Fibroblast-activating protein ligands and their uses

Abstract

The present invention relates to fibroblast-activating protein ligands and their uses, specifically, compounds represented by formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and their uses for diagnosing or treating diseases related to fibroblast-activating proteins, such as tumors or cancer. [Formula 1] JPEG2026523267000231.jpg55140

Description

[Technical Field]

[0001] This disclosure relates to fibroblast-activating protein ligands and their uses, and belongs to the pharmaceutical field. [Background technology]

[0002] In recent years, the tumor microenvironment has attracted attention as a therapeutic target for cancer treatment. The tumor microenvironment may contain the majority of the tumor; for example, in pancreatic ductal carcinoma, it has been reported to form up to 80% of the tumor mass. Cancer-associated fibroblasts are a component of the tumor microenvironment and are abundant in the matrix of tumor entities such as breast cancer and colon cancer. Fibroblast-activating protein (FAP) is a type II transmembrane serine protease and is useful as a tumor-associated fibroblast marker. It is not expressed or is low in normal tissues, but is highly expressed in over 90% of epithelial tumor tissues, such as breast cancer, colorectal cancer, lung cancer, ovarian cancer, and pancreatic cancer. Because FAP expression is limited in normal tissues, it has been identified as a potential pantumor target for treating cancer. In mesenchymal carcinoma indications, particularly sarcomas and mesotheliomas, FAP is expressed in tumor cells in addition to cancer-associated fibroblasts. FAP expression is also present in chronic inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, and cardiac remodeling after myocardial infarction.

[0003] The first approach to targeting FAP for cancer treatment involved using the monoclonal antibody cibrotuzumab to detect colorectal cancer in two forms: unbound and 131I-bound. Other methods targeting FAP, including bispecific antibodies or antibody fragment constructs, chimeric antigen receptor T cells, and antibody-drug conjugates, are currently under investigation, many of which are in preclinical development or Phase 1 clinical trials. Furthermore, small molecule FAP inhibitors (FAPIs) have been discovered and conjugated to radioactive materials to produce excellent imaging agents suitable for various cancer indications (J Nucl Med 2022;63:415-423).

[0004] FAP-2286 contains a peptide that binds to FAP effectively and selectively, is linked to DOTA via a linker, and the compound is currently in the clinical stage. Developing more FAP inhibitors has broad application prospects.

Summary of the Invention

[0005] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

[0006] In a selective embodiment, Y is a chelating agent, which optionally complexes with a nuclide.

[0007] In a selective embodiment, Y is hydrogen.

[0008] In a selective embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by formula (II) or a pharmaceutically acceptable salt thereof. [ka] The aforementioned R 1a , R 1b , v, G1, R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 5a , R 5b , m, R 6a , n, R 7a , R 7b , q, ring A, R 7c , p, R 8a , R 8b ,r,s,X,t,R 10 Y is defined in equation (I).

[0009] In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 2a R is a hydrogen or methyl group, 2b , R 2c Each is independently selected from hydrogen or a methyl group, and selectively, R 2b is hydrogen, and the R 2c is a methyl group, or the R 2b , R 2c These are all methyl groups.

[0010] In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 4a , R 4b Each is independently selected from hydrogen and hydroxyl groups, and selectively, R 4a is hydrogen, and the R4b is a hydroxy group.

[0011] In a selective embodiment, in the compound represented by formula (I) according to the present disclosure or a pharmaceutically acceptable salt thereof, and the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 2a is hydrogen or a methyl group, and the R 2b , R 2c are each independently selected from hydrogen or a methyl group, at least one is a methyl group, the R 4a is hydrogen, the R 4b is a hydroxy group, the R 4c , R 4d are each independently selected from hydrogen.

[0012] In a selective embodiment, in the compound represented by formula (I) according to the present disclosure or a pharmaceutically acceptable salt thereof, and the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 3a , R 3b are each independently selected from hydrogen, C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 R A , and the R A are the same or different and are selected from a hydroxy group, an amino group, a halogen, a C 1-3 alkyl group or a halo C 1-3 alkyl group.

[0013] In a selective embodiment, in the compound represented by formula (I) according to the present disclosure or a pharmaceutically acceptable salt thereof, and the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 3a is a methyl group, and the R 3b is hydrogen.

[0014] In a selective embodiment, in the compound represented by formula (I) according to the present disclosure or a pharmaceutically acceptable salt thereof, and the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 3a , R 3bEach atom, together with the linked atoms, forms a 5-membered nitrogen-containing heterocycloalkyl group, and the 5-membered nitrogen-containing heterocycloalkyl group optionally contains 1, 2, or 3 R atoms. A Replaced by the R A They are the same or different, hydroxyl group, amino group, halogen, C 1-3 Alkyl or halo C 1-3 Selected from alkyl groups.

[0015] In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 3a , R 3b Each atom, together with the atom to which it is linked, forms a five-membered nitrogen-containing heterocycloalkyl group, and the five-membered nitrogen-containing heterocycloalkyl group is not substituted.

[0016] In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 7a , R 7b These are, independently, hydrogen and C 1-3 Selected from alkyl groups, The aforementioned q is selected from 0 or 1. The ring A is selected from a phenyl group or a naphthyl group. The aforementioned R 7c These are, independently, halogen, nitro group, amino group, cyano group, hydroxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, hydroxy C 1-6 Selected from alkyl groups, trifluoromethyl groups, difluoromethyl groups, and trifluoroethyl groups, The aforementioned p is selected from 0, 1, 2, or 3.

[0017] In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 7a , R7b Each is independently selected from hydrogen, The aforementioned q is 0, The aforementioned ring A is a phenyl group, The aforementioned R 7c Each of these is independently selected from fluorine, chlorine, bromine, iodine, or a trifluoromethyl group, a difluoromethyl group, or a trifluoroethyl group. The aforementioned p is selected from 0, 1, or 2.

[0018] In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 1a , R 1b Each is independently selected from either a hydrogen or a methyl group. The aforementioned v is selected from 0 or 1. The aforementioned G1 is -(CO)-LR 1c Selected from, L is C 3-20 Selected from alkylene groups, the R 1c The group is selected from methyl groups.

[0019] In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 1a , R 1b Each is independently selected from hydrogen, The aforementioned v is selected from 0, The aforementioned G1 is -(CO)-LR 1c Selected from, L is C 4-14 Selected from alkylene groups, the R 1c It is selected from methyl groups, In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 1a , R 1b Each is independently selected from either a hydrogen or a methyl group. The aforementioned v is selected from 0 or 1. The aforementioned G1 is -(CO)-LR 1c Selected from, L is C 3-20 Selected from alkylene groups, the R 1c is -NH-(C=NH)-NR 1d R 1f That is to say [ka] Selected from, the R 1d , R 1f Each of these is independently selected from either a hydrogen or a methyl group.

[0020] In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or in the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, The aforementioned R 1a , R 1b Each is independently selected from hydrogen, The aforementioned v is selected from 0, The aforementioned G1 is -(CO)-LR 1c Selected from, L is C 4-14 Selected from alkylene groups, the R 1c is -NH(C=NH)-NR 1d R 1f Selected from, the R 1d , R 1f Each of these is independently selected from either a hydrogen or a methyl group.

[0021] In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 1a , R 1b Each is independently selected from either a hydrogen or a methyl group. The aforementioned v is selected from 0 or 1. The aforementioned G1 is, [ka] The above u is an integer selected from 1 to 5.

[0022] In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the R 1a , R 1b Each is independently selected from hydrogen, The aforementioned v is selected from 0, The aforementioned G1 is, [ka] Selected from, The aforementioned u is selected from 1 or 2.

[0023] In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or in the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, The aforementioned R 5a It is selected from hydrogen, The aforementioned R 5b C 1-6 Selected from alkyl groups, the C 1-6 The alkyl group can optionally consist of 1 or 2 R B Replaced by the R B They are the same or different, selected from a hydroxyl group or a halogen. The aforementioned m is selected from 0 or 1, and the hydrogen in CH2 is optionally a hydroxyl group, a halogen, a hydroxyl group, or C 1-3 Replaced with one or more alkyl groups selected from: The above n is 2, The aforementioned R 6a It is an amino group, The aforementioned R 8a , R 8b Each of these is independently selected from hydrogen, -COOH, and -CONH2, with at least one being -COOH or -CONH2, and r is 1.

[0024] In a selective embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof according to the present disclosure is the compound represented by formula (III) or a pharmaceutically acceptable salt thereof. [ka] The aforementioned R 2a is a hydrogen or methyl group, The aforementioned R 2b , R 2c Each is independently selected from hydrogen or a methyl group, and at least one is a methyl group. The aforementioned R 3a , R 3b These are, independently, hydrogen and C 1-3 Selected from alkyl groups, the C 1-3 The alkyl group optionally consists of 1, 2, or 3 R A Replaced by the R A They are the same or different, hydroxyl group, amino group, halogen, C 1-3 Alkyl or halo C 1-3 Selected from alkyl groups, or the R 3a , R 3b Each atom, together with the linked atoms, forms a 5-membered nitrogen-containing heterocycloalkyl group, and the 5-membered nitrogen-containing heterocycloalkyl group optionally contains 1, 2, or 3 R atoms. A Replaced by the R A They are the same or different, hydroxyl group, amino group, halogen, C 1-3 Alkyl or halo C 1-3 Selected from alkyl groups, The aforementioned R 4a is hydrogen, fluorine, or a trifluoromethyl group, and the R 4b These are fluorine and a hydroxyl group, The aforementioned R 4c , R 4d Each is independently selected from hydrogen, The aforementioned R 7c Each of these is independently selected from fluorine, chlorine, bromine, iodine, or a trifluoromethyl group, a difluoromethyl group, or a trifluoroethyl group. The aforementioned p is selected from 0, 1, or 2. Said G1, s, X, t, R 10 Y is defined in equation (I).

[0025] In a selective embodiment, in a compound represented by formula (III) according to this disclosure or a pharmaceutically acceptable salt thereof, the R 4a is hydrogen, and the R 4b This is a hydroxyl group.

[0026] In a selective embodiment, in a compound represented by formula (III) according to this disclosure or a pharmaceutically acceptable salt thereof, the R 3a is hydrogen, and the R 3b This is a methyl group.

[0027] In a selective embodiment, in a compound represented by formula (III) according to this disclosure or a pharmaceutically acceptable salt thereof, the R 3a , R 3b Each atom, together with the atom to which it is linked, forms a five-membered nitrogen-containing heterocycloalkyl group, and the five-membered nitrogen-containing heterocycloalkyl group is not substituted.

[0028] In a selective embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, s is 1, X is S, and R 10 It is hydrogen.

[0029] In a selective embodiment, in a compound represented by formula (III) according to this disclosure or a pharmaceutically acceptable salt thereof, G1 is -(CO)-LR 1c Selected from, L is C 4-14 Selected from alkylene groups, the R 1c L is selected from methyl groups, and L is selectively, for example, a C4 alkylene group, a C6 alkylene group, a C8 alkylene group, C 10 Alkylene group, C 12Alkylene group or C 14 It is an alkylene group.

[0030] In a selective embodiment, in a compound represented by formula (III) according to this disclosure or a pharmaceutically acceptable salt thereof, G1 is -(CO)-LR 1c Selected from, where L is -(CO)-LR 1c Selected from, L is C 4-14 Selected from alkylene groups, the R 1c is -NH-(C=NH)-NR 1d R 1f Selected from, the R 1d , R 1f Each of these is independently selected from hydrogen or a methyl group, and L is selectively, for example, a C4 alkylene group, a C5 alkylene group, or a C6 alkylene group.

[0031] In a selective embodiment, in a compound represented by formula (III) or a pharmaceutically acceptable salt thereof according to this disclosure, G1 is [ka] The above u is selected from 1 or 2.

[0032] In the compounds disclosed herein, the fragment linked to Y is, specifically, [ka] It refers to the corresponding fragment, which is, [ka] Select from JPEG2026523267000013.jpg238164, JPEG2026523267000014.jpg250156, JPEG2026523267000015.jpg247154, JPEG2026523267000016.jpg238170, JPEG2026523267000017.jpg252162, JPEG2026523267000018.jpg249167, JPEG2026523267000019.jpg237159, JPEG2026523267000020.jpg101162.

[0033] In the compounds disclosed herein, the fragment linked to Y is, specifically, [ka] It refers to the corresponding fragment, which is, [ka] Selected from.

[0034] The chelating agents described herein are selected from DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, NxS4-x (N4, N2S2, N3S), Hynic, and 99mTc(CO)3-chelating agents.

[0035] In a selective embodiment, the chelating agent is [ka] Selected from JPEG2026523267000024.jpg68158.

[0036] In some embodiments, the chelating agent is selected from DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, and N4.

[0037] In some embodiments, the chelating agent is selected from DOTA, DOTAGA, NOTA, and NODAGA.

[0038] This disclosure provides the following compounds or pharmaceutically acceptable salts thereof, which Group 4: [ka] JPEG2026523267000026.jpg237166JPEG2026523267000027.jpg236164JPEG2026523267000028.jpg248161JPEG2026523267000029.jp g254170JPEG2026523267000030.jpg254167JPEG2026523267000031.jpg235162JPEG2026523267000032.jpg248170JPEG2026523267000 033.jpg251170JPEG2026523267000034.jpg250165JPEG2026523267000035.jpg243164JPEG2026523267000036.jpg240166JPEG202652 3267000037.jpg237168JPEG2026523267000038.jpg237163JPEG2026523267000039.jpg227162JPEG2026523267000040.jpg233170JPEG 2026523267000041.jpg243168JPEG2026523267000042.jpg246167JPEG2026523267000043.jpg251166JPEG2026523267000044.jpg240 164JPEG2026523267000045.jpg245163JPEG2026523267000046.jpg235165JPEG2026523267000047.jpg238165JPEG2026523267000048. Select from jpg237161JPEG2026523267000049.jpg253162JPEG2026523267000050.jpg255168JPEG2026523267000051.jpg251163JPEG2026523267000052.jpg239162JPEG2026523267000053.jpg238170JPEG2026523267000054.jpg244166JPEG2026523267000055.jpg118162.

[0039] In the compounds or pharmaceutically acceptable salts thereof according to this disclosure, the chelating agent complexes with a nuclide, the nuclide is a diagnostically active nuclide, and the diagnostically active nuclide is 43 Sc, 44 Sc, 51 Mn, 52 Mn, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 94m Tc, 99m Tc, 111 In, 152 Tb, 155 Tb, 201 Tl, 203 Pb, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 Selected from I.

[0040] In some embodiments, the diagnostically active nuclide is 43 Sc, 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y, 89 Zr, 99m Tc, 111 In, 152 Tb, 155 Tb, 203 Pb, 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 Selected from I.

[0041] In some embodiments, the diagnostically active nuclide is 64 Cu, 68 Ga, 89 Zr, 99m Tc, 111 In, 18 F, 123 I and 124 Selected from I.

[0042] In the compounds or pharmaceutically acceptable salts thereof according to this disclosure, the chelating agent complexes with a radionuclide, and the radionuclide is a therapeutically active radionuclide. 47 Sc, 67 Cu, 89 Sr, 90 Y, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 186 Re, 188 Re, 212 Pb, 213 Bi, 223 Ra, 225 Ac, 226 Th, 227 Th, 131 I, 211 Selected from A.

[0043] In a selective embodiment, the therapeutically active radionuclide is 47 Sc, 67 Cu, 90 Y, 177 Lu, 188 Re, 212 Pb, 213 Bi, 225 Ac, 227 Th, 131 I, 211 Selected from At.

[0044] In a selective embodiment, the therapeutically active radionuclide is 90 Y, 177 Lu, 225 Ac, 227 Th, 131 I and 211 Selected from At.

[0045] This disclosure is, [ka] JPEG2026523267000057.jpg243164JPEG2026523267000058.jpg253161JPEG202652 3267000059.jpg212158JPEG2026523267000060.jpg198165JPEG2026523267000061. jpg201163JPEG2026523267000062.jpg214164JPEG2026523267000063.jpg254165JP EG2026523267000064.jpg254163JPEG2026523267000065.jpg252169JPEG202652326 The present invention provides the compound 7000066.jpg221162JPEG2026523267000067.jpg226164JPEG2026523267000068.jpg207161JPEG2026523267000069.jpg225160JPEG2026523267000070.jpg233170JPEG2026523267000071.jpg233170JPEG2026523267000072.jpg220167JPEG2026523267000073.jpg224168JPEG2026523267000074.jpg228169 or a pharmaceutically acceptable salt thereof.

[0046] The aforementioned compounds as disclosed herein may be used as drugs.

[0047] In another aspect, this disclosure provides a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents, and excipients.

[0048] This disclosure provides, in another aspect, a method for producing the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition, the method comprising the step of complexing the compound or a pharmaceutically acceptable salt thereof with a nuclide.

[0049] In another aspect, the present disclosure provides uses of the aforementioned compounds or pharmaceutically acceptable salts thereof or the aforementioned pharmaceutical compositions for producing drugs for diagnosing or treating diseases, wherein the diseases are diseases relating to fibroblast-activating proteins (FAPs).

[0050] In a selective embodiment, the fibroblast-activating protein (FAP)-related disease is a disease associated with the upregulation of fibroblast-activating protein (FAP) expression.

[0051] In a selective embodiment, the disease relates to cells exhibiting upregulation of fibroblast-activating protein (FAP) expression.

[0052] In a selective embodiment, the disease relates to lesional tissue containing cells that exhibit upregulation of fibroblast-activating protein (FAP) expression.

[0053] In a selective embodiment, the disease is a disease relating to tumor-associated fibroblasts.

[0054] In another aspect, the disclosure further provides uses of the aforementioned compounds or pharmaceutically acceptable salts thereof or the aforementioned pharmaceutical compositions in the manufacture of drugs for diagnosing or treating a disease, wherein the disease is a tumor or cancer.

[0055] In another embodiment, the Disclosure provides uses of the aforementioned compounds or pharmaceutically acceptable salts thereof or the aforementioned pharmaceutical compositions in the manufacture of drugs for diagnosing or treating diseases, wherein the diseases are selected from inflammatory diseases, cardiovascular diseases, autoimmune diseases and fibrotic diseases.

[0056] In a selective embodiment, the disease is an inflammatory disease, such as atherosclerosis, arthritis, or rheumatoid arthritis.

[0057] In a selective embodiment, the disease is a cardiovascular disease.

[0058] In a selective embodiment, the disease is a cardiovascular disease relating to loamylic arteriosclerotic plaques.

[0059] In a selective embodiment, the disease is an atherosclerotic lesion resulting from plaque rupture, acute coronary syndrome, myocardial infarction, thrombosis, or vascular occlusion.

[0060] In a selective embodiment, the disease is a fibrotic disease, such as idiopathic pulmonary fibrosis, Crohn's disease, and hepatic fibrosis.

[0061] The tumors or cancers described herein are selected from solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and cancers, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland cancer, sarcoma, squamous cell carcinoma, glioma (e.g., human glioblastoma cells), and thyroid cancer (e.g., medullary thyroid carcinoma).

[0062] In a selective embodiment, the tumor or cancer described herein is selected from breast cancer, colorectal cancer, cholangiocarcinoma, head and neck cancer, lung cancer, mesothelioma, neuroendocrine tumors and cancers, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and squamous cell carcinoma.

[0063] The disclosure further provides a method for diagnosing or treating a disease, comprising administering to a patient a diagnostically effective amount or a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition, wherein the disease is selected from diseases relating to fibroblast-activating protein (FAP), tumors or cancers, inflammatory diseases, cardiovascular diseases, autoimmune diseases and fibrotic diseases.

[0064] The patients described in this disclosure may be mammals, such as humans, dogs, cats, horses, and cattle.

[0065] In some embodiments, the method for diagnosing a disease with a compound according to the present disclosure is imaging, and the imaging method is selected from scintigraphy, single photon emission computed tomography (SPECT), and positron emission tomography (PET).

[0066] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0067] In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01% to 99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotope-substituted form thereof. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotope-substituted form thereof. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotope-substituted form thereof. In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotope-substituted form thereof. In some embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotope-substituted form thereof.

[0068] In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.

[0069] This disclosure further provides a method for producing the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition, comprising the step of complexing the compound shown in formula (I) or a pharmaceutically acceptable salt thereof with a nuclide, [ka] The aforementioned Y is a chelating agent, and the chelating agent complexes with the nuclide, and the aforementioned R 1a , R 1b , v, G1, R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 5a , R 5b , m, R 6a , n, R 7a , R 7b , q, ring A, R 7c , p, R 8a , R 8b ,r,s,X,t,R 10 This is as defined in equation (I).

[0070] This disclosure further provides a method for producing the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition, which includes the step of reacting the compound shown in formula (I-1) with a chelating agent, [ka] The aforementioned R 1a , R 1b , v, G1, R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 5a , R 5b , m, R 6a , n, R 7a , R 7b , q, ring A, R 7c, p, R 8a , R 8b ,r,s,X,t,R 10 This is as defined in equation (I).

[0071] This disclosure further provides the compound shown in formula (I-2) or a pharmaceutically acceptable salt thereof, [ka] The aforementioned R 1a , R 1b , v, G1, R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 5a , R 5b , m, R 6a , n, R 7a , R 7b , q, ring A, R 7c , p, R 8a , R 8b r is defined in equation (I).

[0072] This disclosure further provides a method for producing the compound shown in formula (III) above or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound shown in formula (III-1) or a pharmaceutically acceptable salt thereof with 2-aminoethanethiol, 1,3,5-tris(bromomethyl)benzene, [ka] The aforementioned Y is hydrogen, and R 10 is hydrogen, t is 1, X is a sulfur atom, s is 1, The aforementioned R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R7c p, G1 are as defined in formula (III).

[0073] Optionally, the method for producing the compound shown in the aforementioned formula (I) or a pharmaceutically acceptable salt thereof according to the present disclosure further includes the steps in the method for producing the compound shown in the aforementioned formula (III) or a pharmaceutically acceptable salt thereof.

[0074] The present disclosure further provides a compound shown in formula (III-1) or a pharmaceutically acceptable salt thereof,

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0076] The pharmaceutically acceptable salts of the compounds described herein may be selected from inorganic salts or organic salts.

[0077] The compounds of this disclosure may have specific geometric or stereoisomeric forms. In this disclosure, all such compounds include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as mixtures concentrated from enantiomers or diastereomers, all of which are assumed to be within the scope of this disclosure. Substituents such as alkyl groups may contain other chiral carbon atoms. All of these isomers and mixtures thereof are within the scope of this disclosure. The chiral carbon-containing compounds of this disclosure can be separated in optically active pure forms or in racemic forms. The optically active pure forms can be separated from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0078] Optically active (R)- and (S)-isomers and D- and L-isomers can be produced by chiral synthesis, chiral reagents, or other prior art. When it is intended to obtain an enantiomer of a compound in this disclosure, it can be produced by asymmetric synthesis or by the inductive action of a chiral auxiliary agent, where the resulting diastereomer mixture is separated and the auxiliary groups are cleaved to provide the pure, desired enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer is formed with a suitable optically active acid or base, and the diastereomer is resolved by a conventional method known in the art, and the resulting pure enantiomer is recovered. The separation of enantiomers and diastereomers is generally completed by chromatography, which employs a chiral stationary phase and optionally combines with a chemical induction method (e.g., producing a carbamate salt from an amine).

[0079] JPEG2026523267000084.jpg62167

[0080] The compounds and intermediates of this disclosure may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure.

[0081] This disclosure further includes several isotope-labeled compounds, which are the same as those described herein, but in which one or more atoms are substituted with atoms whose atomic weight or mass number differs from that commonly found in nature. Examples of isotopes that can be bound to the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, respectively 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Examples include Cl.

[0082] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood to be deuterium having an abundance at least 1000 times greater than the natural abundance of deuterium (0.015%) (i.e., at least 10% deuterium incorporation). In the example compounds, deuterium having an abundance greater than the natural abundance of deuterium may be deuterium having an abundance of at least 1000 times, deuterium having an abundance of at least 2000 times, deuterium having an abundance of at least 3000 times, deuterium having an abundance of at least 4000 times, deuterium having an abundance of at least 5000 times, deuterium having an abundance of at least 6000 times, or deuterium having an abundance higher than that. The disclosure further includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom bonded to a carbon atom can be independently substituted with a deuterium atom. Those skilled in the art can synthesize compounds of formula (I) in deuterated forms by referring to relevant literature. When producing compounds of formula (I) in deuterated form, commercially available deuterated starting materials may be used, or they may be synthesized using conventional techniques with deuterated reagents, which include, but are not limited to, borane deuterated, borane-tetrahydrofuran trihydrogenated solution, lithium aluminum deuterated, iodoethane deuterated, and iodomethane deuterated.

[0083] Explanation of terms "Optionally" or "optionally" means that the event or environment described thereafter may occur, but does not necessarily occur, and the description includes both cases where the event or environment occurs and where it does not occur. For example, "C optionally substituted with a halogen or cyano group." 1-6 The term "alkyl group" means that a halogen or cyano group may be present, but is not necessarily required, and this description includes cases where the alkyl group is substituted with a halogen or cyano group, and cases where the alkyl group is not substituted with a halogen or cyano group.

[0084] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically and pharmaceutically acceptable salts or prodrugs with other chemical components, as well as other components, such as physiologically and pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to a living organism, to facilitate the absorption of the active ingredient, and thereby to exert biological activity.

[0085] "Pharmacologically acceptable excipients" include, but are not limited to, any excipients, carriers, fluidizers, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, humectants, dispersants, suspension aids, stabilizers, isotonic agents, solvents, or emulsifiers approved by the U.S. Food and Drug Administration (FDA) for use in humans or livestock animals.

[0086] The “effective dose” or “effective therapeutic dose” as described in this disclosure includes the amount sufficient to improve or prevent the symptoms or signs of a medical condition. The effective dose also means the amount sufficient to enable or facilitate a diagnosis. The effective dose for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the patient’s overall health, the method, route and dose of administration, and the severity of adverse reactions. The effective dose may be the maximum dose or administration protocol that avoids significant adverse reactions or toxic effects.

[0087] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, and their various branched isomers.

[0088] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, where the ring of the cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl groups.

[0089] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon that contains 3 to 20 ring atoms, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer between 0 and 2), but do not contain -OO-, -OS-, or -SS- ring portions, and the other ring atoms are carbon.

[0090] The term "alkoxy group" refers to an -O-(alkyl group), where the definition of an alkyl group is as described above. Non-exclusive examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy groups.

[0091] The term "alkylene group" refers to the remaining portion after removing two hydrogen atoms from an alkane molecule, and includes linear and branched subunits of 1 to 20 carbon atoms. Non-limiting examples include the methylene group (-CH2-) and the ethylene group (e.g., -CH2CH2- or -CH(CH3)-).

[0092] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably having 6- to 12 members, such as the phenyl group and the naphthyl group.

[0093] The aryl ring can be condensed with a heteroaryl group, a heterocycloalkyl group, or a cycloalkyl group ring, where the ring linked to the basic skeleton is an aryl ring, and a non-limiting example thereof is: [ka] Includes.

[0094] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 6 to 12 members, more preferably 5 or 6 members. Non-limiting examples include imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, oxadiazolyl, pyrazinyl, triazolyl, indozolyl, and benzimidazolyl groups. [ka] This includes, among others.

[0095] The heteroaryl ring can be condensed with an aryl group, a heterocycloalkyl group, or a cycloalkyl group ring, where the ring linked to the basic skeleton is a heteroaryl ring, and a non-limiting example thereof is: [ka] Includes.

[0096] The term "hydroxyl group" refers to the -OH group.

[0097] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0098] The term "cyano group" refers to -CN.

[0099] The term "amino group" refers to -NH2.

[0100] The term "nitro group" refers to -NO2.

[0101] The term "oxo" refers to =O.

[0102] "Substituting" means that one or more hydrogen atoms in a group, preferably up to five, more preferably one to three, are substituted independently by a corresponding number of substituents. If the substituent is a ketone or oxo (i.e., =O), two (2) hydrogen atoms in the atom are substituted.

[0103] [Table 1] JPEG2026523267000089.jpg245148JPEG2026523267000090.jpg56149 [Brief explanation of the drawing]

[0104] [Figure 1] This refers to the amount of the compounds disclosed herein taken up by tumors and various tissues. [Figure 2] This is a curve showing the tumor / renal uptake ratio for the compounds disclosed herein and 68Ga-FAP-2286 (** indicates a statistically significant difference). [Figure 3] These are tumor uptake values ​​for the compounds disclosed herein and 68Ga-FAP-2286 at different time points. [Figure 4] The tumor / renal uptake ratios of the compounds disclosed herein and 68Ga-FAP-2286 at different time points. [Figure 5] These are the tumor uptake values ​​of the compounds disclosed herein and 177Lu-FAP-2286 at different time points. [Figure 6] The tumor / renal uptake ratios of the compounds disclosed herein and 177Lu-FAP-2286 at different time points. [Figure 7] These are tumor uptake values ​​for the compounds disclosed herein and 68Ga-FAP-2286 at different time points. [Figure 8] The tumor / renal uptake ratios of the compounds disclosed herein and 68Ga-FAP-2286 at different time points. [Figure 9]These are the tumor uptake values ​​of the compounds disclosed herein and Al18F-NOTA-2286 at different time points. [Figure 10] These are the tumor / kidney uptake values ​​of the compounds disclosed herein and Al18F-NOTA-2286 at different time points. [Figure 11] These are tumor growth curves (n=8, mean ± standard deviation) of U-87 MG model mice after administration of 177Lu-DOTA-09 at different radioactivity levels. [Figure 12] This shows the change in body weight (n=8, mean ± standard deviation) of mice administered 177Lu-DOTA-09 at different doses. [Figure 13] This shows the survival time of U-87 MG model mice after administration of 177Lu-DOTA-09 at different radioactivity levels. [Modes for carrying out the invention]

[0105] Examples The following synthesis description or specific examples are for illustrative purposes only and should not be construed as limiting in any way to the preparation of the compounds of this disclosure by any other method.

[0106] The chromatography conditions for HPLC / MS analysis are as follows: 10 μl of each sample was automatically dispensed. Mobile phase: A: 0.1% formic acid aqueous solution, B: 0.1% formic acid acetonitrile solution. Flow rate: 1.5 ml / min. Gradient: B was increased from 10% to 95% from 0 to 6 mins, B was increased from 95% to 100% from 6 to 8 mins, B was decreased from 100% to 10% from 8 to 8.10 mins, and B was maintained at 10% from 8.10 to 11.0 mins.

[0107] Equipment model number: Thermo Fisher Ultimate 3000 ISQEM.

[0108] Chromatography column: Eclipse Plus C18, 3.5nm, 4.6×100mm.

[0109] UV detection wavelength: 220 nM.

[0110] The purity data of the compound was obtained by manual integration, and the molecular weight [M+1] + or [M-1] - I collected them.

[0111] The chromatography conditions for the preparative liquid are as follows: Mobile phase: A: 0.1% trifluoroacetic acid aqueous solution, B: 0.1% trifluoroacetic acid acetonitrile solution. Flow rate: 60 ml / min. Gradient: B was increased from 25% to 45% from 0 to 20.0 min, B was increased from 45% to 70% from 20.0 to 30.0 min, and B was maintained at 70% from 30.0 to 40.0 min.

[0112] Equipment model number: Agilent AGILENT 1260II.

[0113] Chromatography column: HPLCONE, 5.0 μm, 30 × 250 mm.

[0114] UV detection wavelength: 220 nM.

[0115] The chromatography conditions for radio-HPLC analysis are as follows: 5-20 μl of each sample was automatically dispensed. Mobile phase: A: 0.1% formic acid aqueous solution, B: 0.1% formic acid acetonitrile solution. Flow rate: 0.8 ml / min. Gradient: B was increased from 10% to 50% from 0-24 min, then reduced from 50% to 10% from 24-25 min, and maintained at 10% from 25-35 min.

[0116] Equipment model number: Thermo Fisher Ultimate 3000 ISQEM.

[0117] Chromatography column: XBridgeC18 3.5μm, 4.6*150mm.

[0118] UV detection wavelength: 225 nM.

[0119] Radioactivity detector: 30000cps / V.

[0120] Radiochemical purity was obtained by manual integration.

[0121] [Table 2]

[0122] Example 1. Manufacturing of DOTA-01 [ka] It can be produced by either of the two solid-phase synthesis schemes.

[0123] Regiment 1 a. Loading of the first amino acid onto a solid support CTC resin (substitution degree = 1.09 mmol / g) was selected as the solid phase support, and the resin was swollen with DMF for 1 hour. Subsequently, an amino acid solution was prepared: 3.00 eq Fmoc-Cys(Trt)-OH and 6.00 eq DIPEA were dissolved in 8 times the mass of resin in DMF, and after homogeneous stirring, the solution was reacted with the resin for 3 hours. The resin was washed, capped with methanol and DIPEA, washed 4 to 6 times with 8 times the mass of resin in DMF, and then sequentially washed with 8 times the mass of resin in isopropyl ether, DCM, and isopropyl ether. After shrinking the resin, it was dried, the degree of substitution was measured, and then it was prepared for use.

[0124] b. Amino acid coupling In the synthesis, each amino acid was coupled using the general coupling method described below.

[0125] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swollen with 8 times its mass of DMF for 1 hour, and the Fmoc protecting group was removed twice with 8 times its mass of 20% piperidine / DMF solution (5 min the first time, 20 min the second time). After deprotection was complete, the resin was washed 4 to 6 times with 8 times its mass of DMF. Preparation of amino acid activation solution: 3.0 eq amino acids and 3.0 eq HOBT were dissolved in 8 Vol DMF, 3.0 eq DIC was added and activated for 2 to 5 minutes, and then the reaction was carried out. After the reaction and deprotection were complete, the resin was washed 4 to 6 times with 8 times its mass of DMF. After completing the coupling of the linear peptide resin using the above method, the resin was washed, shrunk, dried, and prepared for use.

[0126] c. Decomposition The obtained peptide resin was decomposed using a decomposition solution. The mixing ratio of the decomposition solution was TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1, and the amount of decomposition solution added was 8 to 10 times the mass of the peptide resin. After decomposition for 2 hours, the solution was filtered to obtain a filtrate. The obtained filtrate was poured into isopropyl ether in an amount of 80 to 100 times the mass of the peptide resin to crystallize, filtered, rinsed with isopropyl ether, and dried to obtain linear crude peptides.

[0127] d. Cyclization The obtained linear crude peptide was dissolved in a 1:1 mixture of acetonitrile and purified water at a concentration of 400 times the crude peptide mass. First, 7.2 eq of DIPEA was added, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. After the reaction was complete, the mixture was purified by preparative distillation and freeze-dried to obtain a cyclic peptide intermediate.

[0128] Connecting to e.DOTA The lyophilized powder of the obtained cyclic peptide was dissolved in 10 times its mass of DMF, 4.0 eq DIPEA and 2.0 eq DOTA-NHS were added, and the reaction was monitored by LC-MS until complete. After purification by preparative liquid chromatography, the product was lyophilized to obtain the target product. Purity: 98.2%, MS m / z (ESI): 1540.72 [MH] - .

[0129] Regiment 2 1: Loading of the first amino acid onto the solid support. Wang resin (substitution degree = 1.08 mmol / g) was selected as the solid support, and the resin was swollen with 8 times its mass in DMF for 1 hour. Subsequently, an amino acid solution was prepared: 3.00 eq Fmoc-Cys(Mmt)-OH and 3.00 eq HOBT were dissolved in 8 times its mass in DMF, and after homogeneous stirring, 3.00 eq DIC was added to activate the amino acids. After activation was complete, it was added to the swollen resin, uniformly blown in, and then 0.3 eq DMAP was added to catalyze the reaction, which was allowed to proceed for 3 hours. After the reaction was complete, the resin was washed 4-6 times with 8 times its mass of DMF, 3.00 eq acetic anhydride and 6.00 DIPEA were dissolved in 8 times its mass of DMF, capped for 1 hour, washed 4-6 times with 8 times its mass of DMF, shrunk with 8 times its mass of isopropyl ether, DCM, and isopropyl ether, dried, measured the degree of substitution, and then prepared for use.

[0130] 2: Amino acid coupling In the synthesis, each amino acid was coupled using the general coupling method described below.

[0131] The Fmoc-Cys(Mmt)-Wang resin obtained in the previous step was swollen with 8 times its mass of DMF for 1 hour, and the Fmoc protecting group was removed twice with 8 times its mass of 20% piperidine / DMF solution (5 min the first time, 20 min the second time). After deprotection was complete, the resin was washed 4 to 6 times with 8 times its mass of DMF. Preparation of amino acid activation solution: 3.0 eq amino acids and 3.0 eq HOBT were dissolved in 8 Vol DMF, 3.0 eq DIC was added and activated for 2 to 5 minutes, and then the reaction was carried out. After the reaction and deprotection were complete, the resin was washed 4 to 6 times with 8 times its mass of DMF. After completing the coupling of the linear peptide resin using the above method, the resin was washed, shrunk, dried, and prepared for use.

[0132] 3: Solid phase cyclization The Cys side-chain protecting group Mmt was removed with 1% TFA / DCM at 8 times the mass of the resin, the resin was washed 4 to 6 times with DMF at 8 times the mass of the resin, then 8 times the mass of DMF was added as the solvent, 7.2 eq of DIPEA was added, and then 1.2 eq of 1,3,5-tris(bromomethyl)benzene was added. After cyclization was complete, 3.6 eq of mercaptoethylamine was added directly, and after the reaction was complete, the resin was washed 4 to 6 times with DMF at 8 times the mass of the resin.

[0133] 4: Connecting to DOTA 4.0 eq DIPEA and 2.0 eq DOTA-NHS were dissolved in 8 times the volume of DMF to prepare a reaction solution, which was added to a solid-phase column and reacted. After the reaction was complete, the resin was washed 4 to 6 times with 8 times the volume of DMF, and the peptide resin was shrunk with 8 times the volume of isopropyl ether, DCM, and isopropyl ether, then dried and prepared for use.

[0134] 5: Decomposition The obtained peptide resin was decomposed using a decomposition solution. The mixing ratio of the decomposition solution was TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1, and the amount of decomposition solution added was 8 to 10 times the mass of the peptide resin. After decomposition for 2 hours, the solution was filtered to obtain a filtrate. The obtained filtrate was poured into isopropyl ether in an amount of 80 to 100 times the mass of the peptide resin to crystallize, filtered, rinsed with isopropyl ether, and dried to obtain linear crude peptide. Purification was performed using preparative liquid, and the solution was freeze-dried to obtain a freeze-dried powder. Purity: 96.7%, MS m / z (ESI): 1540.72 [MH] - .

[0135] Example 2. Manufacturing of DOTA-02 [ka] Using a method similar to regimen 1 of Example 1, the target compound DOTA-02 was obtained with a purity of 97.7% and an MS m / z (ESI): 1556.34 [MH]. - .

[0136] Example 3. Manufacturing of DOTA-03 [ka] Using a method similar to regimen 1 of Example 1, the target compound DOTA-03 was obtained with a purity of 96.3% and an MS m / z(ESI):1555.08[M+H]. + .

[0137] Example 4. Manufacturing of DOTA-04 [ka] Using a method similar to regimen 1 of Example 1, the target compound DOTA-04 was obtained with a purity of 95.2% and MS m / z(ESI):1545.01[M+H]. + .

[0138] Example 5. Manufacturing of DOTA-05 [ka] Using a method similar to regimen 1 of Example 1, the target compound DOTA-05 was obtained. a. Loading of the first amino acid onto a solid support CTC resin (substitution degree = 1.09 mmol / g) was selected as the solid support, and the resin was swollen with DMF for 1 hour. Then, an amino acid solution was prepared: 3.00 eq Fmoc-Cys(Trt)-OH and 6.00 eq DIPEA were dissolved in 8 times the mass of resin in DMF, and after uniform stirring, the solution was reacted with the resin for 3 hours. The resin was washed, capped with methanol and DIPEA, washed 4 to 6 times with 8 times the mass of resin in DMF, and then sequentially washed with 8 times the mass of resin in isopropyl ether, DCM, and isopropyl ether. After shrinking the resin, it was dried, the degree of substitution was measured, and then it was prepared for use.

[0139] b. Amino acid coupling In the synthesis, each amino acid was coupled using the general coupling method described below.

[0140] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swollen with 8 times its mass of DMF for 1 hour, and the Fmoc protecting group was removed twice with 8 times its mass of 20% piperidine / DMF solution (5 min for the first time, 20 min for the second time). After deprotection was complete, the resin was washed 4-6 times with 8 times its mass of DMF. Preparation of amino acid activation solution: 3.0 eq amino acids and 3.0 eq HBTU were dissolved in 8 Vol DMF, 3.0 eq DEPEA was added and activated for 2-5 minutes, then the reaction was carried out. After the reaction and deprotection were complete, the resin was washed 4-6 times with 8 times its mass of DMF. After completing the coupling of the linear peptide resin using the above method, the resin was washed, shrunk, dried, and prepared for use.

[0141] c. Decomposition The obtained peptide resin was decomposed using a decomposition solution. The mixing ratio of the decomposition solution was TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1, and the amount of decomposition solution added was 8 to 10 times the mass of the peptide resin. After decomposition for 2 hours, the solution was filtered to obtain a filtrate. The obtained filtrate was poured into isopropyl ether in an amount of 80 to 100 times the mass of the peptide resin to crystallize, filtered, rinsed with isopropyl ether, and dried to obtain linear crude peptides.

[0142] d. Cyclization The obtained linear crude peptide was dissolved in a 1:1 mixture of acetonitrile and purified water at a concentration of 400 times the crude peptide mass. First, 7.2 eq of DIPEA was added, followed by 1.2 eq of 1,3,5-trisbromomethylbenzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. After the reaction was complete, the mixture was purified by preparative distillation and freeze-dried to obtain a cyclic peptide intermediate.

[0143] Connecting to e.DOTA The resulting cyclic peptide was dissolved in 10 times its mass of DMF, 4.0 eq DIPEA and 2.0 eq DOTA-NHS were added, and the reaction was monitored by LC-MS until complete. After purification by preparative liquid chromatography, the product was lyophilized to obtain the target product.

[0144] Purity: 97.8%, MS m / z (ESI): 1571.10 [M+H] + .

[0145] Example 6. Manufacturing of DOTA-06 [ka] a. Loading of the first amino acid onto a solid support CTC resin (substitution degree = 1.09 mmol / g) was selected as the solid phase support. The resin was swollen with DMF for 1 hour, and then an amino acid solution was prepared: 3.00 eq Fmoc-Cys(Trt)-OH and 6.00 eq DIPEA were dissolved in 8 times the mass of resin in DMF, and after uniform stirring, the solution was reacted with the resin for 3 hours. The resin was washed, capped with methanol and DIPEA, washed 4 to 6 times with 8 times the mass of resin in DMF, and then sequentially washed with 8 times the mass of resin in isopropyl ether, DCM, and isopropyl ether. After shrinking the resin, it was dried, the degree of substitution was measured, and then it was prepared for use.

[0146] b. Amino acid coupling In the synthesis, each amino acid was coupled using the general coupling method described below.

[0147] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swollen with 8 times its mass of DMF for 1 hour, and the Fmoc protecting group was removed twice with 8 times its mass of 20% piperidine / DMF solution (5 min the first time, 20 min the second time). After deprotection was complete, the resin was washed 4 to 6 times with 8 times its mass of DMF. Preparation of amino acid activation solution: 3.0 eq amino acids and 3.0 eq HBTU were dissolved in 8 vol DMF, 3.0 eq DIPEA was added and activated for 2 to 5 minutes, and then the reaction was carried out. After the reaction and deprotection were complete, the resin was washed 4 to 6 times with 8 times its mass of DMF. After completing the coupling of the linear peptide resin using the above method, the resin was washed, shrunk, dried, and prepared for use.

[0148] c. Decomposition The obtained peptide resin was decomposed using a decomposition solution. The mixing ratio of the decomposition solution was TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1, and the amount of decomposition solution added was 8 to 10 times the mass of the peptide resin. After decomposition for 2 hours, the solution was filtered to obtain a filtrate. The obtained filtrate was poured into isopropyl ether in an amount of 80 to 100 times the mass of the peptide resin to crystallize, filtered, rinsed with isopropyl ether, and dried to obtain linear crude peptides.

[0149] d. Cyclization The obtained linear crude peptide was dissolved in a 1:1 mixture of acetonitrile and purified water at a concentration of 400 times the crude peptide mass. First, 7.2 eq of DIPEA was added, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified using preparative solutions. The mixture was then freeze-dried to obtain a cyclic peptide intermediate.

[0150] Connecting to e.DOTA The resulting cyclic peptide was dissolved in 10 times its mass of DMF, 4.0 eq DIPEA and 2.0 eq DOTA-NHS were added, and the reaction was monitored by LC-MS until complete. After purification by preparative liquid chromatography, the product was lyophilized to obtain the target product.

[0151] Purity: 96.9%, MS m / z (ESI): 1587.88 [MH] - .

[0152] Example 7. Manufacturing of DOTA-07 [ka] Using a method similar to regimen 1 of Example 1, the target compound DOTA-07 was obtained with a purity of 96.9% and an MS m / z (ESI): 1587.84 [MH]. - .

[0153] Example 8. Manufacturing of DOTA-08 [ka] Using a method similar to regimen 1 of Example 1, the target compound DOTA-08 was obtained with a purity of 96.9% and an MS m / z (ESI): 1587.93 [MH]. - .

[0154] Example 9. Manufacturing of DOTA-09 [ka] a. Loading of the first amino acid onto a solid support CTC resin (substitution degree = 1.09 mmol / g) was selected as the solid support, and the resin was swollen with DMF for 1 hour. Then, an amino acid solution was prepared: 3.00 eq Fmoc-Cys(Trt)-OH and 6.00 eq DIPEA were dissolved in 8 times the mass of resin in DMF, and after uniform stirring, the solution was reacted with the resin for 3 hours. The resin was washed, capped with methanol and DIPEA, washed 4 to 6 times with 8 times the mass of resin in DMF, and then sequentially washed with 8 times the mass of resin in isopropyl ether, DCM, and isopropyl ether. After shrinking the resin, it was dried, the degree of substitution was measured, and then it was prepared for use.

[0155] b. Amino acid coupling In the synthesis, each amino acid was coupled using the general coupling method described below.

[0156] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swollen with 8 times its mass of DMF for 1 hour, and the Fmoc protecting group was removed twice with 8 times its mass of 20% piperidine / DMF solution (5 min the first time, 20 min the second time). After deprotection was complete, the resin was washed 4 to 6 times with 8 times its mass of DMF. Preparation of amino acid activation solution: 3.0 eq amino acids and 3.0 eq HBTU were dissolved in 8 vol DMF, 3.0 eq DIPEA was added and activated for 2 to 5 minutes, and then the reaction was carried out. After the reaction and deprotection were complete, the resin was washed 4 to 6 times with 8 times its mass of DMF. After completing the coupling of the linear peptide resin using the above method, the resin was washed, shrunk, dried, and prepared for use.

[0157] c. Decomposition The obtained peptide resin was decomposed using a decomposition solution. The mixing ratio of the decomposition solution was TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1, and the amount of decomposition solution added was 8 to 10 times the mass of the peptide resin. After decomposition for 2 hours, the solution was filtered to obtain a filtrate. The obtained filtrate was poured into isopropyl ether in an amount of 80 to 100 times the mass of the peptide resin to crystallize, filtered, rinsed with isopropyl ether, and dried to obtain linear crude peptides.

[0158] d. Cyclization The obtained linear crude peptide was dissolved in a 1:1 mixture of acetonitrile and purified water at a concentration of 400 times the crude peptide mass. First, 7.2 eq of DIPEA was added, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified using preparative solutions. The mixture was then freeze-dried to obtain a cyclic peptide intermediate.

[0159] Connecting to e.DOTA The lyophilized powder of the obtained cyclic peptide was dissolved in 10 times its mass of DMF, 4.0 eq DIPEA and 2.0 eq DOTA-NHS were added, and the reaction was monitored by LC-MS until complete. After purification by preparative liquid chromatography, the product was lyophilized to obtain the target product. Purity: 98.9%, MS m / z (ESI): 1637.78 [MH] - .

[0160] Example 10. Manufacturing of DOTA-10 [ka] Using a method similar to regimen 1 of Example 1, the target compound DOTA-10 was obtained with a purity of 99.3% and an MS m / z (ESI): 1637.79 [MH]. - .

[0161] Example 11. Manufacturing of DOTA-11 [ka] Using a method similar to regimen 1 of Example 1, the target compound DOTA-11 was obtained with a purity of 99.4% and an MS m / z (ESI): 1603.76 [MH]. - .

[0162] Example 12. Manufacturing of DOTA-12 [ka] Using a method similar to regimen 1 of Example 1, the target compound DOTA-12 was obtained with a purity of 99.1% and an MS m / z (ESI): 1572.31 [MH]. - .

[0163] Example 13. Manufacturing of DOTA-13 [ka] Using a method similar to regimen 1 of Example 1, the target compound DOTA-13 was obtained with a purity of 98.9% and an MS m / z (ESI): 1590.01 [MH]. -.

[0164] Example 14. Manufacturing of DOTA-14 [ka] Using a method similar to regimen 1 of Example 1, the target compound DOTA-14 was obtained with a purity of 97.4% and an MS m / z (ESI): 1589.87 [MH]. - .

[0165] Example 15. Manufacturing of NOTA-04 [ka] a. Loading of the first amino acid onto a solid support CTC resin (substitution degree = 1.09 mmol / g) was selected as the solid phase support. The resin was swollen with DMF for 1 hour, and then an amino acid solution was prepared: 3.00 eq Fmoc-Cys(Trt)-OH and 6.00 eq DIPEA were dissolved in 8 times the mass of resin in DMF, and after uniform stirring, the solution was reacted with the resin for 3 hours. The resin was washed, capped with methanol and DIPEA, washed 4 to 6 times with 8 times the mass of resin in DMF, and then sequentially washed with 8 times the mass of resin in isopropyl ether, DCM, and isopropyl ether. After shrinking the resin, it was dried, the degree of substitution was measured, and then it was prepared for use.

[0166] b. Amino acid coupling In the synthesis, each amino acid was coupled using the general coupling method described below.

[0167] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swollen with 8 times its mass of DMF for 1 hour, and the Fmoc protecting group was removed twice with 8 times its mass of 20% piperidine / DMF solution (5 min the first time, 20 min the second time). After deprotection was complete, the resin was washed 4 to 6 times with 8 times its mass of DMF. Preparation of amino acid activation solution: 3.0 eq amino acids and 3.0 eq HBTU were dissolved in 8 vol DMF, 3.0 eq DEPEA was added and activated for 2 to 5 minutes, and then the reaction was carried out. After the reaction and deprotection were complete, the resin was washed 4 to 6 times with 8 times its mass of DMF. After completing the coupling of the linear peptide resin using the above method, the resin was washed, shrunk, dried, and prepared for use.

[0168] c. Decomposition The obtained peptide resin was decomposed using a decomposition solution. The mixing ratio of the decomposition solution was TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1, and the amount of decomposition solution added was 8 to 10 times the mass of the peptide resin. After decomposition for 2 hours, the solution was filtered to obtain a filtrate. The obtained filtrate was poured into isopropyl ether in an amount of 80 to 100 times the mass of the peptide resin to crystallize, filtered, rinsed with isopropyl ether, and dried to obtain linear crude peptides.

[0169] d. Cyclization The obtained linear crude peptide was dissolved in a 1:1 mixture of acetonitrile and purified water at a concentration of 400 times the crude peptide mass. First, 7.2 eq of DIPEA was added, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified using preparative solutions. The mixture was then freeze-dried to obtain a cyclic peptide intermediate.

[0170] Linking to e.NOTA The lyophilized powder of the obtained cyclic peptide was dissolved in 10 times its mass of DMF, 4.0 eq DIPEA and 2.0 eq NOTA-NHS were added, and the reaction was monitored by LC-MS until completion. After purification by preparative liquid, the product was lyophilized to obtain the target product.

[0171] Purity: 97.20%, MS m / z (ESI): 1442.89 [MH] - .

[0172] Example 16. Manufacturing of NOTA-05 [ka] Using a method similar to that of Example 15, the target compound NOTA-05 was obtained with a purity of 97.20% and an MS m / z(ESI): 1470.33[M+H]. + .

[0173] Example 17. Manufacturing of NOTA-06 [ka] Using a method similar to that of Example 15, the target compound NOTA-06 was obtained with a purity of 99.2% and an MS m / z (ESI): 1486.94 [MH]. - .

[0174] Example 18. Manufacturing of NOTA-07 [ka] Using a method similar to that of Example 15, the target compound NOTA-07 was obtained with a purity of 99.0% and an MS m / z (ESI): 1486.91 [MH]. - .

[0175] Example 19. Manufacturing of NOTA-08 [ka] Using a method similar to that of Example 15, the target compound NOTA-08 was obtained with a purity of 99.6% and an MS m / z (ESI): 1486.86 [MH]. - .

[0176] Example 20. Manufacturing of NOTA-09 [ka] a. Loading of the first amino acid onto a solid support CTC resin (substitution degree = 1.09 mmol / g) was selected as the solid phase support. The resin was swollen with DMF for 1 hour, and then an amino acid solution was prepared: 3.00 eq Fmoc-Cys(Trt)-OH and 6.00 eq DIPEA were dissolved in 8 times the mass of resin in DMF, and after uniform stirring, the solution was reacted with the resin for 3 hours. The resin was washed, capped with methanol and DIPEA, washed 4 to 6 times with 8 times the mass of resin in DMF, and then sequentially washed with 8 times the mass of resin in isopropyl ether, DCM, and isopropyl ether. After shrinking the resin, it was dried, the degree of substitution was measured, and then it was prepared for use.

[0177] b. Amino acid coupling In the synthesis, each amino acid was coupled using the general coupling method described below.

[0178] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swollen with 8 times its mass of DMF for 1 hour, and the Fmoc protecting group was removed twice with 8 times its mass of 20% piperidine / DMF solution (5 min the first time, 20 min the second time). After deprotection was complete, the resin was washed 4 to 6 times with 8 times its mass of DMF. Preparation of amino acid activation solution: 3.0 eq amino acids and 3.0 eq HBTU were dissolved in 8 vol DMF, 3.0 eq DEPEA was added and activated for 2 to 5 minutes, and then the reaction was carried out. After the reaction and deprotection were complete, the resin was washed 4 to 6 times with 8 times its mass of DMF resin. After completing the coupling of the linear peptide resin using the above method, the resin was washed, shrunk, dried, and prepared for use.

[0179] c. Decomposition The obtained peptide resin was decomposed using a decomposition solution. The mixing ratio of the decomposition solution was TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1, and the amount of decomposition solution added was 8 to 10 times the mass of the peptide resin. After decomposition for 2 hours, the solution was filtered to obtain a filtrate. The obtained filtrate was poured into isopropyl ether in an amount of 80 to 100 times the mass of the peptide resin to crystallize, filtered, rinsed with isopropyl ether, and dried to obtain linear crude peptides.

[0180] d. Cyclization The obtained linear crude peptide was dissolved in a 1:1 mixture of acetonitrile and purified water at a concentration of 400 times the crude peptide mass. First, 7.2 eq of DIPEA was added, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified using preparative solutions. The mixture was then freeze-dried to obtain a cyclic peptide intermediate.

[0181] Linking to e.NOTA The lyophilized powder of the obtained cyclic peptide was dissolved in 10 times its mass of DMF, 4.0 eq DIPEA and 2.0 eq NOTA-NHS were added, and the reaction was monitored by LC-MS until complete. After purification by preparative liquid chromatography, the product was lyophilized to obtain the target product. Purity: 99.7%, MS m / z (ESI): 1536.65 [MH] - .

[0182] Example 21. Preparation of NOTA-12 [ka] Using a method similar to that of Example 15, the target compound NOTA-12 was obtained with a purity of 98.8% and an MS m / z (ESI): 1470.88 [MH]. - .

[0183] Example 22. Preparation of NOTA-13 [ka] Using a method similar to that of Example 15, the target compound NOTA-13 was obtained with a purity of 98.6% and an MS m / z (ESI): 1488.96 [MH]. - .

[0184] Example 23. Preparation of NOTA-14 [ka] Using a method similar to that of Example 15, the target compound NOTA-14 was obtained with a purity of 97.9% and an MS m / z (ESI): 1538.94 [MH]. - .

[0185] Example 24. Preparation of NOTA-15 [ka] Using a method similar to that of Example 15, the target compound NOTA-15 was obtained with a purity of 97.3% and an MS m / z (ESI): 1456.95 [MH]. - .

[0186] Example 25. Preparation of NOTA-16 [ka] Using a method similar to that of Example 15, the target compound NOTA-16 was obtained with a purity of 97.8% and an MS m / z (ESI): 1506.90 [MH]. - .

[0187] Example 26. 68 Manufacturing of Ga-DOTA-05 [ka] With 0.1N hydrochloric acid 68 Rinse the GaCl3 solution, add 0.1 ml of 1 mM sodium acetate aqueous solution to the reaction vessel, then add 0.9 ml of the above 68GaCl3 solution was added. 5 μl of DOTA-05 (1 mg / ml) solution and 67 μl of gentisic acid solution (15 mg / ml) were added and mixed uniformly. The reaction mixture was heated for 15 minutes at pH 3.5-5.0 and 95°C. Radiochemical purity was detected by radio-HPLC and found to be 97.54%.

[0188] If the radiochemical purity is 90% or higher, it can be used directly. If the radiochemical purity is less than 90%, it is purified using a C18 cartridge, rinsed with ethanol, and diluted with physiological saline until the ethanol content is 10% or less.

[0189] Example 27. 68 Manufacturing of Ga-DOTA-06 [ka] Using a method similar to that of Example 26, the target compound 68 Ga-DOTA-06 was obtained, with a radiochemical purity of 92.64%.

[0190] Example 28. 68 Manufacturing of Ga-DOTA-07 [ka] Using a method similar to that of Example 26, the target compound 68 Ga-DOTA-07 was obtained, with a radiochemical purity of 94.76%.

[0191] Example 29. 68 Manufacturing of Ga-DOTA-08 [ka] Using a method similar to that of Example 26, the target compound 68 Ga-DOTA-08 was obtained, with a radiochemical purity of 93.99%.

[0192] Example 30. 68 Manufacturing of Ga-DOTA-09 [ka] With 0.1N hydrochloric acid 68 Rinse the GaCl3 solution, add 0.1 ml of 1 mM sodium acetate aqueous solution to the reaction vessel, then add 0.9 ml of the above 68 GaCl3 solution was added. 5 μl of DOTA-09 (1 mg / ml) solution and 67 μl of gentisic acid solution (15 mg / ml) were added and mixed uniformly. The reaction mixture was heated for 15 minutes at pH 3.5-5.0 and 95°C. Radiochemical purity was detected by radio-HPLC and was found to be 93.38%.

[0193] Example 31. 68 Manufacturing of Ga-DOTA-12 [ka] Using a method similar to that of Example 26, the target compound 68 Ga-DOTA-12 was obtained, with a radiochemical purity of 97.57%.

[0194] Example 32. 68 Manufacturing of Ga-DOTA-13 [ka] Using a method similar to that of Example 26, the target compound 68 Ga-DOTA-13 was obtained, with a radiochemical purity of 95.81%.

[0195] Example 33. 177 Manufacturing of Lu-DOTA-05 [ka] 75 μl of 0.4 M acetic acid / sodium acetate buffer, 7.5 μl of DOTA-05 solution (1 mg / ml), 31.5 μl (15 mg / ml) of gentisic acid solution, and 7-15 mCi Lu-177 radionuclides were sequentially added to a reaction vessel and mixed uniformly. The reaction solution pH was 4.0-4.5 and the mixture was heated for 15 minutes at 90-95°C. After cooling to room temperature, 1.4 ml of diluent (10 mg / ml vitamin C saline solution) was added. Radiochemical purity was detected by radio-HPLC and was found to be 96.28%.

[0196] Example 34. 177 Lu-DOTA-06 Manufacturing [ka] Using a method similar to that of Example 33, the target compound 177 Lu-DOTA-06 was obtained, with a radiochemical purity of 96.18%.

[0197] Example 35. 177 Manufacturing of Lu-DOTA-09 [ka] 75 μl of 0.4 M acetic acid / sodium acetate buffer, 7.5 μl of DOTA-09 solution (1 mg / ml), 31.5 μl (15 mg / ml) of gentisic acid solution, and 7-15 mCi Lu-177 radionuclides were sequentially added to a reaction vessel and mixed uniformly. The reaction solution pH was 4.0-4.5 and the mixture was heated for 15 minutes at 90-95°C. After cooling to room temperature, 1.4 ml of diluent (10 mg / ml vitamin C saline solution) was added. Radiochemical purity was detected by radio-HPLC and was found to be 94.20%.

[0198] Example 36. 177 Manufacturing of Lu-DOTA-13 [ka] Using a method similar to that of Example 33, the target compound 177Lu-DOTA-13 was obtained, with a radiochemical purity of 95.95%.

[0199] Example 37. 177 Manufacturing of Lu-DOTA-14 [ka] Using a method similar to that of Example 33, the target compound 177 Lu-DOTA-14 was obtained, with a radiochemical purity of 97.45%.

[0200] Example 38. 68 Manufacturing of Ga-NOTA-05 [ka] With 0.1N hydrochloric acid 68 Rinse the GaCl3 solution, add 0.1 ml of 1 mM sodium acetate aqueous solution to the reaction vessel, then add 0.9 ml of the above 68 GaCl3 solution was added. 5 μl of NOTA-05 aqueous solution (1 mg / ml) and 67 μl of gentisic acid aqueous solution (15 mg / ml) were added and mixed uniformly. The reaction solution pH was 3.5 to 5.0, and the reaction was carried out for 15 minutes under room temperature conditions. Radiochemical purity was detected by radio-HPLC and was found to be 91.07%.

[0201] If the radiochemical purity is 90% or higher, it can be used directly. If the radiochemical purity is less than 90%, it is purified using a C18 cartridge column, rinsed with ethanol, and diluted with physiological saline until the ethanol content is 10% or less.

[0202] Example 39. 68 Manufacturing of Ga-NOTA-06 [ka] Using a method similar to that of Example 38, the target compound 68 Ga-NOTA-06 was obtained, with a radiochemical purity of 91.38%.

[0203] Example 40. 68 Manufacturing of Ga-NOTA-07 [ka] Using a method similar to that of Example 38, the target compound 68 Ga-NOTA-07 was obtained, with a radiochemical purity of 92.54%.

[0204] Example 41. 68 Manufacturing of Ga-NOTA-09 [ka] With 0.1N hydrochloric acid 68 Rinse the GaCl3 solution, add 0.1 ml of 1 mM sodium acetate aqueous solution to the reaction vessel, then add 0.9 ml of the above 68 GaCl3 solution was added. 5 μl of NOTA-09 aqueous solution (1 mg / ml) and 67 μl of gentisic acid aqueous solution (15 mg / ml) were added and mixed uniformly. The reaction solution pH was 3.5 to 5.0, and the reaction was carried out for 15 minutes under room temperature conditions. Radiochemical purity was detected by radio-HPLC and was found to be 92.36%.

[0205] Example 42. Al 18 Manufacturing of F-NOTA-05 [ka] Dissolve 1 μl of 10 mM NOTA-05 aqueous solution in 50-100 μl of 0.5 M acetic acid / sodium acetate buffer at pH=4.0-4.4, then add 2 mM AlCl3 aqueous solution in a 2:1 molar ratio to obtain 1850 MBq of QMA purified 18F. - 50 μl of ions were added, and the reaction was carried out at 100°C for 10-15 minutes. The solution was purified using an HLB cartridge column, rinsed with ethanol / water (1:1), and diluted with physiological saline until the ethanol content was less than 10%. Radiochemical purity was detected using radio-HPLC, and the radiochemical purity was 92.37%.

[0206] Example 43. Al18 Manufacturing of F-NOTA-09 [ka] Dissolve 1 μl of 10 mM NOTA-09 aqueous solution in 50-100 μl of 0.5 M acetic acid / sodium acetate buffer at pH=4.0-4.4, then add 2 mM AlCl3 aqueous solution in a 2:1 molar ratio to obtain 1850 MBq of QMA purified 18F. - 50 μl of ions were added, and the reaction was carried out at 100°C for 10-15 minutes. The solution was purified using an HLB cartridge column, rinsed with ethanol / water (1:1), and diluted with physiological saline until the ethanol content was less than 10%. Radiochemical purity was detected using radio-HPLC, and the radiochemical purity was 91.57%.

[0207] Example 44. Al 18 Manufacturing of F-NOTA-14 [ka] Using a method similar to that of Example 42, the target compound Al 18 F-NOTA-14 was obtained, with a radiochemical purity of 90.33%.

[0208] Example 45. Al 18 Manufacturing of F-NOTA-15 [ka] Using a method similar to that of Example 42, the target compound Al 18 F-NOTA-15 was obtained, with a radiochemical purity of 92.94%.

[0209] Example 46. Al 18 Manufacturing of F-NOTA-16 [ka] Using a method similar to that of Example 42, the target compound Al 18 F-NOTA-16 was obtained, with a radiochemical purity of 91.60%.

[0210] Example 47. 64 Manufacturing of cu-DOTA-09 [ka] Dissolve 5 μl of 10 mM DOTA-09 aqueous solution in 100 μl of sodium acetate solution with a pH of 3.5-6.5, and then dissolve 1850 MBq of it in 0.1 M hydrochloric acid. 64 50 μl of CuCl2 solution was added, and the reaction was carried out at 80°C for 15 minutes. The solution was purified using a C18 column and diluted with physiological saline until the ethanol content was less than 10%. Radiochemical purity was detected by radio-HPLC and found to be 98.59%.

[0211] Example 48. 64 Manufacturing of Cu-NOTA-09 [ka] Dissolve 5 μl of 10 mM NOTA-09 aqueous solution in 100 μl of sodium acetate solution with a pH of 3.5-6.5, and then dissolve 1850 MBq of it in 0.1 M hydrochloric acid. 64 50 μl of CuCl2 solution was added, and the reaction was carried out at 80°C for 15 minutes. The solution was purified using a C18 column and diluted with physiological saline until the ethanol content was less than 10%. Radiochemical purity was detected by radio-HPLC and found to be 97.37%.

[0212] Example 49. 225 Manufacturing of Ac-DOTA-09 [ka] Add 318 μl of trishydroxymethylaminomethane buffer (pH 8, 0.25 M), 5 μl of DOTA-09 solution (1 μmol / ml), and 20-50 μl of Ci to the reaction vessel. 225Ac radionuclides were added sequentially and mixed uniformly. An appropriate amount of 0.1N hydrochloric acid was added to adjust the pH of the reaction system to 6.0-8.0, and the mixture was heated at 90-95°C for 10-20 minutes. After heating was complete, the mixture was cooled to room temperature, and 0.65 ml of 10 mg / ml sodium ascorbate solution in physiological saline was added. Radiochemical purity was detected using radio-HPLC, and the radiochemical purity exceeded 90%.

[0213] Comparative Example 1. Manufacturing of NOTA-2286 [ka] Using a method similar to that of Example 15, the target compound NOTA-2286 was obtained with a purity of 97.35% and an MS m / z (ESI): 1367.78 [MH]. - .

[0214] Comparative Example 2. Al 18 Manufacturing of F-NOTA-2286 [ka] Using a method similar to that of Example 42, the target compound Al 18 F-NOTA-2286 was obtained, with a radiochemical purity of 95.37%.

[0215] Comparative Example 3. 68 Manufacturing of Ga-NOTA-2286 [ka] Using a method similar to that of Example 38, the target compound 68 Ga-NOTA-2286 was obtained, with a radiochemical purity of 96.29%.

[0216] Comparative Example 4. 68 Manufacturing of Ga-FAP-2286 [ka] Using a method similar to that of Example 26, the target compound 68Ga-FAP-2286 was obtained, with a radiochemical purity of 94.98%. [ka]

[0217] Comparative Example 5. 177 Manufacturing of Lu-FAP-2286 Using a method similar to that of Example 33, the target compound 177 Lu-FAP-2286 was obtained, with a radiochemical purity of 97.76%.

[0218] Biological evaluation The following sections will further explain and interpret this disclosure in conjunction with test examples, but these test examples are not intended to limit the scope of this disclosure.

[0219] Test Example 1: Enzyme Activity Test of FAPα 1.1 Experimental materials and equipment

[0220] [Table 3]

[0221] 1.2 Experimental Steps A 0.5 mM stock solution was prepared by diluting the substrate (Z-Gly-Pro-AMC) with DMSO, and before each experiment, the 0.5 mM stock solution was diluted to 50 μM with PBS to prepare for use. The FAPα protein was diluted to 0.5 ng / μl with PBS to prepare for use. The test compound and positive control were diluted to a concentration of 100 nM or 200 nM with PBS and used to measure the single-point inhibition rate. For compounds whose single-point inhibition rate was equivalent to that of the positive control compound, IC was then performed. 50The values ​​were measured. The test compound and positive control were diluted in PBS to a maximum concentration of 10 μM and a minimum concentration of 0 nM, and a 5-fold gradient dilution was performed using a total of 8 gradients to prepare for use. Test method: 85 μl of FAPα diluent and 10 μl of compound diluent were placed in a microplate and mixed uniformly, incubated at 37°C for 10 min, 5 μl of 50 μM substrate was added and mixed uniformly, and incubated at 37°C for 10 min. The values ​​were read using a microplate reader, with the excitation light at 380 nm and the emission light at 465 nm.

[0222] 1.3 Experimental Results

[0223] [Table 4] [ka]

[0224] Test Example 2: PET / SPECT Imaging Test of Labeled Compounds 2.1 Experimental Materials Cell information: U-87 MG cells (Wuhan Pnuosai Life Science and Technology Co., Ltd.), culture conditions: U-87 MG cell special medium (MEM+10% FBS+1% P / S), passage number: 6 to 9 generations.

[0225] Experimental animals: Strain: B-NDG (Biocytogen Jiangsu Genetic Biotechnology Co., Ltd.), Age: 5-8 weeks old, Weight: 20-24g.

[0226] JPEG2026523267000149.jpg21166

[0227] Instruments: Small animal PET / CT (ediso, nanoScan PET / CT 4heads), activity meter (Capintec, activity meter), electronic balance (Changzhou Shuangjie, DT100).

[0228] 2.2. Experimental Steps Model Building A sufficient quantity of U-87 MG cells was prepared and inoculated into the right forelimb of B-NDG mice at a slightly posterior position, with an inoculation volume of 100 μl, and mixed with 50% Matrigel and 5 × 10⁶ cells. 6 It contains individual cells. After inoculation, tumor volume and animal body weight are monitored twice a week, and when the tumor volume reaches 200-500 m³ 3 We selected a model mouse and incorporated it into this experiment, then randomly divided the groups according to tumor volume.

[0229] Operation Steps 1) Wipe the work surface with 75% medical alcohol, and lay down a sterilized disposable tablecloth. 2) Prepare a 0.5 mL insulin syringe, alcohol swab, cotton swab, and marking pen in the injection room, place them in the mouse fixator, and disinfect the mouse's tail using the alcohol swab. 3) The prepared test sample was administered to each mouse via tail vein, and the time of each injection, the capacity of the syringe, and the capacity of the empty syringe were recorded. 4) After isoflurane anesthesia, the tumor-bearing mouse is placed face down on a PET / SPECT bed and fixed in place. 5) After administration, PET / SPECT static images were collected at different time points, and a whole-body CT scan was performed before each static scan to obtain images of the whole-body distribution of the labeled compound in tumor-bearing mice, and PET / SPECT imaging figures were obtained for each experimental animal at different time points after administration. Major organs were selected and drawn, specifically including areas such as tumors, muscles, skeleton, lungs, brain, liver, and kidneys. 6) Radioactive enrichment and clearance of labeled compounds were observed in tumors and non-target tissues of tumor-bearing mice.

[0230] 2.3 Experimental Results

[0231] [Table 5]

[0232] 68 Ga-DOTA-05 and positive control 68Ga-FAP-2286 shows similar uptake rates in tumors in model mice. 68 Ga-DOTA-06 is taken up by tumors. 68 It was clearly higher than Ga-FAP-2286. 68 Ga-DOTA-05 and 68 Ga-DOTA-06 has lower renal uptake and a higher tumor / renal uptake ratio (Figure 1). Over time, 68 Ga-DOTA-05 and 68 The tumor / kidney uptake ratio of Ga-DOTA-06 increased, 68 The tumor / renal uptake ratio of Ga-FAP-2286 was reduced (Figure 2).

[0233] [Table 6]

[0234] In the mouse model, 68 Ga-DOTA-06, 68 Ga-DOTA-07, 68 Ga-DOTA-08, 68 Ga-DOTA-09, 68 Ga-DOTA-12 and 68 Ga-DOTA-13 was controlled by tumor uptake (Figure 3) and tumor / kidney ratio (Figure 4). 68 It was clearly higher than Ga-FAP-2286.

[0235] [Table 7]

[0236] In the mouse model, 177 Lu-DOTA-09 and 177 Lu-DOTA-14 slowly decreases in tumors and maintains a relatively stable intratumoral presence. 177 Lu-FAP-2286 showed a rapid decrease in intratumoral retention after 4 hours (Figure 5), 177 Lu-DOTA-09 and 177Lu-DOTA-14 is used as a control for tumor / kidney ratio (Figure 6). 177 It was more expensive than Lu-FAP-2286.

[0237] [Table 8]

[0238] In the mouse model, 68 Ga-NOTA-05, 68 Ga-NOTA-06, 68 Ga-NOTA-07 and 68 Ga-DOTA-09 was used as a control for tumor uptake (Figure 7) and tumor / kidney ratio (Figure 8). 68 It was clearly higher than Ga-NOTA-2286.

[0239] [Table 9]

[0240] In the mouse model, Al 18 F-NOTA-09 and Al 18 F-NOTA-14 showed improved tumor uptake (Figure 9) and tumor / kidney ratio (Figure 10) compared to control Al 18 It was clearly higher than F-NOTA-2286.

[0241] Test example 3, 177 Blood concentration experiment of Lu-labeled compounds 3.1 Experimental Materials Laboratory animals: Strain: SD rat (Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.), Age: 5-6 weeks old, Weight: 100-150g.

[0242] Reagent: Sodium chloride injection solution (Shandong Qidu Pharmaceutical).

[0243] Instruments: Activity meter (Capintec), 1:10,000 balance (Sartorius Scientific Instruments, Inc.), low-energy gamma counter (PerkinElmer Instruments, Inc.).

[0244] 3.2. Experimental Steps 1) Empty tubes for gamma-count measurement were weighed and labeled in advance.

[0245] 2) After injecting the test substance into the tail vein of rats, blood was collected from the animals by orbital blood collection at 2 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 24 h, 48 h, and 72 h, respectively, and the sample tubes containing the blood were weighed.

[0246] 3) The net weight of the blood was calculated, and radioactivity was counted on the collected blood using a gamma counter.

[0247] 4) The distribution of the labeled compound in rat blood at different time points was measured. The test sample was accurately diluted 100-fold, 0.5 ml was taken and placed in a counting tube to make a standard 1% ID (i.e., 1% of the injection volume), and the radioactivity count of the 1% ID standard and the organism was simultaneously measured using a gamma counter.

[0248] 5) Pharmacokinetic parameters were calculated using DAS software. Data in rat blood are expressed as the percentage of radioactivity counts per gram of blood relative to the total dose (radioactivity count) (%ID / g). Specific calculation formula: %ID / g = CPM organ or tissue / (Total CPM dose × W organ or tissue) × 100% The data for each sampling point is expressed as mean ± standard deviation (mean ± SD).

[0249] In addition, the drug concentration in the blood was estimated based on the radioactivity count in the blood. Specific calculation formula:

number

[0250] 3.3 Experimental Results

[0251] [Table 10]

[0252] According to the in vivo pharmacokinetic study, 177 Lu-DOTA-09, 177 Lu-DOTA-06, 177 Lu-DOTA-13, 177 Lu-DOTA-14 had longer half-life (t 1 / 2 ) and mean residence time (MRTlast) than Lu-FAP-2286 in rats, which was consistent with the long tumor retention time in mouse imaging studies. 177 Lu-FAP-2286 in mouse imaging studies.

[0253] Test Example 4, In Vivo Pharmacodynamic Experiment of the Compounds of the Present Disclosure in U-87 MG Model Mice 4.1, Cell Information Name: U-87 MG cells Supplier: Wuhan Procell Life Science & Technology Co., Ltd. Product Number: CL-0238 Lot Number: YBMIL8BQH0 Culture Conditions: Special Medium for U-87 MG Cells (90% MEM + 10% FBS + 1% P / S) Passage Number: 23 - 36 passages

[0254] 4.2, Experimental Animals Strain: B-NDG Grade: SPF grade Age: 5 weeks old Weight: 21 - 24 g Gender and Quantity: 90 male mice were introduced and used for the construction of the U-87 MG model, and 40 mice were selected and included. Supplier: Biositegen Jiangsu Gene Biotechnology Co., Ltd. Production License: SCXK (Su) 2021 - 0005. Certificate Number: B202311200038

[0255] 4.3, Experimental Drugs ) Name: 177 Lu-DOTA-09 (manufacture refer to Example 35) Specifications and composition: 31 mCi / 2.5 mL / 37.5 nmol 177 Lu-FAP-2286 (See Comparative Example 5) Specifications and composition: 15.87 mCi / 1.25 mL / 18.75 nmol

[0256] 4.4. Instrument and Equipment Information

[0257] [Table 11]

[0258] 4.5 Reagent Information

[0259] [Table 12]

[0260] 4.6. Experimental Design Approximately 4.5×10 8 A suspension prepared with 100 μL of U-87 MG cells was inoculated into the right forelimb of B-NDG mice at a slightly posterior position, with an inoculation volume of 100 μL, and 50% Matrigel and 5 × 10⁶ cells. 6 It contains individual cells. A total of 90 mice were inoculated, and the mouse tumors grew to approximately 150 cm². 3 Once the tumors had grown to a certain size, 40 individuals with uniform tumor size were selected and included in the study.

[0261] The administration regimen is as follows: Route of administration: Intravenous injection into the tail vein. Dosage volume: 0.03-0.07 mL / animal Frequency and dosage: The control group was administered PBS. 177 The Lu-FAP-2286 group received a single dose of 0.8 mCi / animal. 177 The Lu-DOTA-09 0.4mCi group was given a single dose of 0.4mCi / animal. 177 The Lu-DOTA-09 0.8mCi group was given a single dose of 0.8 mCi / animal. 177Lu-DOTA-09 was administered to two groups of mice at a dose of 0.8 mCi per mouse, in two divided doses, with a 35-day interval between doses. Each group consisted of 8 mice, and the administration time and administration activity for each mouse were recorded in detail.

[0262] 4.7. Operation Steps After tumor modeling, tumor size was observed, tumor volume was measured with a digital caliper the day before or on the day of administration, animal body weight was recorded, and the animals were uniformly divided into five groups according to tumor volume, with each group being a control group. 177 Lu-FAP-2286 0.8 mCi group, 177 Lu-DOTA-09 0.4mCi group, 177 Lu-DOTA-09 0.8mCi group, 177 There are two groups of Lu-DOTA-09 0.8mCi, with 8 individuals in each group.

[0263] The test samples were received on the day of administration and prepared (using the undiluted test solution directly), and the activity of the prepared samples was measured. The workbench was wiped with 75% medical alcohol, and a sterile disposable tablecloth was laid down. A 0.5 mL insulin syringe, alcohol swabs, cotton swabs, and a marking pen were prepared in the injection room. The mice were placed in a fixation device, and their tails were disinfected with alcohol swabs. The prepared test samples were administered intravenously to each mouse, and the time of each injection was recorded.

[0264] Starting the day after administration, begin measuring tumor size and body weight. These measurements should be performed twice a week, recording the longest and shortest diameters of the tumor each time. The measurement location should be kept as consistent as possible. Animal abnormalities and mortality should be recorded in real time. If the average tumor diameter exceeds 20 mm, or if tumor ulceration or necrosis is observed, the animal must be euthanized. Tumor volume calculation method: Tumor volume (mm²) 3 ) = major axis × minor axis × minor axis × 0.52.

[0265] 4.8 Experimental Results and Discussion Tumor growth curve According to the experimental results, different doses 177Lu-DOTA-09 showed some degree of tumor growth inhibitory effect in U-87 MG model mice (Figure 11).

[0266] U-87 MG tumors grow rapidly; in the control group, the tumor size was already 3057.58 ± 715.73 mm 20 days after administration. 3 Reached 177 The tumor size in the Lu-FAP-2286 0.8 mCi group was 1833.89 ± 338.00 mm. 3 And, 177 The tumor size in the Lu-DOTA-09 0.4 mCi group was 790.09 ± 618.40 mm. 3 And, 177 Lu-DOTA-09 0.8 mCi group and 177 The tumor size in the Lu-DOTA-09 0.8 mCi*2 group was 314.25 ± 65.57 mm, respectively. 3 and 326.04±82.5mm 3 On day 20 after administration, the tumor suppression rates for the four treatment groups were 40.02%, 74.16%, 89.72%, and 89.34%, respectively.

[0267] 35 days after the first dose, 177 In the Lu-DOTA-09 0.8 mCi*2 group, a second dose was administered, and tumor growth could be continuously suppressed.

[0268] On the 46th day after administration, 177 The tumor size in the Lu-DOTA-09 0.8 mCi group was 3605.05 ± 803.40 mm. 3 And, 177 The tumor size in the Lu-DOTA-09 0.8 mCi*2 group was 1735±482.69 mm. 3 That is the case.

[0269] Mouse weight 177 During the Lu-DOTA-09 administration period, mouse body weight was simultaneously monitored, and no significant changes in body weight were observed in any of the four dose groups. 177Lu-DOTA-09 did not cause the toxic side effect of weight loss in tumor-bearing animals (Figure 12).

[0270] Mouse survival period According to the statistics, 177 Lu-DOTA-09 significantly improved the survival rate of U-87 MG model mice (13). In the control group, tumor overload appeared from day 20 after administration, and all mice died from tumor burden on day 42, with a median survival time of 35 days. 177 In the Lu-DOTA-09 0.8 mCi*2 mouse group, approximately half of the mice were still alive at 59 days post-administration. 177 Lu-DOTA-09 was shown to significantly improve the survival of tumor-bearing mice. Statistically, compared to the control group, 177 Lu-FAP-2286 0.8 mCi group, 177 Lu-DOTA-09 0.4mCi group, 177 Lu-DOTA-09 0.8mCi group and 177 The median survival times for the Lu-DOTA-09 0.8mCi*2 group were 35 days, 39 days, 42 days, 49 days, and 57.5 days, respectively.

[0271] Experimental conclusion 177 Lu-DOTA-09 is 177 As a Lu-labeled radiotarget drug, it significantly suppressed the growth of FAP-positive tumors in U-87 MG model mice and extended the survival time of the mice.

Claims

1. A compound shown in formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Here, R １ａ , R １ｂ Each is independently selected from either a hydrogen or a methyl group. The aforementioned v is selected from 0 or 1. Said G １ is selected from -(CO)-L-R １ｃ wherein L is selected from C ３－２０ alkylene groups, and R １ｃ is a methyl group or -NH-(C=NH)-NR １ｄ R １ｆ selected from １ｄ wherein R １ｆ , R １ｆ are each independently selected from hydrogen or a methyl group, or said G １ is 【Chemistry 2】 Selected from, where u is an integer selected from 1 to 5, The aforementioned R ２ａ , R ２ｂ , R ２ｃ Each of them independently consists of hydrogen or C １－３ Selected from alkyl groups, The aforementioned R ３ａ , R ３ｂ These are, independently, hydrogen and C １－３ Selected from alkyl groups, or R ３ａ , R ３ｂ Together with the atoms to which they are linked, each forms a 5-6 member nitrogen-containing heterocycloalkyl group, and the C １－３ Alkyl alkyl groups or 5-6 member nitrogen-containing heterocycloalkyl groups optionally contain 1, 2, or 3 R groups. Ａ Replaced by the R Ａ They are the same or different, hydroxyl group, amino group, halogen, C １－３ Alkyl or halo C １－３ Selected from alkyl groups, The aforementioned R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ These are, independently, hydrogen, hydroxyl group, amino group, halogen, and C. １－３ Alkyl or halo C １－３ Selected from alkyl groups, The aforementioned R ５ａ It is selected from hydrogen or a methyl group, The aforementioned R ５ｂ C １－６ Selected from alkyl groups, 6-10 membered aryl groups, or 5-6 membered heteroaryl groups, the C １－６ Alkyl groups, 6-10 membered aryl groups, or 5-6 membered heteroaryl groups optionally have 1 or 2 R Ｂ Replaced by the R Ｂ They are the same or different, hydroxyl group, amino group, halogen, -CONH ２ Selected from, The aforementioned m is selected from 1, 2, or 3, CH ２ In this case, hydrogen can optionally be a hydroxyl group, halogen, or C １－３ Substituted with one or more alkyl groups, 6-10 membered aryl groups, or 5-6 membered heteroaryl groups, The aforementioned R ６ａ It is selected from a hydroxyl group or an amino group, The aforementioned n is selected from 1, 2, or 3. The aforementioned R ７ａ , R ７ｂ These are, independently, hydrogen and C １－３ Selected from alkyl groups, The aforementioned q is selected from 0 or 1. The ring A is selected from a phenyl group, a pyridyl group, a naphthyl group, or a thienyl group. The aforementioned R ７ｃ These are, independently, halogen, nitro group, amino group, cyano group, hydroxyl group, and C １－６ Alkyl alkyl group, C １－６ Alkoxy group, hydroxy C １－６ Selected from alkyl groups, trifluoromethyl groups, difluoromethyl groups, and trifluoroethyl groups, The aforementioned p is selected from 0, 1, 2, or 3. The aforementioned R ８ａ , R ８ｂ These are, independently, hydrogen, -COOH, and -CONH. ２ ,CH ２ -OH, -CONHR ８ｃ , -(CO)-(NR ８ｃ )-R ８ｄ Selected from, the R ８ｃ , R ８ｄ Each of them is independent of C １－６ Selected from alkyl groups, The aforementioned r is selected from 0 or 1. The aforementioned s is selected from 0 or 1. The aforementioned X is O, S, or NR ９ Selected from, the R ９ is hydrogen or C １－６ Selected from alkyl groups, The aforementioned t is selected from 1, 2, 3, 4, 5 or 6. The aforementioned R １０ is hydrogen or C １－６ Selected from alkyl groups, The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is a chelating agent or hydrogen, and the chelating agent optionally complexes with a nuclide, preferably Y is a chelating agent.

2. The compound shown in formula (II) or a pharmaceutically acceptable salt thereof, 【Transformation 3】 The aforementioned R １ａ , R １ｂ , v, G １ , R ２ａ , R ２ｂ , R ２ｃ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , R ５ａ , R ５ｂ , m, R ６ａ ,n,R ７ａ , R ７ｂ , q, ring A, R ７ｃ , p, R ８ａ , R ８ｂ , r, s, X, t, R １０ Y is as defined in claim 1, the compound represented by formula (I) in claim 1 or a pharmaceutically acceptable salt thereof.

3. Said R ２ａ is a hydrogen or methyl group, and R ２ｂ , R ２ｃ are each independently selected from a hydrogen or methyl group, preferably, said R ２ｂ is hydrogen, said R ２ｃ is a methyl group, or said R ２ｂ , R ２ｃ are both methyl groups, the compound represented by formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

4. The aforementioned R ４ａ , R ４ｂ Each is independently selected from hydrogen and a hydroxyl group, preferably the R ４ａ is hydrogen, and the R ４ｂ The compound represented by formula (I) according to any one of claims 1 to 3, wherein is a hydroxyl group, or a pharmaceutically acceptable salt thereof.

5. The R ２ａ is hydrogen or a methyl group, and the R ２ｂ , R ２ｃ are each independently selected from hydrogen or a methyl group, at least one being a methyl group, the R ４ａ is hydrogen, the R ４ｂ is a hydroxy group, the R ４ｃ , R ４ｄ are each independently selected from hydrogen, a compound represented by the formula (I) according to claim 3 or 4, or a pharmaceutically acceptable salt thereof. e

6. The aforementioned R ３ａ , R ３ｂ These are, independently, hydrogen and C １－３ Selected from alkyl groups, the C １－３ The alkyl group optionally consists of 1, 2, or 3 R Ａ Replaced by the R Ａ They are the same or different, hydroxyl group, amino group, halogen, C １－３ Alkyl or halo C １－３ Selected from alkyl groups, preferably the R ３ａ is a methyl group, and the R ３ｂ The compound represented by formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

7. The aforementioned R ３ａ , R ３ｂ Each atom, together with the linked atoms, forms a five-membered nitrogen-containing heterocycloalkyl group, and the five-membered nitrogen-containing heterocycloalkyl group optionally contains 1, 2, or 3 R atoms. Ａ Replaced by the R Ａ They are the same or different, hydroxyl group, amino group, halogen, C １－３ Alkyl or halo C １－３ A compound represented by formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from alkyl groups, preferably the five-membered nitrogen-containing heterocycloalkyl group is unsubstituted.

8. The aforementioned R ７ａ , R ７ｂ These are, independently, hydrogen and C １－３ Selected from alkyl groups, The aforementioned q is selected from 0 or 1. The ring A is selected from a phenyl group or a naphthyl group. The aforementioned R ７ｃ These are, independently, halogen, nitro group, amino group, cyano group, hydroxyl group, and C １－６ Alkyl alkyl group, C １－６ Alkoxy group, hydroxy C １－６ Selected from alkyl groups, trifluoromethyl groups, difluoromethyl groups, and trifluoroethyl groups, The aforementioned p is selected from 0, 1, 2, or 3. Preferably, The aforementioned R ７ａ , R ７ｂ Each is independently selected from hydrogen, The aforementioned q is 0, The ring A is selected from phenyl groups, The aforementioned R ７ｃ Each of these is independently selected from fluorine, chlorine, bromine, iodine, or a trifluoromethyl group, a difluoromethyl group, or a trifluoroethyl group. The p is selected from 0, 1, or 2, and is a compound represented by formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. The aforementioned R １ａ , R １ｂ Each is independently selected from either a hydrogen or a methyl group. The aforementioned v is selected from 0 or 1. The aforementioned G １ is -(CO)-LR １ｃ Selected from, L is C ３－２０ Selected from alkylene groups, the R １ｃ It is selected from methyl groups, Preferably, the R １ａ , R １ｂ Each is independently selected from hydrogen, The aforementioned v is selected from 0, The aforementioned G １ is -(CO)-LR １ｃ Selected from, L is C ４－１４ Selected from alkylene groups, the R １ｃ is a compound represented by formula (I) according to any one of claims 1 to 8, selected from methyl groups, or a pharmaceutically acceptable salt thereof.

10. The aforementioned R １ａ , R １ｂ Each is independently selected from either a hydrogen or a methyl group. The aforementioned v is selected from 0 or 1. The aforementioned G １ is -(CO)-LR １ｃ Selected from, L is C ３－２０ Selected from alkylene groups, the R １ｃ is -NH-(C=NH)-NR １ｄ R １ｆ Selected from, the R １ｄ , R １ｆ Each is independently selected from either a hydrogen or a methyl group. Preferably, The aforementioned R １ａ , R １ｂ Each is independently selected from hydrogen, The aforementioned v is selected from 0, The aforementioned G １ is -(CO)-LR １ｃ Selected from, L is C ４－１４ Selected from alkylene groups, the R １ｃ is -NH-(C=NH)-NR １ｄ R １ｆ Selected from, the R １ｄ , R １ｆ Each of these is independently selected from a hydrogen or a methyl group, and is a compound represented by formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

11. The aforementioned R １ａ , R １ｂ Each is independently selected from either a hydrogen or a methyl group. The aforementioned v is selected from 0 or 1. The aforementioned G １ teeth, 【Chemistry 4】 Selected from, where u is an integer selected from 1 to 5, Preferably, The aforementioned R １ａ , R １ｂ Each is independently selected from hydrogen, The aforementioned G １ teeth, 【Transformation 5】 Selected from, The aforementioned v is selected from 0, The above u is a compound represented by formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from 1 or 2.

12. The aforementioned R ５ａ It is selected from hydrogen, The aforementioned R ５ｂ C １－６ Selected from alkyl groups, the C １－６ The alkyl group optionally consists of one or two R Ｂ Replaced by the R Ｂ They are the same or different, selected from a hydroxyl group or a halogen. The aforementioned m is selected from 0 or 1, CH ２ In this case, hydrogen can optionally be a hydroxyl group, halogen, or C １－３ Replaced with one or more alkyl groups selected from: The above n is 2, The aforementioned R ６ａ It is an amino group, The aforementioned R ８ａ , R ８ｂ These are, independently, hydrogen, -COOH, and -CONH. ２ Selected from, with at least one being -COOH, -CONH ２ The compound represented by formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein r is 1.

13. The compound shown in formula (III) or a pharmaceutically acceptable salt thereof, 【Transformation 6】 The aforementioned R ２ａ is a hydrogen or methyl group, The aforementioned R ２ｂ , R ２ｃ Each is independently selected from hydrogen or a methyl group, and at least one is a methyl group. The aforementioned R ３ａ , R ３ｂ These are, independently, hydrogen and C １－３ Selected from alkyl groups, the C １－３ The alkyl group optionally consists of 1, 2, or 3 R Ａ Replaced by the R Ａ They are the same or different, hydroxyl group, amino group, halogen, C １－３ Alkyl or halo C １－３ Selected from alkyl groups, or the R ３ａ , R ３ｂ Each atom, together with the linked atoms, forms a five-membered nitrogen-containing heterocycloalkyl group, and the five-membered nitrogen-containing heterocycloalkyl group optionally contains 1, 2, or 3 R atoms. Ａ Replaced by the R Ａ They are the same or different, hydroxyl group, amino group, halogen, C １－３ Alkyl or halo C １－３ Selected from alkyl groups, The aforementioned R ４ａ is hydrogen, fluorine, or a trifluoromethyl group, and the R ４ｂ These are fluorine and a hydroxyl group, The aforementioned R ４ｃ , R ４ｄ Each is independently selected from hydrogen, The aforementioned R ７ｃ Each of these is independently selected from fluorine, chlorine, bromine, iodine, or a trifluoromethyl group, a difluoromethyl group, or a trifluoroethyl group. The aforementioned p is selected from 0, 1, or 2. The aforementioned G １ s, X, t, R １０ Y is as defined in claim 1, the compound represented by formula (I) in claim 1 or a pharmaceutically acceptable salt thereof.

14. The aforementioned R ４ａ is hydrogen, and the R ４ｂ The compound represented by formula (I) in claim 13 or a pharmaceutically acceptable salt thereof, wherein is a hydroxyl group.

15. The aforementioned R ３ａ is a methyl group, and the R ３ｂ The compound represented by formula (I) in claim 14 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

16. The aforementioned R ３ａ , R ３ｂ The compounds represented by formula (I) according to claim 14 or pharmaceutically acceptable salts thereof, wherein each atom, together with the linked atoms, forms a five-membered nitrogen-containing heterocycloalkyl group, and the five-membered nitrogen-containing heterocycloalkyl group is unsubstituted.

17. The aforementioned s is 1, X is S, and R １０ The compound represented by formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

18. The aforementioned G １ is -(CO)-LR １ｃ Selected from, L is C ４－１４ Selected from alkylene groups, the R １ｃ is selected from methyl groups, preferably L is C ４ Alkylene group, C ６ Alkylene group, C ８ Alkylene group, C １０ Alkylene group, C １２ Alkylene group or C １４ A compound represented by formula (I) according to claim 17, or a pharmaceutically acceptable salt thereof, selected from alkylene groups.

19. The aforementioned G １ is -(CO)-LR １ｃ Selected from, where L is -(CO)-L-R １ｃ Selected from, L is C ４－１４ Selected from alkylene groups, the R １ｃ is -NH(C=NH)-NR １ｄ R １ｆ Selected from, the R １ｄ , R １ｆ Each is independently selected from hydrogen or a methyl group, and preferably L is C ４ Alkylene group, C ５ Alkylene group or C ６ A compound represented by formula (I) according to claim 17, or a pharmaceutically acceptable salt thereof, selected from alkylene groups.

20. The aforementioned G １ teeth, 【Transformation 7】 A compound represented by formula (I) according to claim 17 or a pharmaceutically acceptable salt thereof, selected from, wherein u is selected from 1 or 2.

21. The fragments connected to Y are group 1: 【Transformation 8】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound represented by formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, selected from among.

22. The chelating agents mentioned above are DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, DFO, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, and NxS. ４ -x(N) ４ , N ２ S ２ , N ３ S), Hynic, 99mTc(CO) ３ - Chelating agents, 【Chemistry 9】 【change】 Selected from, preferably DOTA, DOTAGA, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, N ４ A compound represented by formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, most preferably DOTA, DOTAGA, NOTA and NODAGA.

23. Group 4: 【Chemistry 10】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound represented by formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, selected from among.

24. The chelating agent complexes with a nuclide, and the nuclide includes a diagnostically active nuclide or a therapeutically active nuclide, and the diagnostically active nuclide is ４３ Sc, ４４ Sc, ５１ Mn, ５２ Mn, ６４ Cd, ６７ Ga, ６８ Ga, ８６ Y, ８９ Zr, ９４ｍ Tc, ９９ｍ Tc, １１１ In, １５２ Tb, １５５ Tb, ２０１ Tl, ２０３ Pb, １８ F, ７６ Br, ７７ Br, １２３ I, １２４ I, １２５ Selected from I, preferably, ４３ Sc, ４４ Sc, ６４ Cd, ６７ Ga, ６８ Ga, ８６ Y, ８９ Zr, ９９ｍ Tc, １１１ In, １５２ Tb, １５５ Tb, ２０３ Pb, １８ F, ７６ Br, ７７ Br, １２３ I, １２４ I, １２５ I is most preferably, ６４ Cd, ６８ Ga, ８９ Zr, ９９ｍ Tc, １１１ In, １８ F, １２３ I and １２４ I is the therapeutically active nuclide, ４７ Sc, ６７ Cd, ８９ Sr, ９０ Y, １５３ Sm, １４９ Tb, １６１ Tb, １７７ Lu, １８６ Re, １８８ Re, ２１２ Pb, ２１３ Bi, ２２３ Ra, ２２５ Ac, ２２６ Th, ２２７ Th, １３１ I, ２１１ Selected from At, preferably, ４７ Sc, ６７ Cd, ９０ Y, １７７ Lu, １８８ Re, ２１２ Pb, ２１３ Bi, ２２５ Ac, ２２７ Th, １３１ I, ２１１ At is most preferably, ９０ Y, １７７ Lu, ２２５ Ac, ２２７ Th, １３１ I and ２１１ A compound represented by formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein At. 【Request Item 25】 【Chemistry 11】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound represented by formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, selected from among.

26. A pharmaceutical composition comprising a compound represented by formula (I) as described in any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

27. A method for producing a compound represented by formula (I) according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, wherein the method comprises the step of complexing the compound or a pharmaceutically acceptable salt thereof with a radionuclide.

28. Uses of a compound represented by formula (I) according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, in the manufacture of a drug for diagnosing or treating a disease, wherein the disease is a disease relating to fibroblast-activating protein (FAP), preferably, the disease relating to fibroblast-activating protein (FAP) is a disease related to the upregulation of fibroblast-activating protein (FAP) expression, and more preferably, the disease relates to diseased tissue, such as a tumor or cancer, containing cells that exhibit upregulation of fibroblast-activating protein (FAP) expression or cells that exhibit upregulation of fibroblast-activating protein (FAP) expression.

29. Uses of a compound represented by formula (I) according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, in the manufacture of a drug for diagnosing or treating a disease, wherein the disease is a tumor or cancer, and the tumor or cancer is selected from solid tumors, epithelial tumors, bladder cancer, breast cancer, cervical cancer, colorectal cancer, bile duct cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, head and neck cancer, liver cancer, lung cancer, melanoma, mesothelioma, neuroendocrine tumors and cancers, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, salivary gland cancer, sarcoma, squamous cell carcinoma, glioma (e.g., human glioblastoma astrocytoma), and thyroid cancer (e.g., medullary thyroid carcinoma).

30. Uses of a compound represented by formula (I) according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, in the manufacture of a drug for diagnosing or treating a disease, wherein the disease is selected from inflammatory diseases, cardiovascular diseases, autoimmune diseases and fibrotic diseases.

31. A method for producing a compound represented by formula (I) according to claim 24 or 25 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, the method comprising the step of complexing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof with a nuclide, 【Chemistry 12】 The aforementioned Y is a chelating agent, and the chelating agent complexes with the nuclide, and the aforementioned R １ａ , R １ｂ , v, G １ , R ２ａ , R ２ｂ , R ２ｃ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , R ５ａ , R ５ｂ , m, R ６ａ ,n,R ７ａ , R ７ｂ , q, ring A, R ７ｃ , p, R ８ａ , R ８ｂ , r, s, X, t, R １０ A manufacturing method as defined in claims 1 to 25.

32. A method for producing a compound represented by formula (I) according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, wherein the method comprises the step of reacting a compound represented by formula (I-1) with a chelating agent, 【Chemistry 13】 The aforementioned R １ａ , R １ｂ , v, G １ , R ２ａ , R ２ｂ , R ２ｃ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , R ５ａ , R ５ｂ , m, R ６ａ ,n,R ７ａ , R ７ｂ , q, ring A, R ７ｃ , p, R ８ａ , R ８ｂ , r, s, X, t, R １０ A manufacturing method as defined in claims 1 to 25.

33. A compound shown in formula (I-2) or a pharmaceutically acceptable salt thereof, 【Chemistry 14】 The aforementioned R １ａ , R １ｂ , v, G １ , R ２ａ , R ２ｂ , R ２ｃ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , R ５ａ , R ５ｂ , m, R ６ａ ,n,R ７ａ , R ７ｂ , q, ring A, R ７ｃ , p, R ８ａ , R ８ｂ , r is as defined in claims 1 to 25, the compound shown in formula (I-2) or a pharmaceutically acceptable salt thereof.

34. A method for producing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 13 to 25, the method comprising the step of reacting a compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof with 2-aminoethanethiol, 1,3,5-tris(bromomethyl)benzene, 【Chemistry 15】 Y is hydrogen, and R １０ is hydrogen, t is 1, X is a sulfur atom, s is 1, The aforementioned R ２ａ , R ２ｂ , R ２ｃ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , R ７ｃ , p, G １ The manufacturing method is as defined in paragraphs 13 to 25.

35. The manufacturing method according to claim 31 or 32, further comprising the step in the manufacturing method according to claim 34.

36. A compound shown in formula (III-1) or a pharmaceutically acceptable salt thereof, 【Chemistry 16】 The aforementioned R ２ａ , R ２ｂ , R ２ｃ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , R ７ｃ , p, G １ The compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof, as defined in claims 13 to 25.

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