1 or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, wherein LK1 is More specifically for 6. The compound of claim 1 or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, wherein LK1 is pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, triazinyl, tetraazinyl, quinolinyl, or indoleyl, more specifically... More specifically for 7. The compound of claim 1 or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, wherein LK1 is a 5-membered heteroaryl group; specifically, the 5-membered heteroaryl group has one or two N heteroatoms; more specifically, the 5-membered heteroaryl group is...

8. The compound of claim 1 or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, wherein LK2 is 9. The compound of claim 1 or its pharmaceutically acceptable salt, crystal, eutectic, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, wherein n3 is 1.

10. The compound of claim 1 or its pharmaceutically acceptable salt, crystal, eutectic, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, wherein R4 is OH.

11. A compound or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, wherein the compound is 12. A radiolabeled compound comprising a complex formed by coordination of a compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt, crystal, eutectic, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate with a radionuclide.

13. The radiolabeled material as claimed in claim 12, wherein, The radionuclides are selected from 18 F-Al, 90 Y、 153 Sm、 166 Ho、 186 Re、 188 Re、 46 Sc、 177 Lu、 89 Sr、 223 Ra、 225 Ac、 67 Ga、 68 Ga、 99m Tc, 111 In、 159 Gd, 149 Tb, 161 Tb, 212 Pb, 43 Sc、 47 Sc、 67 Cu and 64 Cu; specifically, the radioactive nuclide is 177 Lu.

14. Radioactive markers, which are 15. A pharmaceutical composition comprising a compound of any one of claims 1-11 or a pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate thereof, or a radiolabeled substance of any one of claims 12-14, and a pharmaceutically acceptable carrier, excipient, or excipient.

16. Use of any compound of claims 1-11 or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or any radiolabeled product of claims 12-14, in the preparation of a medicament for the treatment / prevention of bone diseases; preferably, the medicament is a bone-targeting drug; specifically, the bone disease is bone cancer, osteosarcoma, bone metastasis of tumors, or diseases caused by them; more specifically, the bone metastasis of tumors is bone metastasis of breast cancer, prostate cancer, thyroid cancer, lung cancer, bladder cancer, renal cell carcinoma, or melanoma; more specifically, the bone metastasis of tumors is osteolytic bone metastasis or osteoblastic bone metastasis; more specifically, the diseases caused by bone cancer, osteosarcoma, or bone metastasis of tumors are bone pain, spinal cord compression, pathological fractures, or hypercalcemia; more specifically, the medicament for the treatment / prevention of bone diseases is also used as an imaging agent.

17. Use of any compound of claims 1-11 or its pharmaceutically acceptable salt, crystal, eutectic, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or any radiolabeled product of claims 12-14, in the preparation of a pharmaceutical product for the diagnosis and / or treatment of nuclear medicine; specifically, the diagnosis and / or treatment of nuclear medicine is for positron emission tomography and single-photon emission computed tomography; more specifically, the pharmaceutical product for the diagnosis and / or treatment of nuclear medicine is also used for the treatment / prevention of bone diseases.

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