Bicyclic peptide compound, nuclide complex containing same, pharmaceutical composition of bicyclic peptide compound and application of bicyclic peptide compound and nuclide complex

Abstract

The invention provides a Nectin-4 targeting bicyclic peptide compound as shown in a formula (I), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof as a nuclide ligand, and belongs to the field of medicines. The invention also provides a complex containing the bicyclic peptide compound, the bicyclic peptide compound is further connected with radionuclide, a pharmaceutical composition containing the complex, and application of the complex and the pharmaceutical composition in preparation of drugs for preventing, treating, treating and / or alleviating cancers. # imgabs0 #

Description

Field of the Invention

[0001] The present invention belongs to the field of medicine, and specifically relates to a new class of bicyclic peptide compounds, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, as radionuclide ligands. The present invention also provides a complex comprising the bicyclic peptide compound of the present invention, wherein the bicyclic peptide compound is further connected to a radionuclide, a pharmaceutical composition comprising the complex, and the use of the complex and the pharmaceutical composition thereof in the preparation of a drug for preventing, treating, curing, and / or alleviating cancer. Background of the Invention

[0003] Nectin-4 is a single-chain intercellular adhesion molecule with a molecular weight of 66 kDa. It belongs to the Nectin family and is mainly present on the cell membrane surface. It forms multiple important adhesion binding sites in the extracellular structure. Nectin-4 has a complex and precise molecular structure, which includes three Immunoglobulin superfamily domains (Ig-like domains), namely V-type, C1-type and C2-type domains. These domains give Nectin-4 special functions in cell adhesion. Among them, the V-type domain can bind to Nectin-4 on the surface of homologous or heterologous cells to form intercellular adhesion connections; C1 and C2 domains are involved in regulating a series of signal transductions in this process. Nectin-4 forms physical connections between adjacent cells, which is essential for achieving intercellular communication, migration and cellular processes. Through its interaction with other intercellular adhesion molecules, it regulates cell morphology, maintains the integrity of tissue structure, and plays a regulatory role in the interaction of immune cells.

[0004] Nectin-4 is mainly expressed in the embryonic period and its expression declines in adulthood. Normal human tissues show weak to moderate immunohistochemical expression of Nectin-4, including the placenta, skin, salivary glands, esophagus and stomach. In contrast, Nectin-4 is widely present in solid tumors, and is highly expressed in tumors such as urothelial carcinoma, breast cancer, lung cancer, head and neck cancer, pancreatic cancer, and ovarian cancer. It promotes tumor proliferation and migration by activating the P13K / Akt pathway. Therefore, Nectin-4 has become a hot topic in the field of cancer research and is considered to be a highly specific tumor biomarker for imaging and targeted therapy.

[0005] Integrated diagnosis and treatment is the combination of imaging diagnosis and internal irradiation therapy using different diagnostic and therapeutic radionuclide probes, thereby achieving the purpose of visual diagnosis and precise treatment, that is, diagnostic radiopharmaceutical molecular imaging, usually using 68 Ga labeling can show lesions; lesions can also be targeted for uptake 177Radioactive drugs labeled with Lu or other therapeutic radionuclides can achieve personalized diagnosis and treatment by precisely treating discovered lesions.

[0006] The research and development of drugs targeting Nectin-4 covers multiple directions, including monoclonal antibody drugs, antibody-drug conjugates (ADCs), peptide-drug conjugates (PDCs), radionuclide-drug conjugates (RDCs) diagnostic agents, etc. Astellas' Padcev received FDA Fast Track certification in 2019 for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or after treatment with PD-1 / PD-L1 inhibitors. It is the first approved ADC targeting Nectin-4. Because the drug uses the non-site-specific conjugation technology of the first-generation ADC, it has problems with low specific uptake, weak tumor penetration, and high immunogenicity. Other ADC drugs targeting Nectin-4 are also generally limited by defects such as large antibody molecular weight, high immunogenicity, long metabolism time in the body, poor cell membrane permeability, and high blood background. In terms of imaging agents targeting Nectin-4, 68 Ga-labeled N188 is suitable for the diagnosis of metastatic urothelial carcinoma, but it has many defects such as short half-life, fast clearance, and short drug retention time in the tumor, which makes the probe only suitable for cancer lesion localization imaging and unsuitable for targeted therapy. However, it also fully demonstrates that the radionuclide drug conjugate (RDC) targeting Nectin-4 can specifically identify tumor cells through the targeting ligand, and then combine with radioactive isotopes to achieve efficient integration of diagnosis and treatment. Therefore, RDC drugs that integrate diagnosis and treatment can achieve accurate diagnosis, targeted treatment, individualized treatment, and efficacy evaluation, and have good advantages in clinical application.

[0007] The present invention provides a bicyclic peptide compound targeting nectin-4, which is used as a nuclide ligand and combined with different radionuclides to obtain a nuclear medicine small molecule diagnostic and therapeutic agent that can be used to target nectin-4 and can achieve a combination of diagnosis and treatment. The bicyclic peptide radionuclide complex of the present invention has high tumor uptake, good in vivo metabolic performance, good half-life, and has very good clinical application prospects. Summary of the invention

[0008] The present invention provides a novel bicyclic peptide compound targeting nectin-4, which, as a nuclide ligand, is further connected to a radionuclide (e.g., a diagnostic nuclide, a therapeutic nuclide) through DOTA or NOTA or other chelating agents to form a bicyclic peptide radionuclide complex. The bicyclic peptide radionuclide complex provided by the present invention can be used for preventing, treating, treating, alleviating, and / or diagnosing cancer in a subject in need thereof, has high tumor uptake, good in vivo metabolic performance, and good half-life in the patient's body, and has very good clinical application prospects.

[0009] In one aspect, the present invention provides a compound targeting nectin-4, which has a structure shown in formula (I):

[0010]

[0011] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;

[0012] in,

[0013] L is

[0014] represents the attachment point connected to R;

[0015] y1 is 0 or 1; y2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; y3 is 0 or 1;

[0016] y1, y2 and y3 are not 0 at the same time;

[0017] y4 is 0, 1, 2, 3, or 4;

[0018] k1 is 0 or 1; k2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; k3 is 0 or 1; k4 is 0 or 1; k5 is 0 or 1;

[0019] When multiple Q1 appear, each Q1 is independently selected from -CH2-, -CH2OCH2-, phenylene (e.g. ), cyclohexylene (e.g. );

[0020] When multiple Q2 appear, each Q2 is independently selected from -CH2-, -CH2OCH2-, phenylene (e.g. ), cyclohexylene (e.g. );

[0021] Optionally, each Q1 and Q2 is replaced by 0, 1, 2, 3, 4 or 5 independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, -(CH2) t3 -C(=O)OR a 、-(CH2) t3 -C(=O)NHR a 、-(CH2) t3 -S(=O)2OR a and -(CH2) t3 -S(=O)2NHR a The group substitution;

[0022] When multiple R e and R f , each R e and R f are independently selected from: H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, -(CH2) t3 -C(=O)OR a 、-(CH2) t3 -C(=O)NHR a 、-(CH2) t3 -S(=O)2OR a and -(CH2) t3 -S(=O)2NHR a ;

[0023] When multiple R c and R d , each R c and R d Independently selected from: H, -C 1-22 Aliphatic-C 3-7 Heterocyclic group, -C 1-22 Aliphatic-C 3-8 Cycloalkyl, -C 1-22 Aliphatic-C 6-10 Aryl, -C 1-22 Aliphatic-C 1-9 Heteroaryl, -(CH2) t2 -OC(=O)R a 、-(CH2) t2 -NHC(=O)R a 、-(CH2) t2 -C(=O)OR a 、-(CH2) t2 -C(=O)NHR a 、-(CH2)t2 -C(=O)R a 、-(CH2) t2 -S(=O)2OR a 、-(CH2) t2 -S(=O)2NHR a or -(CH2) t2 -S(=O)2R a ; said C 3-7 Heterocyclic group, C 3-8 Cycloalkyl, C 6-10 Aryl or C 1-9 Each heteroaryl is independently, optionally substituted by 0, 1, 2, 3, 4 or 5 independently selected from oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution with haloalkyl and halosilyl (e.g. di-tert-butylfluorosilyl) groups;

[0024] R a At each occurrence, it is independently H, C 6-10 Aryl, -C 1-22 Aliphatic, -C 1-22 Aliphatic -C(=O)OR b , -C 1-22 Aliphatic -C(=O)NHR b , -C 1-22 Aliphatic-C 3-7 Heterocyclic group, -C 1-22 Aliphatic-C 3-8 Cycloalkyl, -C 1-22 Aliphatic-C 6-10 Aryl, or -C 1-22 Aliphatic-C 1-9 Heteroaryl; wherein the C 6-10 Aryl, C 1-22 Aliphatic, -C 1-22 Aliphatic -C(=O)OR b , -C 1-22 Aliphatic-C 3-7 Heterocyclic group, -C 1-22 Aliphatic-C 3-8 Cycloalkyl, -C 1-22 Aliphatic-C 6-10 Aryl and -C 1-22 Aliphatic-C 1-9 The heteroaryl group is optionally substituted by 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Substitution with haloalkyl and halosilyl (e.g. di-tert-butylfluorosilyl) groups;

[0025] R b At each occurrence, each is independently H, or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN and -NO2;

[0026] t2 is independently 0, 1, 2, 3, 4 or 5 at each occurrence;

[0027] t3 is independently 0, 1, 2, 3, 4 or 5 at each occurrence;

[0028] R is

[0029] R 1 yes

[0030] n is 1, 2, or 3.

[0031] In some embodiments, L is selected from:

[0032]

[0033]

[0034] Among them, y 4a Is 1, 2, or 3.

[0035] In some embodiments, L is in represents the attachment point connected to R;

[0036] X 1 and X 2 Each independently does not exist, or each independently has the structure shown in the following formula:

[0037] Where X 1 and X 2 The groups represented by are each optionally and independently substituted by 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, -(CH2) t3 -C(=O)OR a、-(CH2) t3 -C(=O)NHR a , and -(CH2) t3 -S(=O)2OR a and -(CH2) t3 -S(=O)2NHR a The group substitution;

[0038] X 3 At each occurrence, each independently does not exist, or each independently is

[0039] X 4 Does not exist, or X 4 is -C(=O)-(CH2) m1 - or -C(=O)-(CH2) m1 -C(=O)-;

[0040] X 5 Yes -(CH2-O-CH2) m2 -CH2-NH- or -NH-CH2-(CH2-O-CH2) m2 -CH2-NH-;

[0041] R is

[0042] R 1 yes

[0043] R 2 At each occurrence, each is independently -C 1-22 Aliphatic-C 6-10 Aryl, -(CH2) t2 -C(=O)OR a 、-(CH2) t2 -C(=O)NHR a 、-(CH2) t2 -C(=O)R a 、-(CH2) t2 -S(=O)2OR a 、-(CH2) t2 -S(=O)2NHR a , or -(CH2) t2 -S(=O)2R a ;

[0044] R a At each occurrence, it is independently H, C 6-10 Aryl, -C 1-22 Aliphatic, -C 1-22 Aliphatic -C(=O)ORb , -C 1-22 Aliphatic -C(=O)NHR b , -C 1-22 Aliphatic-C 3-7 Heterocyclic group, -C 1-22 Aliphatic-C 3-8 Cycloalkyl, -C 1-22 Aliphatic-C 6-10 Aryl, or -C 1-22 Aliphatic-C 1-9 Heteroaryl; wherein the C 6-10 Aryl, C 1-22 Aliphatic, -C 1-22 Aliphatic -C(=O)OR b , -C 1-22 Aliphatic-C 3-7 Heterocyclic group, -C 1-22 Aliphatic-C 3-8 Cycloalkyl, -C 1-22 Aliphatic-C 6-10 Aryl and -C 1-22 Aliphatic-C 1-9 The heteroaryl group is optionally substituted by 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution with haloalkyl and halosilyl (e.g. di-tert-butylfluorosilyl) groups;

[0045] R b At each occurrence, each is independently H, or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN and -NO2;

[0046] t is 1, 2, 3, 4, or 5;

[0047] t1 is independently 0, 1, 2, 3, or 4 at each occurrence;

[0048] t2 is independently 0, 1, 2, 3, 4, or 5 at each occurrence;

[0049] t3 is independently 0, 1, 2, 3, 4, or 5 at each occurrence;

[0050] m1 is 1, 2, 3, or 4;

[0051] m2 is an integer from 1 to 12; and

[0052] n is 1, 2, or 3.

[0053] In some embodiments, X 1 and X 2 Each independently does not exist, or each independently has the structure shown in the following formula:

[0054] Where X 1 and X 2 The groups represented by are each optionally and independently substituted by 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, -C(=O)OR a ,-C(=O)NHR a , and -S(=O)2OR a and -S(=O)2NHR a The group is substituted.

[0055] In some embodiments, X 3 At each occurrence, each is independently

[0056] In some embodiments, m2 is 1, 2, 3, 4, 5, or 6.

[0057] In some embodiments, R 1 yes:

[0058]

[0059] In some embodiments, R a At each occurrence, it is independently H, C 6-10 Aryl, -C 1-18 Aliphatic, -C 1-18 Aliphatic -C(=O)OR b , -C 1-18 Aliphatic -C(=O)NHR b , -C 1-12 Aliphatic -phenyl, or -C 1-18 Aliphatic-C 1-9 Heteroaryl; wherein the C 6-10 Aryl, -C 1-18 Aliphatic, -C 1-18 Aliphatic -C(=O)OR b , -C 1-18 Aliphatic -C(=O)NHR b , -C 1-12Aliphatic -phenyl and -C 1-18 Aliphatic-C 1-9 The heteroaryl group is optionally substituted by 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 The alkyl radicals are substituted with halogenated alkyl and di-tert-butylfluorosilyl.

[0060] In some embodiments, it is a compound having one of the following structures:

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0084] Unless otherwise indicated, stereoisomers, tautomers, or pharmaceutically acceptable salts of the compounds represented by formula (I) are all within the scope of the present invention.

[0085] The compounds disclosed in the present invention may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. The present invention is intended to make all stereoisomeric forms of the compounds represented by formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof such as racemic mixtures, become part of the present invention.

[0086] In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are encompassed by the present invention and are included in the present invention as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, the stereoisomers of the structure are thus unambiguous and defined.

[0087] In another aspect, the present invention relates to an intermediate for preparing the compound represented by formula (I).

[0088] In another aspect, the present invention relates to methods for preparing, separating and purifying the compound represented by formula (I).

[0089] In another aspect, the present invention provides a complex comprising the compound targeting nectin-4 of the present invention, wherein the compound targeting nectin-4 is further linked to a radionuclide.

[0090] In some embodiments, the compounds targeting nectin-4 described herein are linked to a radionuclide (eg, a diagnostic nuclide, a therapeutic nuclide) via a DOTA or NOTA chelating moiety.

[0091] In another aspect, the present invention provides a bicyclic peptide radionuclide probe targeting nectin-4, wherein the radionuclide is a diagnostic radionuclide or a therapeutic radionuclide.

[0092] In some embodiments, the bicyclic peptide radionuclide probe is prepared by labeling the bicyclic peptide compound targeting nectin-4 with a radionuclide. Specifically, the bicyclic peptide derivative is dissolved in a radioactive labeling buffer, and then a diagnostic radionuclide or a therapeutic radionuclide is added to react to obtain the corresponding bicyclic peptide radionuclide probe targeting nectin-4.

[0093] In some embodiments, the radionuclide is a diagnostic radionuclide or a therapeutic radionuclide.

[0094] In another embodiment, the diagnostic radionuclide is 68 Ga, 64 Cu, 18 F. 86 Y. 90 Y. 89 Zr, 111 In, 99m Tc, 11 C. 123 I. 125 I and 124 At least one of I.

[0095] In another embodiment, the therapeutic radionuclide is 177 Lu, 125 I. 131 I. 211 At 111 In, 153 Sm, 186 Re, 188 Re, 67 Cu, 212 Pb, 225 Ac, 213 Bi, 212 Bihe 212 At least one of Pb.

[0096] In another aspect, the present invention provides a pharmaceutical composition comprising the complex of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, diluent, or carrier, or a combination thereof. In another embodiment, the pharmaceutical composition can be in liquid, solid, semi-solid, gel or spray form.

[0097] In some embodiments, the pharmaceutical composition described herein further comprises an additional therapeutic agent.

[0098] In another aspect, the present invention provides use of the complex of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing, treating, curing, alleviating, and / or diagnosing cancer in a subject in need thereof.

[0099] In some embodiments, the cancer is selected from urological cancer, colorectal cancer, non-small cell lung cancer, breast cancer, gastric cancer, sarcoma, myeloma, nasopharyngeal / laryngeal / esophageal cancer, ovarian cancer, epithelial cancer, melanoma, glioma, astrocytoma, glioblastoma, neuroblastoma, mesothelioma, bladder cancer, hepatocellular carcinoma, and prostate cancer.

[0100] The bicyclic peptide radionuclide complex or probe provided by the present invention has high tumor uptake, good in vivo metabolic performance, good half-life, and good clinical application prospects.

[0101] Definition of terms

[0102] Certain embodiments of the present invention are now described in detail, and examples thereof are illustrated by the accompanying structural formula and chemical formula. The present invention is intended to cover all substitutions, modifications and equivalent technical solutions, which are all included within the scope of the invention defined in the appended claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described in the present invention can be used to practice the present invention. The present invention includes but is not limited to the methods and materials described in the present invention. In the case where one or more of the combined documents, patents and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0103] "Stereoisomers" refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0104] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general compounds of the present invention, or as the specific examples, subclasses, and classes of compounds included in the embodiments.

[0105] It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent, whether the hydrogen atom is attached to C or N or other atoms. "Optionally" unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at each position in the same or different manner.

[0106] The term "optionally substituted by..." can be used interchangeably with the term "unsubstituted or substituted by...", i.e., the structure is unsubstituted or substituted by one or more substituents described in the present invention, and the substituents described in the present invention include, but are not limited to, H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, -(CH2) t3 -C(=O)OR a 、-(CH2) t3 -C(=O)NHR a , and -(CH2) t3 -S(=O)2OR a and -(CH2) t3 -S(=O)2NHR a , C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 Alkyl, C 2-7 Heterocyclic group, C 2-7 Heterocyclyl C 1-6 Alkyl, C 6-12 Aryl, C 6-12 Aryl C 1-6 Alkyl, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 wherein each substituent is independently optionally replaced by 0, 1, 2, 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -OH, -NH2, -CN, -NO2, C 1-6 Alkyl and C 1-6 Alkoxy group substitution, etc. Among them, R a and t3 have the definitions described in the present invention.

[0107] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-4 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl and C4 alkyl as disclosed independently.

[0108]

[0043] The term "aliphatic" or "aliphatic" as used herein includes the terms alkyl, alkenyl, and alkynyl, each of which is optionally substituted as described below.

[0109] The term "alkyl" or "alkyl group" as used herein refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 22 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, an alkyl group contains 1-22, 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein.

[0110] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -CH(CH3)CH2CH3), u, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl- 1-Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2C H3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, etc.

[0111] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 22 carbon atoms and having at least one site of unsaturation, i.e., a carbon-carbon sp 2 Double bonds, including "cis" and "trans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2-22, 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like. The alkenyl group may be optionally substituted with one or more substituents described herein.

[0112] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing 2-22 carbon atoms, wherein at least one unsaturated site, i.e., a carbon-carbon sp triple bond. In one embodiment, the alkynyl group comprises 2-22, 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc. The alkynyl group may optionally be substituted by one or more substituents described herein.

[0113] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the definition as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

[0114] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), and the like.

[0115] The term "haloalkyl" or "haloalkoxy" means that an alkyl or alkoxy group is substituted by one or more halogen atoms. Examples of such groups include, but are not limited to, trifluoromethyl (-CF3), trifluoromethoxy (-OCF3), difluoroethyl (-CH2CHF2, -CF2CH3, -CHFCH2F), trifluoroethyl (-CH2CF3, -CF2CH2F, -CFHCHF2), -CF(CH3)2, etc.

[0116] The term "cycloalkyl" refers to a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. Bicyclic cycloalkyls include spirobicyclic alkyls, fused bicyclic alkyls and bridged bicyclic alkyls. In some embodiments, the cycloalkyl contains 3-12 carbon atoms; in other embodiments, the cycloalkyl contains 3-10 carbon atoms; in other embodiments, the cycloalkyl contains 3-8 carbon atoms; in other embodiments, the cycloalkyl contains 3-7 carbon atoms; in other embodiments, the cycloalkyl contains 3-6 carbon atoms; in still other embodiments, the cycloalkyl is C7-C 12 Cycloalkyl containing C7-C 12 Monocyclic alkyl, C7-C 12 Bicyclic alkyl (such as C7-C 12 Spirobicycloalkyl, C7-C 12 Fused bicycloalkyl and C7-C 12 bridged bicycloalkyl) or C7-C12 Tricycloalkyl. The cycloalkyl group can be independently unsubstituted or substituted by one or more substituents described in the present invention. The term "monocyclic cycloalkyl" or "monocyclic alkyl" represents a cycloalkyl of a monocyclic system, wherein the cycloalkyl has the definition as described above, and the monocyclic cycloalkyl group can be independently unsubstituted or substituted by one or more substituents described in the present invention. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.

[0117] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, monovalent or polyvalent, saturated or partially unsaturated, non-aromatic, wherein at least one ring atom is selected from nitrogen, oxygen and sulfur atoms. In some embodiments, the heterocyclyl or heterocycle contains 4-12 ring atoms. In some embodiments, the heterocyclyl or heterocycle contains 5-12 ring atoms. In some embodiments, the heterocyclyl or heterocycle contains 4-8 ring atoms. In some embodiments, the heterocyclyl or heterocycle contains 3-10 ring atoms. In some embodiments, the heterocyclyl or heterocycle contains 3-8 ring atoms. In some embodiments, the heterocyclyl or heterocycle contains 3-6 ring atoms. In some embodiments, the heterocyclyl or heterocycle contains 4-7 ring atoms. Unless otherwise specified, the heterocyclic group can be a carbon group or a nitrogen group, and the -CH2- group can be optionally replaced by -C(=O)-, the sulfur atom of the ring can be optionally oxidized to S-oxide, and the nitrogen atom of the ring can be optionally oxidized to N-oxygen compound. The heterocyclic group includes saturated heterocyclic groups (heterocycloalkyl) and partially unsaturated heterocyclic groups. The heterocyclic group has one or more points of attachment to the rest of the molecule. Examples of heterocyclic groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, azepanyl, oxazepanyl, oxe ... Base (eg, 1,4-oxazepine 1,2-oxazepine , diazepine Base (eg, 1,4-diazepine 1,2-diazepine , dioxa Base (such as 1,4-dioxa 1,2-dioxa , thiazolin Base (such as 1,4-thiazepine 1,2-thiazepine 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 2-azaspiro[4.4]nonyl, 1,6-dioxaspiro[4.4]nonyl, 2-azaspiro[4.5]decyl, 8-azaspiro[4.5]decyl, 7-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 2-azaspiro[5.5]undecyl, octahydro-1H-isoindolyl, octahydrocyclopenta[c]pyrrolyl, dihydroindolyl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydrofuro[3,2-b]furanyl and dodecahydroisoquinolinyl, and the like. Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidone and 3,5-dioxopiperidinyl. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, cyclopentane sulfone and 1,1-dioxothiomorpholinyl. The heterocyclic group may be optionally substituted by one or more substituents described herein.

[0118] In one embodiment, the heterocyclic group is a 4-7 atom heterocyclic group, which refers to a monovalent or polyvalent, saturated or partially unsaturated non-aromatic monocyclic or bicyclic ring containing 4-7 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, the 4-7 atom heterocyclic group can be a carbon group or a nitrogen group, and the -CH2- group can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. The 4-7 atom heterocyclic group has one or more points of attachment to the rest of the molecule. Examples of monocyclic heterocyclic groups of 4 to 7 atoms include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, 1,4-oxazepine 1,2-oxazepine , diazepine 1,4-diazepine 1,2-diazepine yl) and thiazepine 1,4-thiazepine 1,2-thiazepine Examples of bicyclic heterocyclic groups composed of 4 to 7 atoms include, but are not limited to: 3-azabicyclo[3,2,0]heptane, 3-oxobicyclo[3,2,0]heptane, etc.; Examples of heterocyclic groups composed of 4 to 7 atoms in which -CH2- groups are replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidone and 3,5-dioxopiperidinyl; Examples of heterocyclic groups composed of 4 to 7 atoms in which sulfur atoms are oxidized include, but are not limited to, cyclopentanesulfonyl, 1,1-dioxotetrahydrothiophene, 1,1-dioxotetrahydrothiopyran, 1,1-dioxothiomorpholinyl. The heterocyclic groups composed of 4 to 7 atoms may be optionally substituted by one or more substituents described in the present invention.

[0119] The term "aryl" refers to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains a ring consisting of 3-7 atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups can include phenyl, naphthyl and anthracenyl. The aryl groups can be independently optionally substituted with one or more substituents described herein.

[0120] The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein all rings are aromatic and at least one aromatic ring contains one or more heteroatoms, wherein each ring system contains 5-7 ring atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In one embodiment, heteroaryl is a heteroaryl containing 5-12 atoms of 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In another embodiment, heteroaryl is a heteroaryl containing 5-10 atoms of 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In another embodiment, heteroaryl is a heteroaryl containing 5-6 atoms of 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. The heteroaryl group is optionally substituted with one or more substituents described herein.

[0121] Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl , 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0122] The term "halogen" refers to F, Cl, Br or I.

[0123] The term "radionuclide" includes, but is not limited to, diagnostic radionuclides and therapeutic radionuclides, such as 68 Ga, 64 Cu, 18 F. 86 Y. 90 Y. 89 Zr, 111 In, 99m Tc, 11 C. 123 I. 125 I. 124 I, etc., wherein the therapeutic radionuclide is such as 177 Lu, 125 I. 131 I. 211 At 111 In, 153 Sm, 186 Re, 188 Re, 67 Cu, 212 Pb, 225 Ac, 213 Bi, 212 Bi, 212 Pb, etc.

[0124] The “chelating agent” used in the present invention includes but is not limited to DOTA, NOTA, DOTA-NHS, p-SCN-Ba-NOTA, p-SCN-Ba-PCTA, DTPA, TETA, HBED, NODAG, CB-TE2A, HOPO, DTPA, EDTA, etc., wherein DOTA and NOTA have the following structures respectively:

[0125]

[0126] Pharmaceutical compositions, preparations and administration of the compounds of the present invention

[0127] The present invention provides a pharmaceutical composition, which comprises a bicyclic peptide nuclide ligand or a bicyclic peptide radionuclide complex disclosed in the present invention, or a compound listed in the embodiments, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, a diluent, a carrier, a solvent, or a combination thereof. The amount of the bicyclic peptide nuclide ligand or the bicyclic peptide radionuclide complex in the pharmaceutical composition disclosed in the present invention refers to an amount that has a higher uptake in a biological sample or a patient's tumor tissue, and the uptake of the tumor increases over time.

[0128] Various carriers for configuring pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in documents such as Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, and the contents of each of these documents are incorporated herein by reference. Except for any commonly used carriers that are incompatible with the bicyclic peptide nuclide ligands or bicyclic peptide radionuclide complexes disclosed in the present invention, such as due to any undesirable biological effects or in a harmful manner interacting with any other ingredients in the pharmaceutically acceptable composition, it is contemplated that their use belongs to the scope of the present invention.

[0129] The pharmaceutical composition provided by the present invention can be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or co-formulated with substances that supplement the intended effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0130] Figure 1 Cellular internalization results of the compounds are shown.

[0131] Figure 2 Micro-PET 1 h imaging of the compounds is shown.

[0132] Figure 3 A histogram of tumor to kidney ratio versus time is shown for each example.

[0133] Figure 4 In vivo biodistribution results of the compounds are shown.

[0134] Figure 5 A histogram of tumor / tissue ratios is shown.

[0135] Figure 6 Shows 68 Ga-INN01( 68 Ga-Example 1) Micro-PET imaging results in tumor-bearing mice in the experimental group.

[0136] Figure 7 The mass spectrum of Example 1 (INN01) is shown.

[0137] Figure 8 The mass spectrum of Example 2 (INN02) is shown.

[0138] Fig. 9 The mass spectrum of Example 3 (INN03) is shown.

[0139] Fig.10 The mass spectrum of Example 4 (INN04) is shown.

[0140] Fig.11 The mass spectrum of Example 5 (INN05) is shown. DETAILED DESCRIPTION

[0141] The bicyclic peptide radionuclide complex or probe provided by the present invention is prepared by labeling the bicyclic peptide compound targeting nectin-4 with a radionuclide. Specifically, the bicyclic peptide derivative is dissolved in a radioactive labeling buffer, and then a diagnostic radionuclide or a therapeutic radionuclide is added for reaction to obtain the corresponding bicyclic peptide radionuclide probe targeting nectin-4.

[0142] The bicyclic peptide compound (nuclide ligand) targeting nectin-4 of the present invention can be synthesized by the route shown in Scheme 1:

[0143] Step 1) synthesizing a precursor polypeptide resin by a solid phase synthesis method;

[0144] Step 2) Optionally, the precursor polypeptide resin obtained in step 1) is coupled with an Fmoc-protected linker to obtain an L-precursor polypeptide resin;

[0145] Step 3) Optionally, the L-precursor polypeptide resin obtained in step 2) is subjected to a coupling reaction with DOTA or NOTA in a weakly alkaline organic solvent, and then the resin is washed with trifluoroacetic acid to obtain R-L-precursor polypeptide-NH2;

[0146] Step 4) subjecting the R—L—precursor polypeptide—NH2 obtained in step 3) to a cyclization reaction with 1,3,5-triacryloylhexahydro-1,3,5-triazine to obtain a bicyclic peptide compound targeting nectin-4;

[0147] Solution 1

[0148]

[0149]

[0150] Example

[0151] Synthesis of Example 1 (INN01)

[0152]

[0153]

[0154] Example 1 (INN01) The steps of the solid phase synthesis route are as follows: (a) First, Fmoc-Cys(Trt)-OH is coupled to Rink Amide MBHA resin was then coupled with Fmoc-Trp(Boc)-OH, Fmoc-Hyp(tBu)-OH, Fmoc-Pro-OH, Fmoc-Thr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-HomoArg(Pbf)-OH, Fmoc-Met-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-1Nal-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-β-Ala-OH and Fmoc-Glu(OtBu)-OH in sequence. All amino acids were coupled in DMF using DIC (3.0 equivalents) and HOBT (3.0 equivalents) as coupling reagents; (b) all Fmoc protecting groups were cleaved using 20% ​​piperidine / DMF solvent; (c) DOTA was coupled to the peptide chain using HBTU (3.0 equivalents) and HOBT (3.0 equivalents) as coupling reagents in a weakly alkaline solvent NMM and DMF; (d) finally, TFA was used to cleave from the resin at room temperature for 2 h to obtain the former The crude peptide was purified by HPLC on a C18 preparative column; (e) TATA cyclization step: the precursor peptide 01 was dissolved in a mixed solvent of 0.05M ammonium bicarbonate and acetonitrile in a volume ratio of 1:1, 1,3,5-triacryloylhexahydro-1,3,5-triazine was dissolved in acetonitrile and added to the mixed solution, and the reaction was fully reacted at room temperature for 1 hour, and the reaction was monitored by LC-MS. After the reaction of the raw material was complete, it was purified on a reverse phase preparative column and freeze-dried to obtain the target product INN01. INN01 was identified by mass spectrometry, such as Figure 7 shown.

[0155] Synthesis of Example 2 (INN02)

[0156]

[0157] Example 2 (INN02) The steps of the solid phase synthesis route are as follows: (a) First, Fmoc-Cys(Trt)-OH is coupled to Rink Amide MBHA resin, and then Fmoc-Trp(Boc)-OH, Fmoc-Hyp(tBu)-OH, Fmoc-Pro-OH, Fmoc-Thr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-HomoArg(Pbf)-OH, Fmoc-Met-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-1Nal-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH and Fmoc-β-Ala-OH are coupled in sequence. All amino acids were coupled in DMF using DIC (3.0 equivalents) and HOBT (3.0 equivalents) as coupling reagents; (b) Fmoc protecting group was cleaved with 20% piperidine / DMF solvent to obtain precursor polypeptide resin 02; (c) Fmoc-4-aminomethylbenzoic acid was coupled with precursor polypeptide resin 02 in DMF using DIC (3.0 equivalents) and HOBT (3.0 equivalents) as coupling reagents; (d) Fmoc protecting group was cleaved with 20% piperidine / DMF solvent to obtain precursor polypeptide resin 03; (e) Fmoc-Glu(OtBu)-OH was coupled with precursor polypeptide resin 03 in DMF using DIC (3.0 equivalents) and HOBT (3.0 equivalents) as coupling reagents; (f) Fmoc protecting group was cleaved with 20% piperidine / DMF solvent to obtain precursor polypeptide resin 04; The precursor peptide resin 04 was obtained by cleavage with pyridine / DMF solvent; (g) DOTA was coupled with the peptide chain using HBTU (3.0 equivalents) and HOBT (3.0 equivalents) as coupling reagents in weakly alkaline solvents NMM and DMF; (h) Finally, TFA was used to cleave from the resin for 2 hours at room temperature to obtain the precursor peptide 02; the crude peptide was purified by HPLC on a C18 preparative column; (i) TATA cyclization step: the precursor peptide 02 was dissolved in a mixed solvent of 0.05M ammonium bicarbonate and acetonitrile in a volume ratio of 1:1, 1,3,5-triacryloylhexahydro-1,3,5-triazine was dissolved in acetonitrile and added to the above mixed solution, and the reaction was fully reacted at room temperature for 1 hour, and the reaction was monitored by LC-MS. After the reaction of the raw material was complete, it was purified on a reverse phase preparative column and freeze-dried to obtain the target product INN02. INN02 was identified by mass spectrometry, such as Figure 8 shown.

[0158] Synthesis of Example 3 (INN03)

[0159]

[0160] Example 3 (INN03) The steps of the solid phase synthesis route are as follows: (a) First, Fmoc-Cys(Trt)-OH is coupled to Rink Amide MBHA resin, and then Fmoc-Trp(Boc)-OH, Fmoc-Hyp(tBu)-OH, Fmoc-Pro-OH, Fmoc-Thr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-HomoArg(Pbf)-OH, Fmoc-Met-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-1Nal-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH and Fmoc-β-Ala-OH are coupled in sequence. All amino acids were coupled in DMF using DIC (3.0 equivalents) and HOBT (3.0 equivalents) as coupling reagents; (b) Fmoc protecting group was cleaved with 20% piperidine / DMF solvent to obtain precursor peptide resin 02; (c) Fmoc-4-aminomethylbenzoic acid was coupled with precursor peptide resin 02 in DMF using DIC (3.0 equivalents) and HOBT (3.0 equivalents) as coupling reagents; (d) Fmoc protecting group was cleaved with 20% piperidine / DMF solvent to obtain precursor peptide resin 03; (e) Fmoc-Cys(SO3H)-OH was coupled with precursor peptide resin 03 in DMF using DIC (3.0 equivalents) and HOBT (3.0 equivalents) as coupling reagents; (f) Fmoc protecting group was cleaved with 20% piperidine / DMF solvent to obtain precursor peptide resin 03; The precursor peptide resin 05 was obtained by cleavage with pyridine / DMF solvent; (g) DOTA was coupled with the peptide chain using HBTU (3.0 equivalents) and HOBT (3.0 equivalents) as coupling reagents in weakly alkaline solvents NMM and DMF; (h) Finally, TFA was used to cleave from the resin for 2 hours at room temperature to obtain the precursor peptide 03; the crude peptide was purified by HPLC on a C18 preparative column; (i) TATA cyclization step: the precursor peptide 03 was dissolved in a mixed solvent of 0.05M ammonium bicarbonate and acetonitrile in a volume ratio of 1:1, 1,3,5-triacryloylhexahydro-1,3,5-triazine was dissolved in acetonitrile and added to the above mixed solution, and the reaction was fully reacted at room temperature for 1 hour, and the reaction was monitored by LC-MS. After the reaction of the raw material was complete, it was purified on a reverse phase preparative column and freeze-dried to obtain the target product INN03. INN03 was identified by mass spectrometry, such as Fig. 9 shown.

[0161] Synthesis of Example 4 (INN04)

[0162]

[0163] Example 4 (INN04) The steps of the solid phase synthesis route are as follows: (a) First, Fmoc-Cys(Trt)-OH is coupled to Rink Amide MBHA resin was then coupled with Fmoc-Trp(Boc)-OH, Fmoc-Hyp(tBu)-OH, Fmoc-Pro-OH, Fmoc-Thr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Met-OH, Fmoc-Cys(Trt)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-1Nal-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH, Fmoc-β-Ala-OH, Fmoc-D-2Nal-OH and Fmoc-Cys(SO3H)-OH in sequence. All amino acids were coupled in DMF using DIC (3.0 equivalents) and HOBT (3.0 equivalents) as coupling reagents; (b) Fmoc protecting group was cleaved with 20% piperidine / DMF solvent to obtain precursor polypeptide resin 06; (c) DOTA was coupled with precursor polypeptide resin 06 using HBTU (3.0 equivalents) as coupling reagent in NMM and DMF; (d) Boc, pbf and other protecting groups were cleaved with TFA to obtain precursor polypeptide 04; (d) TATA cyclization step: Precursor polypeptide 04 was dissolved in a mixed solvent of 0.05M ammonium bicarbonate and acetonitrile in a volume ratio of 1:1, 1,3,5-triacryloylhexahydro-1,3,5-triazine was dissolved in acetonitrile and added to the above mixed solution, and the reaction was fully reacted at room temperature for 1 hour, and the reaction was monitored by LC-MS. After the reaction of the raw material was complete, it was purified on a reverse phase preparative column and freeze-dried to obtain the target product INN04. INN04 was identified by mass spectrometry. Fig.10 shown.

[0164] Synthesis of Example 5 (INN05)

[0165]

[0166] Example 5 (INN05) The steps of the solid phase synthesis route are as follows: First, Fmoc-Cys(Trt)-OH is coupled to RinkAmide On MBHA resin, then Fmoc-Trp(Boc)-OH; Fmoc-Hyp(tBu)-OH; Fmoc-Pro-OH; Fmoc-Thr(tBu)-OH; Fmoc-Ser(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Asp(OtBu)-OH; Fmoc-HomoArg(Pbf)-OH; Fmoc-Met-OH; Fmoc-Cys(Trt)-OH; Fmoc-D-Asp(OtBu)-OH; Fmoc-1Nal-OH; Fmoc-Pro-OH; Fmoc-Cys(Trt)-OH; Fmoc-βAla-OH; Fmoc-D-Dap(Dde)-OH; Fmoc-Cys(SO3H)-OH are coupled in sequence. All amino acids were coupled in DMF using DIC (3eq) and HOBt (3eq) as coupling reagents. The Fmoc protecting group was cleaved with 20% Pip / DMF solvent. DOTA was coupled with the previous resin peptide using HATU (1.5eq) as a coupling reagent in NMM (3eq) and DMF. The Dde protecting group was cleaved with 4% hydrazine hydrate / DMF solution. 4-(Di-tert-butylfluorosilyl)benzoic acid was coupled with the previous resin peptide using HATU (1.5eq) as a coupling reagent in NMM (3eq) and DMF. Finally, the crude peptide Compd1 was obtained by cleavage from the resin with TFA solution at room temperature for 2h. The crude peptide was purified by HPLC on a C18 preparative column to obtain pure Compound 1 (Compd1). Subsequently, Compd1 (1.0 eq) was dissolved in a mixed solution of 15 mL ACN and 15 mL water, compd2 was dissolved in acetonitrile and added to the reaction solution, and then 10 mL 1 M NH4HCO3 was added. The reaction was fully reacted at room temperature for 1 h. The reaction was completed under LC-MS monitoring, and INN05 was directly purified by reverse phase preparative liquid phase.

[0167] The mass spectrometry identification results of the bicyclic peptide compounds targeting nectin-4 are shown in Table 1. The mass spectra of Examples 1-5 are shown in Table 1. Figure 7-11 shown.

[0168] Table 1. Mass spectrometry results of compound INN01-05

[0169]

[0170] Radiolabeling and quality control

[0171] 68 Ga: add 2mL 68Ga eluent (388.5MBq, 0.6M HCl) was added to 700μL 3M sodium acetate solution and shaken; a certain mass of bicyclic peptide compound as nuclide ligand (e.g., Example 1, 50μg, 18nmol) was accurately weighed, dissolved with DMSO (20uL), and added to the above mixture, and after shaking, the new mixture was reacted at 106°C for 15min. Then, it was diluted with sterile water for injection and separated and purified by C18 column purification (ethanol / water (1 / 1, v / v), 2mL).

[0172] 177 Lu: Accurately weigh a certain amount of bicyclic peptide compound (e.g., 50 μg, 18 nmol) as a nuclide ligand and dissolve it in 0.16 mL of NaOAc (0.4 M, pH = 5.5). Then, add 185 MBq of 177 LuCl3, and gentisic acid (2.0 mg) was added, and the reaction mixture was reacted at 95°C for 15-20 min.

[0173] Quality control: After labeling, the compounds were quality controlled and purified using analytical radio-HPLC. The radiochemical purity of all complexes was greater than 95%. The obtained complexes will be used for in vitro and in vivo experiments.

[0174] Biological tests

[0175] In vitro activity test

[0176] MC38 cells with high expression of Nectin-4 were plated in a 24-well plate containing culture medium (the number of cells was counted by a cell counting plate, about 0.6 million per well). After culturing for 1 day, the culture medium was removed, leaving the cultured MC38 cells, and fresh culture medium without fetal bovine serum was added. Radioactive tracers were added to different wells of the cell plate. 68 Ga-N188 (1.0 μCi / well) and different concentrations of precursors (10 -5 ~10 -12 mol / L) (4 wells per group), incubate at 37°C for 60 minutes, remove the radioactive culture medium, wash the cells twice with PBS (1 mL), and then lyse the cells with a NaOH solution (1 mL, 1 M) containing 0.2% SDS, and count the lysate with a γ-counter.

[0177] Results: The different concentration groups (10 -5 ~10 -12 mol / L) (4 wells per group) and counted and plotted, and the IC values ​​of Examples 1-4 and the positive drug N188 were calculated. 50The experimental results are shown in Table 2. The results show that the patented compound has significantly superior in vitro activity compared with the positive drug N188 (+<5nM; 5nM<++<50nM; 50nM<+++).

[0178] Table 2, in vitro activity results of compounds

[0179]

[0180]

[0181] LogD Test

[0182] The radioactive drug (0.74-0.185 MBq) was added to PBS (pH 7.4, 5 mL) and n-octanol (5 mL), vortexed vigorously for 1 min at ambient temperature, and then centrifuged (1000 rpm, 3 min). Three samples (1 mL) were taken from each phase and the radioactivity was measured using a γ-counter.

[0183] Table 3, LogD values ​​of compounds

[0184] Example 1 Example 2 Example 3 Example 4 LogD -3.16±0.06 -2.74±0.04 -2.67±0.04 -2.31±0.03

[0185] In vitro stability testing

[0186] The radiolabeled test compound was incubated in normal saline at room temperature, or in mouse serum, human serum and culture medium at 37°C for 0.5h, 1h, 2h, acetonitrile was added to precipitate plasma protein, centrifuged at 10000rpm for 5min, and the radiochemical purity in the supernatant was detected by HPLC. Examples 1-4 had good in vitro stability, and more than 75% of the prototype drug was not decomposed within 2h.

[0187] Table 4, in vitro stability results of compounds

[0188] Radiochemical purity (%) Example 1 Example 2 Example 3 Example 4 N188 Purified solution 99.4±0.01 99.2±0.01 99.4±0.04 99.1±0.08 99.3±0.04 PBS 99.4±0.01 98.9±0.31 99.4±0.01 98.9±0.15 99.2±0.01 Rat serum 74.6±0.66 90.3±1.97 83.9±0.10 96.2±0.64 84.0±3.71 human serum 78.0±0.49 90.1±0.40 82.1±1.47 95.3±0.26 87.3±0.25

[0189] In vivo rapid half-life and stability testing

[0190] The radiolabeled test compound (7.4MBq [200uCi]) was injected into the tail vein of C57 mice. After injection, blood was collected from the orbital vein at different time points (10s, 30s, 60s, 120s, 300s, 600s, 1800s, 3600s, 7200s). The blood radioactivity was quantified by γ-counter, and the %ID / g at different time points was calculated and plotted. The rapid half-life was also calculated. The results are shown in Table 5. The rapid half-life of the four compounds of this patent is relatively long and has good in vivo stability. At 0.5h, the orbital blood of mice was taken and acetonitrile was added to precipitate plasma protein. The mixture was centrifuged at 10000rpm for 5min. The radiochemical purity in the supernatant was detected by radio-HPLC. The radiochemical purity (%) of each embodiment was determined. The compounds of this patent have good in vivo stability, and the results are shown in Table 6.

[0191] Table 5, In vivo rapid half-life results of compounds

[0192] Compound No. Time(s) Example 1 63.3±19.7 Example 2 66.1±7.9 Example 3 98.9±15.3 Example 4 61.5±18.5 N188 33.7±0.8

[0193] Table 6, in vivo stability results of compounds

[0194] Compound No. Radiochemical purity (%) Example 1 40.0±4.04 Example 2 44.5±481 Example 3 40.9±6.91 Example 4 66.0±4.09 N188 18.1±2.8

[0195] In vitro cell experiments

[0196] Cell culture conditions:

[0197] Cell lines RT4 and 5637 (Chinese Academy of Sciences) were cultured using 5A medium and RDIP1640 medium (Gibco) supplemented with 10% fetal bovine serum (FBS, Procell) and 1% penicillin-streptomycin (Gibco).

[0198] IC 50 Detection:

[0199] Cells (105 cells / well) were seeded in 24-well plates, and the complete medium was replaced with fresh FBS-free medium containing radioactive markers. Different concentrations of the test compound were added to each well and incubated for 60 minutes. After the incubation, the medium was removed, and the plates were washed twice with PBS. 1 mL of lysis solution (1 M NaOH, 2% SDS, PH = 2.2) was added to each well, and the cells were measured with a γ-counter.

[0200] In vitro cell internalization assay

[0201] Cells (105 cells / well) were seeded in 24-well plates, and each well was incubated with a culture medium containing 0.37 MBq of radioactively labeled test compound at 37°C for 1 h. After the incubation, the culture medium was discarded and the cells were washed twice with ice-cold PBS buffer, and the radioactivity was measured using a γ-counter.

[0202] Then the cells were lysed with lysis buffer and collected, and the radioactivity was measured by γ-counter. The cell uptake of the patented compound increased significantly over time, and at 120 minutes, it was above 15%. The cell uptake values ​​of Examples 3 and 4 were higher than 30%, and the internalization rate was about 5%. The patented compound has high cell uptake and internalization efficiency. Figure 1 shown.

[0203] Micro-PET imaging

[0204] Nude mice (n=3-4) bearing RT4 or 5637 tumors were anesthetized and placed in a prone position in a Micro-PET imaging scanner. 68 Dynamic PET / CT images were collected for 2 h after the injection of Ga-labeled compound INN01-04 (7.4-1.1 MBq). 4 h after injection, 10 min scans were performed every hour. For data analysis, Inevon Research Workplace 4.1 software was used to reconstruct nude mouse images and manually draw target regions (ROIs) on tumors and major organs.

[0205] Nude mice (n=3-4) bearing MC38-Nectin4 tumors were anesthetized and placed in a prone position in a Micro-PET imaging scanner. 68 After the injection of Ga-labeled compound INN01-04 (7.4-1.1 MBq), dynamic PET / CT images were collected for 2 hours. After 4 hours of injection, a 10-minute scan was performed every hour. For data analysis, the nude mouse images were reconstructed using Inevon Research Workplace4.1 software, and target regions (ROIs) were manually drawn on the tumors and major organs. The compounds of Examples 1-4 of this patent were significantly enriched in MC38-Nectin4 tumors, with clear imaging and less background noise. The results are shown in Figure 2. Figure 2 shown.

[0206] Diagnostic Nuclide 68 Ga-labeled Examples 1-4 ( 68 Ga-INN01 / 02 / 03 / 04) are mainly enriched in MC38-Nectin4 tumors and excreted through the kidneys. The kidney is the main non-target organ for the enrichment of these compounds. Figure 3 This is the tumor kidney ratio / time bar graph of the patented compound. 1h and 2h, 68 The tumor-kidney ratio of Ga-INN01 / 02 / 03 was superior to 68 Ga-INN04. 68 Ga-INN04 had a longer retention time in tumors and a higher tumor-to-kidney ratio.

[0207] In vivo biodistribution: mice were injected with RT4 or 5637 cell xenograft models via the tail vein with 0.74 MBq of radiolabeled test compound (0.033 mg / kg). The animals were killed 1 hour after injection, and the organs to be tested were stained and weighed. The radioactivity was measured by γ-counter and calculated as the percentage of injected dose uptake per gram of tissue (%ID / g).

[0208] Mice carrying MC38-Nectin4 xenograft models were injected with 0.74MBq of radiolabeled test compound (0.033mg / kg) via the tail vein. The animals were killed 1 hour after injection, and the organs to be tested were stained and weighed. The radioactivity was measured by γ-counter and calculated as the percentage of injected dose uptake per gram of tissue (%ID / g). Figure 4 It is the in vivo biodistribution result of the patented compound. 68 Renal uptake ratio of Ga-INN03 68 Ga-INN01, 68 Ga-INN02, 68 Ga-INN04 and 68 Ga-N188 is lower. 68 Ga-INN03 has higher tumor uptake than other compounds. The uptake of each compound in non-target tissues is relatively low, the tumor / tissue ratio is relatively high, and it has good safety. The tumor / tissue ratio results are as follows Figure 5 shown. Figure 6 Shows 68 The results of Micro-PET imaging of Ga-INN01 in tumor-bearing mice in the experimental group showed that, through comparative analysis of tumor and normal muscle areas, 68 Ga-INN01 is mainly excreted through the kidneys and bladder, and is rapidly cleared from non-target organs. 68 Ga-INN01 has a high uptake in tumor tissues, and the uptake of tumors increases with time. In conclusion, the bicyclic peptide nuclide complex targeting nectin-4 has good clinical application prospects.

[0209] Finally, it should be noted that there are other ways to implement the present invention. Accordingly, the embodiments of the present invention are described as examples, but are not limited to the contents described in the present invention, and may also be modified within the scope of the present invention or added to the claims. All publications or patents cited in the present invention will be used as references of the present invention.

Claims

1. A compound having a structure shown in formula (I): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof; in, L is represents the attachment point connected to R; y1 is 0 or 1; y2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; y3 is 0 or 1; y1, y2 and y3 are not 0 at the same time; y4 is 0, 1, 2, 3, or 4; k1 is 0 or 1; k2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; k3 is 0 or 1; k4 is 0 or 1; k5 is 0 or 1; When multiple Q1 appear, each Q1 is independently selected from -CH2-, -CH2OCH2-, phenylene (e.g. ), cyclohexylene (e.g. ); When multiple Q2 appear, each Q2 is independently selected from -CH2-, -CH2OCH2-, phenylene (e.g. ), cyclohexylene (e.g. ); Optionally, each Q1 and Q2 is replaced by 0, 1, 2, 3, 4 or 5 independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, -(CH2) t3 -C(=O)OR a 、-(CH2) t3 -C(=O)NHR a 、-(CH2) t3 -S(=O)2OR a and -(CH2) t3 -S(=O)2NHR a The group substitution; When multiple R e and R f , each R e and R f are independently selected from: H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, -(CH2) t3 -C(=O)OR a 、-(CH2) t3 -C(=O)NHR a 、-(CH2) t3 -S(=O)2OR a and -(CH2) t3 -S(=O)2NHR a ; When multiple R c and R d , each R c and R d Independently selected from: H, -C 1-22 Aliphatic-C 3-7 Heterocyclic group, -C 1-22 Aliphatic-C 3-8 Cycloalkyl, -C 1-22 Aliphatic-C 6-10 Aryl, -C 1-22 Aliphatic-C 1-9 Heteroaryl, -(CH2) t2 -OC(=O)R a 、-(CH2) t2 -NHC(=O)R a 、-(CH2) t2 -C(=O)OR a 、-(CH2) t2 -C(=O)NHR a 、-(CH2) t2 -C(=O)R a 、-(CH2) t2 -S(=O)2OR a 、-(CH2) t2 -S(=O)2NHR a or -(CH2) t2 -S(=O)2R a ; said C 3-7 Heterocyclic group, C 3-8 Cycloalkyl, C 6-10 Aryl or C 1-9 Each heteroaryl is independently, optionally substituted by 0, 1, 2, 3, 4 or 5 independently selected from oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution with haloalkyl and halosilyl (e.g. di-tert-butylfluorosilyl) groups; R a At each occurrence, it is independently H, C 6-10 Aryl, -C 1-22 Aliphatic, -C 1-22 Aliphatic -C(=O)OR b , -C 1-22 Aliphatic -C(=O)NHR b , -C 1-22 Aliphatic-C 3-7 Heterocyclic group, -C 1-22 Aliphatic-C 3-8 Cycloalkyl, -C 1-22 Aliphatic-C 6-10 Aryl, or -C 1-22 Aliphatic-C 1-9 Heteroaryl; wherein the C 6-10 Aryl, C 1-22 Aliphatic, -C 1-22 Aliphatic -C(=O)OR b , -C 1-22 Aliphatic-C 3-7 Heterocyclic group, -C 1-22 Aliphatic-C 3-8 Cycloalkyl, -C 1-22 Aliphatic-C 6-10 Aryl and -C 1-22 Aliphatic-C 1-9 The heteroaryl group is optionally substituted by 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution with haloalkyl and halosilyl (e.g. di-tert-butylfluorosilyl) groups; R b At each occurrence, each is independently H, or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN and -NO2; t2 is independently 0, 1, 2, 3, 4 or 5 at each occurrence; t3 is independently 0, 1, 2, 3, 4 or 5 at each occurrence; R is R 1 yes n is 1, 2, or 3.

2. The compound according to claim 1, wherein L is selected from: Among them, y 4a Is 1, 2, or 3.

3. The compound according to claim 1, wherein L is in represents the attachment point connected to R; X 1 and X 2 Each independently does not exist, or each independently has the structure shown in the following formula: Where X 1 and X 2 The groups represented by are each optionally and independently substituted by 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, -(CH2) t3 -C(=O)OR a 、-(CH2) t3 -C(=O)NHR a 、-(CH2) t3 -S(=O)2OR a and -(CH2) t3 -S(=O)2NHR a The group substitution; X 3 At each occurrence, each independently does not exist, or each independently is X 4 Does not exist, or X 4 is -C(=O)-(CH2) m1 - or -C(=O)-(CH2) m1 -C(=O)-; X 5 Yes -(CH2-O-CH2) m2 -CH2-NH- or -NH-CH2-(CH2-O-CH2) m2 -CH2-NH-; R is R 1 yes R 2 At each occurrence, independently -C 1-22 Aliphatic-C 6-10 Aryl, -(CH2) t2 -C(=O)OR a 、-(CH2) t2 -C(=O)NHR a 、-(CH2) t2 -C(=O)R a 、-(CH2) t2 -S(=O)2OR a 、-(CH2) t2 -S(=O)2NHR a or -(CH2) t2 -S(=O)2R a ; R a At each occurrence, it is independently H, C 6-10 Aryl, -C 1-22 Aliphatic, -C 1-22 Aliphatic -C(=O)OR b , -C 1-22 Aliphatic -C(=O)NHR b , -C 1-22 Aliphatic-C 3-7 Heterocyclic group, -C 1-22 Aliphatic-C 3-8 Cycloalkyl, -C 1-22 Aliphatic-C 6-10 Aryl, or -C 1-22 Aliphatic-C 1-9 Heteroaryl; wherein the C 6-10 Aryl, C 1-22 Aliphatic, -C 1-22 Aliphatic -C(=O)OR b , -C 1-22 Aliphatic-C 3-7 Heterocyclic group, -C 1-22 Aliphatic-C 3-8 Cycloalkyl, -C 1-22 Aliphatic-C 6-10 Aryl and -C 1-22 Aliphatic-C 1-9 The heteroaryl group is optionally substituted by 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Substitution with haloalkyl or halosilyl (e.g. di-tert-butylfluorosilyl); R b At each occurrence, each is independently H, or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN and -NO2; t is 1, 2, 3, 4, or 5; t1 is independently 0, 1, 2, 3 or 4 at each occurrence; t2 is independently 0, 1, 2, 3, 4 or 5 at each occurrence; t3 is independently 0, 1, 2, 3, 4 or 5 at each occurrence; m1 is 1, 2, 3, or 4; m2 is an integer from 1 to 12; and n is 1, 2, or 3.

4. The compound according to claim 3, wherein X 3 At each occurrence, each is independently 5. The compound according to claim 3, wherein m2 is 1, 2, 3, 4, 5 or 6.

6. The compound according to any one of claims 1 to 5, wherein R 1 yes:

7. The compound according to claim 1 or 3, wherein R a At each occurrence, it is independently H, C 6-10 Aryl, -C 1-18 Aliphatic, -C 1-18 Aliphatic -C(=O)OR b , -C 1-18 Aliphatic -C(=O)NHR b , -C 1-12 Aliphatic -phenyl, or -C 1-18 Aliphatic-C 1-9 Heteroaryl; wherein the C 6-10 Aryl, -C 1-18 Aliphatic, -C 1-18 Aliphatic -C(=O)OR b , -C 1-18 Aliphatic -C(=O)NHR b , -C 1-12 Aliphatic -phenyl or -C 1-18 Aliphatic-C 1-9 The heteroaryl group is optionally substituted by 0, 1, 2, 3, 4 or 5 groups independently selected from H, oxo (=O), F, Cl, Br, I, -OH, -NH2, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 The alkyl radicals are substituted with halogenated alkyl and di-tert-butylfluorosilyl.

8. The compound according to claim 1 or 3, which is a compound having one of the following structures: or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

9. A complex comprising the compound according to any one of claims 1 to 8, wherein the compound is further linked to a radionuclide.

10. The complex according to claim 9, wherein The radionuclide is a diagnostic radionuclide or a therapeutic radionuclide.

11. The complex according to claim 10, wherein The diagnostic radionuclide is 68 Ga, 64 Cu, 18 F. 86 Y. 90 Y. 89 Zr, 111 In, 99m Tc, 11 C. 123 I. 125 I and 124 At least one of I; and / or The therapeutic radionuclide is 177 Lu, 125 I. 131 I. 211 At 111 In, 153 Sm, 186 Re, 188 Re, 67 Cu, 212 Pb, 225 Ac, 213 Bi, 212 Bihe 212 At least one of Pb.

12. A pharmaceutical composition comprising the complex according to any one of claims 9 to 11, and a pharmaceutically acceptable excipient, diluent or carrier, or a combination thereof.

13. A probe comprising the compound according to any one of claims 1 to 8, the complex according to any one of claims 9 to 11, or the pharmaceutical composition according to claim 12; Optionally, the probe is used for tumor imaging; Optionally, the tumor contains Nectin-4; Optionally, the tumor comprises urological cancer, colorectal cancer, non-small cell lung cancer, breast cancer, gastric cancer, sarcoma, myeloma, nasopharyngeal / laryngeal / esophageal cancer, ovarian cancer, epithelial cancer, urothelial cancer, lung cancer, head and neck cancer, pancreatic cancer, melanoma, glioma, astrocytoma, glioblastoma, neuroblastoma, mesothelioma, bladder cancer, hepatocellular carcinoma or prostate cancer.

14. Use of the compound according to any one of claims 1 to 8, the complex according to any one of claims 9 to 11 or the pharmaceutical composition according to claim 12 in the preparation of a drug or agent for targeting nectin-4.

15. Use of the complex according to any one of claims 9 to 11 or the pharmaceutical composition according to claim 12 in the preparation of a medicament for preventing, treating, curing, alleviating, and / or diagnosing cancer; optionally, the cancer comprises urinary system cancer, colorectal cancer, non-small cell lung cancer, breast cancer, gastric cancer, sarcoma, myeloma, nasopharyngeal / laryngeal / esophageal cancer, ovarian cancer, epithelial cancer, urothelial cancer, lung cancer, head and neck cancer, pancreatic cancer, melanoma, glioma, astrocytoma, glioblastoma, neuroblastoma, mesothelioma, bladder cancer, hepatocellular carcinoma or prostate cancer.

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