Peptidoid compound as well as complex, pharmaceutical composition and application thereof

Abstract

The invention discloses a peptoid compound and a complex thereof, and a pharmaceutical composition comprising the peptoid compound, the peptoid compound can target integrin proteins such as alpha v beta 5 or alpha 5 beta 1 or alpha v beta 3, is enriched in tumor cells with high expression of integrin, and can be used for preparing medicines for treating tumors. The peptoid compound and the complex and the pharmaceutical composition thereof can be used for diagnosis and / or treatment of tumors.

Description

[0001] This application claims the priority of the Chinese patent application filed with the China Patent Office on June 21, 2023, with application number 2023107486486, and invention name “A peptoid compound and its complex, pharmaceutical composition and application”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a peptoid compound and its complex, a pharmaceutical composition containing the same and its medical use. The peptoid compound is specifically a compound with integrin inhibitory activity. Background Art

[0003] Integrin is a transmembrane glycoprotein, which is widely present in cells. It is a member of the cell adhesion molecule family and the most important molecule that mediates the interaction between cells and the extracellular matrix (ECM). It is a type of cell membrane surface receptor that can recognize and bind to the corresponding ligand in the extracellular matrix, provide attachment points for cell adhesion, regulate cell movement, proliferation and apoptosis, mediate mutual recognition and adhesion between cells and between cells and the extracellular matrix, and has the function of connecting the external action of cells with the internal structure of cells. Integrin is a heterodimer composed of two subunits, α and β, connected by non-covalent bonds in a ratio of 1:1. It consists of three parts: the extracellular region, the transmembrane region and the intracellular region. It is connected into a spherical region in the extracellular region and contains a divalent cation binding domain. According to the specificity of integrin recognition of ligands, integrins can be roughly divided into integrins that recognize arginase-glycinase-aspartase peptide (RGD tripeptide) sequence, laminin-linked integrins, leukocyte integrins and collagen-linked integrins. Integrins bind to ECM proteins such as collagen, laminin, vitronectin, fibronectin or some cell surface molecules through their extracellular regions. Integrins are involved in many important physiological processes, including embryogenesis, coagulation, and maintaining the integrity of tissues and organs in the body. Many pathological processes, such as inflammation, thrombosis, angiogenesis, and the growth, infiltration and metastasis of malignant tumors, are all related to abnormal regulation of integrins.

[0004] Dysregulation of integrin expression on cancer cells has been extensively studied in both cell and animal models, and targeting integrins has been shown to inhibit tumor growth, reduce resistance to chemotherapy or radiotherapy, and mitigate invasion and metastasis. Studies using transgenic mouse models or using immunodeficient mouse xenograft models have shown that loss of integrins in cancer cells or prevention of integrin function by blocking antibodies or peptides interferes with tumor growth, metastasis, and resistance to chemotherapy or radiotherapy. For β1 integrin, dual roles in growth and metastasis suggest that it may serve as a potential therapeutic target. Integrins, such as αvβ3, αvβ5, and α5β1, are not only expressed on tumor cells, but are also induced on endothelial cells during angiogenesis. These integrins have been shown to be targets for anti-angiogenic therapy of cancer.

[0005] Recent studies have found that a series of other integrin subtypes are involved in the process of cancer development, including the establishment of pre-metastatic niches, epithelial-mesenchymal transition (EMT), metabolic reorganization, and cancer cell stemness and dormancy. Integrin αvβ6 is involved in the activation of TGFβ and is associated with SOX4-mediated cancer immune escape: αvβ6 blocking antibodies can inhibit SOX4 expression and sensitize triple-negative breast cancer mouse models to T cell-mediated killing responses caused by immune checkpoint inhibitors. Integrin αvβ8 can be used as a target for regulating anti-tumor immunity. αvβ8 blocking antibodies or specific blocking of integrin αvβ8 on the surface of regulatory T cells can weaken TGFβ-mediated inhibition of CD8+T cells, thereby restoring the tumor killing ability of CD8+T cells and synergizing with radiation or immunotherapy.

[0006] Expression of integrin αvβ3 is widely associated with the progression of melanoma from the early radial growth stage to invasive vertical growth and metastasis. Studies have found that αvβ3 is significantly upregulated in malignant primary neuroendocrine prostate cancer and its lung metastatic lesions, and αvβ3 may serve as a biomarker for the early detection of malignant transformation in prostate cancer. Expression of integrin αvβ5 is considered a predictive biomarker in several cancer types, including breast cancer, liver cancer, and gastric cancer. Elevated levels of αvβ5 have been detected in patients with glioblastoma or colorectal cancer, and overexpression of αvβ5 is associated with unfavorable overall survival. Integrin α5β1 is involved in tumor-promoting processes such as angiogenesis, proliferation, and metastasis. In patients with early breast cancer, expression of α5β1 in primary tumors was associated with the presence of disseminated tumor cells in bone marrow aspirates and poor metastasis-free survival. The same study showed that silencing of the α5 gene or pharmacological inhibition of α5β1 with vorximab attenuated bone colonization in mice after intravenous injection of tumor cells. Integrin α5β1 has also been found to be upregulated in some gastrointestinal tumors, among which enhanced expression of ITGA5 corresponds to poor prognosis.

[0007] The abnormal expression of integrins such as αvβ3, αvβ5, and α5β1 in various tumors and their role in the occurrence and development of tumors make them drug targets for tumor targeted therapy. Drug molecules targeting integrins can not only directly kill tumor cells, but also serve as targeted carriers to accurately deliver cytotoxins, radionuclides, etc. to tumor cells to achieve the purpose of killing tumors. In addition, the combination of radionuclides, fluorescent molecules and integrin targeting molecules can be used in the fields of tumor diagnosis and surgical navigation. Summary of the invention

[0008] Based on the above background, the present invention provides a peptidomimetic compound and its complex, as well as a pharmaceutical composition comprising the peptidomimetic compound. The compound can target integrin proteins such as αvβ5 or α5β1 or αvβ3, and is used for the diagnosis and / or treatment of tumors.

[0009] The present invention includes the following technical solutions:

[0010] In the first aspect, the present invention provides a peptidomimetic compound, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs thereof, wherein the compound has the following structural formula:

[0011] ZT-PD, or ZT-Linker-PD;

[0012] Among them, the ZT structure is one of ZT1 to ZT4:

[0013]

[0014] na is an integer selected from 1 to 8.

[0015] The Linker structure is as follows:

[0016]

[0017] X L Selected from N-alkyl substituted D- or L-amino acid, or one of the structures X1-X8:

[0018]

[0019] LL is selected from one of the following structures:

[0020]

[0021] LR does not exist or is selected from one of the following structures:

[0022]

[0023] The absence of LR indicates that the carbonyl group on the left side of LR is directly connected to PD.

[0024] m and n are independently selected from integers between 0 and 16;

[0025] R 1L is selected from hydrogen, hydrocarbon or substituted hydrocarbon, alkene or alkene derivatives, alkynyl or alkynyl derivatives, aryl and substituted aryl, heteroaryl or substituted heteroaryl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno) group, haloalkylthio (or seleno) group, thiol (or seleno) group, alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl , ester group, sulfonyl group, alkylsulfonyl group, halogenated alkylsulfonyl group, sulfonic acid group, sulfonamide group, phosphoric acid group, phosphate ester group, unsubstituted aromatic group, aromatic heterocyclic group, monocyclic heterocyclic group, carboxyl group, -CHF2, -CF3, -NHOH, -SO3H, -SOMe, -SO2Me, -SOEt, -SO2Et, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, p-toluenesulfonamide group, sulfonic acid ester group.

[0026] R 2L Selected from -OH, -NH2, -NHMe, -N(Me)2, -N(Et)2.

[0027] Y L It has a diamine structure, one end of which is connected to Z L The fragment is coupled to form urea, and the other end forms an amide bond, carbonate bond or urea with ZT. L Selected from one of the structures Y1-Y4:

[0028]

[0029] Z L With Y L The urea structure formed by coupling is selected from one of Z1-Z4:

[0030]

[0031] In a preferred embodiment of the present invention, the Linker structure is shown in L1 to L10:

[0032]

[0033]

[0034] m, n, R 1L , R 2L , X L, Y L , Z L The groups are as described above.

[0035] In a specific embodiment of the present invention, Linker is selected from the following structure:

[0036]

[0037]

[0038] PD is a polypeptide compound, a compound and / or its derivatives prepared by amino condensation of one or more of the compounds of formula 1 to formula 6:

[0039] The amino group in the PD compound is condensed and connected with the Linker. For the convenience of description, the PD compound described below is a reaction raw material without forming a linker.

[0040]

[0041] In Formula 1 to Formula 6:

[0042] m, n, and n1 are independently selected from integers between 0 and 5;

[0043] R is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group; preferably, R is an alkyl group having 1 to 20 carbon atoms, more preferably an alkyl group having 1 to 15 carbon atoms, more preferably an alkyl group having 1 to 10 carbon atoms, more preferably an alkyl group having 1 to 5 carbon atoms, and most preferably a methyl group or an ethyl group.

[0044] R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, hydrocarbon or substituted hydrocarbon, olefin or olefin derivative, alkynyl or alkynyl derivative, aryl and substituted aryl, heteroaryl or substituted heteroaryl; wherein the substituent is selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or selenium), haloalkylthio (or selenium), thiol (or selenium), alkylthio (or selenium) ether, arylthio (or selenium) ether, hydroxyl, cyano, nitro, carboxyl derivative, aryloxy, amide, acylamine, amino alkyl, -S02Me, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, p-toluenesulfonamide, and sulfonate.

[0045] Preferably, the hydrocarbon group in R1, R2, R3, R4, R5 and R6 is selected from hydrocarbon groups with 1 to 20 carbon atoms, more preferably hydrocarbon groups with 1 to 10 carbon atoms; the hydrocarbon group is an alkyl group, an alkynyl group, an alkenyl group or a fatty chain.

[0046] The substituent in the substituted hydrocarbon group in R1, R2, R3, R4, R5 and R6 is preferably N, O, S or Se.

[0047] The aryl group in R1, R2, R3, R4, R5 and R6 is preferably selected from an aliphatic ring or an aromatic ring.

[0048] The substituents in the substituted aryl or substituted heteroaryl in R1, R2, R3, R4, R5 and R6 are preferably -F, -Cl, -Br, -I, -OH, -NH2, -NHOH, -COOH, -COH, -SO3H, -SH, -SMe, -SEt, -OPO3H, -NO2, -NO, -SOMe, -SO2Me, -SOEt, -SO2Et, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, -OSO2Ph, phosphate group or sulfonate group.

[0049] When R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y, and Z are absent;

[0050] When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y, and Z are independently selected from hydrogen, amino, carboxyl, sulfhydryl, -SMe, -SEt, phosphate, nitro, -F, -Cl, -Br, -I, -CHF2, -CF3, -NHOH, -SO3H, -SOMe, -SO2Me, -SOEt, -SO2Et, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, -SeMe, -SeEt, p-toluenesulfonamide, phosphate, sulfonic acid Ester group, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), thiol (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, carboxyl derivative group, aryloxy, amide, acylamine, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester group, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphoric acid, unsubstituted aryl, aryl heterocyclic group, monocyclic heterocyclic group, methylthio (or seleno), ethylthio (or seleno), -NHOH.

[0051] In the present invention, the PD polypeptide compound is preferably synthesized by condensing one or more amino acids or amino acid-like compounds in Formulas 1 to 6 into an amide bond through the amino end and the carboxyl end, and / or by condensing an amino group and a sulfonic acid group into a sulfonamide bond; and / or by condensing an amino group and a sulfinic acid group into a sulfinamide bond.

[0052] Preferably, the PD polypeptide compound is preferably formed by condensing 5 amino acids or amino acid-like compounds, forming 4 amide bonds, sulfonamide bonds, and sulfenamide bonds, and the left end of the amino acid or amino acid-like structure is the nitrogen end, and the right end is the carbon end.

[0053] In a preferred embodiment of the present invention, the compounds (amino acids or amino acid-like compounds) of formula 1 to formula 6 are selected from one or more of Gln, Glu, Asn, Asp, homoaspartic acid, homoasparagine, homoglutamine, homoglutamic acid, Arg-Gly-Asp, Gly, Ala, Leu, Val, Leu, Phe, Ser, Thr, Phe, Tyr, Tyr(OMe) and Tyr(OEt); the amino acids in the compounds of formula 1 to formula 6 preferably include one or both of L-configuration and D-configuration structures.

[0054] More preferably, PD is selected from one of the compounds of formula II to formula VII:

[0055]

[0056] In formula II, m, n, n1, n2, n3, n4, m1, m2, m3, and m4 are selected from integers between 0 and 5;

[0057] R1 is selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp amino acid, amine derivative group, hydrocarbon group or substituted hydrocarbon;

[0058] R2 is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group, an acyl derivative group, a sulfonyl derivative group, X5-Arg-Gly-Asp-;

[0059] R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 independently selected from hydrogen, hydrocarbon or substituted hydrocarbon, heteroatom substituted hydrocarbon, alkene or alkene derivative, alkynyl or alkynyl derivative, aryl and substituted aryl, heteroaryl or substituted heteroaryl;

[0060] X, X1, X2, X3, X4, and X5 are independently selected from hydrogen, hydroxy, amino, hydrocarbon or substituted hydrocarbon.

[0061] In the present invention, the PD is a polypeptide compound preferably having a structure of formula III:

[0062]

[0063] In formula III, k1 and k2 are independently selected from integers between 0 and 16;

[0064] R', R'1, R'2 and R'3 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon;

[0065] X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon;

[0066] AA1 is selected from one of the structures of Formula 7 to Formula 12:

[0067]

[0068] In Formulae 7 to 12: the acyl end of the general formula AA3 is coupled to the nitrogen end of the main chain;

[0069] m, n, and n1 are independently selected from integers between 0 and 5;

[0070] R, Z' are independently selected from hydrogen, -OH, -NH2, hydrocarbon or substituted hydrocarbon, acyl derivative groups, sulfonyl derivative groups;

[0071] R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, hydrocarbon or substituted hydrocarbon, olefin or olefin derivatives, alkynyl or alkynyl derivatives, aryl and substituted aryl, heteroaryl or substituted heteroaryl;

[0072] When R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y, and Z are absent;

[0073] When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y, and Z are independently selected from hydrogen, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphate, phosphate ester, unsubstituted aryl, aryl heterocyclic group, and monocyclic heterocyclic group.

[0074] In the present invention, the PD is a polypeptide compound preferably having a structure of Formula IV:

[0075]

[0076] In formula IV, k1 and k2 are independently selected from integers between 0 and 16;

[0077] R', R'1, R'2 and R'3 are independently selected from hydrogen, hydroxyl, hydrocarbon or substituted hydrocarbon;

[0078] X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl;

[0079] X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3, connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon;

[0080] AA2 is selected from one of the structures of Formula 13 to Formula 18:

[0081]

[0082] In Formulae 13 to 18: the acyl end of the general formula AA2 is coupled to the nitrogen end of the main chain, and the acyl end of the main chain is coupled to the nitrogen end of the general formula AA2;

[0083] m, n, n1 are independently selected from 0 to 5;

[0084] R is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group;

[0085] R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, hydrocarbon or substituted hydrocarbon, olefin or olefin derivatives, alkynyl or alkynyl derivatives, aryl and substituted aryl, heteroaryl or substituted heteroaryl;

[0086] When R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y, and Z are absent;

[0087] When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y, and Z are independently selected from hydrogen, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphate, phosphate ester, unsubstituted aryl, aryl heterocyclic group, and monocyclic heterocyclic group.

[0088] In the present invention, the PD is a polypeptide compound preferably having a structure of Formula V:

[0089]

[0090] In formula V, k, k1 and k2 are independently selected from integers between 0 and 16;

[0091] R', R'1, R'2 and R'3 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon;

[0092] X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl;

[0093] X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon;

[0094] The selection range of AA3 is consistent with the selection range of AA2 in formula III described in the above technical solution.

[0095] In the present invention, the PD is a polypeptide compound preferably having a structure of Formula VI:

[0096]

[0097] In Formula VI, k, k1 and k2 are independently selected from integers between 0 and 16;

[0098] R', R'1, R'2 and R'3 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon;

[0099] X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl;

[0100] X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon;

[0101] The selection range of AA4 is consistent with the selection range of AA2 in formula III described in the above technical solution.

[0102] In the present invention, the PD is a polypeptide compound preferably having a structure of Formula VII:

[0103]

[0104] In Formula VII, k and k1 are independently selected from integers between 0 and 16;

[0105] R', R'1, R'2 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon;

[0106] X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl;

[0107] X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon;

[0108] AA5 is selected from one of the structures of Formula 19 to Formula 24:

[0109]

[0110] In Formulae 19 to 24: the main chain acyl end is coupled to the general nitrogen end of AA5;

[0111] m, n, and n1 are independently selected from integers between 0 and 5;

[0112] R is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group;

[0113] R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, hydrocarbon or substituted hydrocarbon, olefin or olefin derivatives, alkynyl or alkynyl derivatives, aryl and substituted aryl, heteroaryl or substituted heteroaryl;

[0114] When R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y, and Z are absent;

[0115] When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y, and Z are independently selected from hydrogen, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphoric acid, phosphoric acid ester, unsubstituted aryl, aryl heterocyclic group, and monocyclic heterocyclic group;

[0116] R x Selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form a lipid derivative group, an amine derivative group, an olefin group or an olefin derivative, an alkynyl group or an alkynyl derivative, an aryl group and a substituted aryl group, a heteroaryl group or a substituted heteroaryl group, Z 1 , Z 2 independently selected from alkyl, Z 3 It is selected from hydrogen, hydroxyl, amino, an ester derivative group formed with the carbon end of Asp, an amine derivative group, a hydrocarbon group or a substituted hydrocarbon.

[0117] In a specific embodiment of the present invention, the PD polypeptide compound has the following structure:

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125] Preferably, the peptoid compound provided by the present invention has the following structure:

[0126]

[0127]

[0128]

[0129]

[0130] In a second aspect, the present invention provides a complex of a peptoid compound, wherein the complex is formed by reacting the peptoid compound, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs thereof with a metal; the metal is selected from rare earth elements, Cu, Ga, In, Bi, Al 18 One of F, At, Ac, Bi or an isotope thereof.

[0131] The “rare earth elements” mentioned above include lanthanum (La), cerium (Ce), rhodium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), yttrium (Y), and scandium (Sc).

[0132] Preferably, the metal is Gd, 177 Lu, 64 Cu, 68 Ga, 111 In, 211 At 225 Ac, 90 Y. 213 Bi、Al 18 F or its isotopes.

[0133] In a specific embodiment of the present invention, the complex structure of the peptoid compound is as follows:

[0134]

[0135]

[0136]

[0137] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned peptidomimetic compound, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs and / or complexes of the peptidomimetic compound.

[0138] Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients and / or carriers.

[0139] In a fourth aspect, the present invention provides a peptidomimetic compound, and its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs and / or complexes of peptidomimetic compounds and / or the use of the above-mentioned pharmaceutical compositions in the preparation of drugs for diagnosing and / or treating diseases related to integrin αvβ5, and / or integrin α5β1, and / or integrin αvβ3, and / or integrin αvβ6.

[0140] The diagnosis includes but is not limited to PET / CT and magnetic resonance imaging.

[0141] The diseases associated with integrin αvβ5, and / or integrin α5β1, and / or integrin αvβ3, and / or integrin αvβ6 described in the present invention include one or more of lung adenocarcinoma, breast cancer, pancreatic cancer, melanoma, malignant primary neuroendocrine prostate cancer and its lung metastatic lesions, breast cancer, ovarian cancer, and gastrointestinal tumors.

[0142] The peptidyl ...

[0143] In the structural formula of the compound of the present invention Indicates the bond between two groups.

[0144] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is substantially non-toxic to an organism. In the present invention, pharmaceutically acceptable salts generally include (but are not limited to) salts formed by reacting the compound of the present invention with a pharmaceutically acceptable inorganic / organic acid or inorganic / organic base. Such salts are also referred to as acid addition salts or base addition salts.

[0145] In the present invention, the term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to an organism and is hydrolyzed in vivo to form a compound of the present invention or a salt thereof. In the present invention, pharmaceutically acceptable esters generally include (but are not limited to) esters formed between a compound of the present invention and a pharmaceutically acceptable carboxylic acid or sulfonic acid, which are also referred to as carboxylic acid esters or sulfonic acid esters.

[0146] In the present invention, the term "isomer" refers to a compound having the same molecular weight due to the same number of atoms and atomic types, but different spatial arrangements or configurations of atoms. The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a vertical asymmetric plane due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane polarized light. Since the compounds of the present invention have asymmetric centers and other chemical structures that may cause stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (or their pharmaceutically acceptable salts) include asymmetric carbon atoms, they can exist in the form of a single stereoisomer, a racemate, an enantiomer, and a mixture of diastereomers. Generally, these compounds can be prepared in the form of racemates. However, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in a single stereoisomer (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, or ≥80%). Single stereoisomers of a compound are prepared synthetically from optically active starting materials containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatography, use of a chiral resolving agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds of a particular stereochemistry are either commercially available or prepared by methods well known in the art and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that do not form mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention. The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be converted to each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (or prototransfer tautomers) include (but are not limited to) interconversions carried out by proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imino alcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0147] In the present invention, the term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. Polymorphs of a molecule can be obtained by many known methods by those skilled in the art. These methods include (but are not limited to) melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion and sublimation.

[0148] In the present invention, the term "solvate" refers to a substance formed by the combination of the compound of the present invention (or its pharmaceutically acceptable salt) and at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetoneates, etc.

[0149] In the present invention, the term "nitrogen oxide" refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound structure. For example, a nitrogen atom in a parent core structure can form a corresponding nitrogen oxide.

[0150] In the present invention, the term "isotope-labeled compound" refers to a derivative compound formed by replacing a specific atom in the compound of the present invention with its isotope atom. Unless otherwise specified, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as 2 H(D), 3 H(T), 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 S and 37 Cl.

[0151] In the present invention, the term "metabolite" refers to a derivative compound formed after the compound of the present invention is metabolized. Further information on metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9th ed.) [M], McGraw-Hill International Editions, 1996.

[0152] In the present invention, the term "prodrug" refers to a derivative compound that can directly or indirectly provide a compound of the present invention after being administered to an individual. Particularly preferred derivative compounds or prodrugs are compounds that can increase the bioavailability of the compound of the present invention when administered to an individual (e.g., more easily absorbed into the blood), or compounds that promote the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.

[0153] In the present invention, the terms "comprises", "including", "having" or "containing" or any other variations thereof are intended to cover non-exclusive or open-ended inclusions. For example, a composition, method or apparatus comprising a list of elements is not necessarily limited to the elements explicitly listed but may also include other elements not explicitly listed or inherent to the composition, method or apparatus.

[0154] The present invention has no special restrictions on the preparation method of the peptoid compound. The solid phase piece-by-piece, fragment synthesis, and liquid phase synthesis of peptide compounds by a resin skilled in the art can be used, and the desired amino acids, quasi-amino acids, or peptide substances can be used for synthesis according to the compound structure; the general steps in the preparation process of the peptide compound preferably include: initial resin synthesis, deprotection group (Fmoc protecting group), coupling amino acids, and the desired peptide compound is gradually synthesized by repeating the deprotection group and amino acid coupling operations. BRIEF DESCRIPTION OF THE DRAWINGS

[0155] Figure 1 HPLC spectrum of compound TM1;

[0156] Figure 2 HPLC spectrum of compound TM13;

[0157] Figure 3 HPLC spectrum of compound Ga-TM2;

[0158] Figure 4 PET / CT imaging of Experimental Example 2. DETAILED DESCRIPTION

[0159] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only some embodiments of the present invention, not all. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0160] Synthesis of Peptide-like Compounds

[0161] Example 1 Synthesis of TM1 Compound

[0162] The structural formula of TM1 compound is as follows:

[0163]

[0164] Step 1: Synthesis of Fmoc-Asn(Trt)-resin

[0165] Take 2-CTC Resin (1g, 1mmol) in a peptide synthesis tube, swell with dichloromethane (DCM) (10mL) at room temperature for 15 minutes, and drain the solvent. Add Fmoc-Asn(Trt)-OH (715mg, 1.2mmol), DCM (10mL) and diisopropylethylamine (DIEA) (310mg, 2.4mmol), blow nitrogen at room temperature for 2 hours, and drain the solvent. Wash the resin with DCM (10mL) three times. Add a mixed solution of methanol (MeOH) and DIEA in DCM (15mL, V DCM :V MeOH :V DIEA =75:25:5) and continued the reaction for 15 minutes, drained the reaction solution, washed three times with DCM (5 mL), and finally washed three times with N,N-dimethylformamide (DMF) (5 mL), drained the solvent to obtain Fmoc-Asn(Trt)-resin, which was directly used in the next reaction.

[0166] Step 2:

[0167] Synthesis of tBuO-DOTA-PEG3-Asp(OtBu)-Pro-Val-PEG4-Asn(Trt)-Asp(OtBu)-Aib-Ile-Asn(Trt)-resin

[0168] Removal of Fmoc protecting group: Add piperidine in DMF solution (10 mL, V 哌啶 :V DMF =1:4), react at room temperature for 5 minutes, drain, and add piperidine DMF solution (10 mL, V 哌啶 :V DMF =1:4) at room temperature for 10 minutes. After the reaction is completed, the reaction solution is drained and washed with DMF (10 mL) 3 times, and the solvent is drained. A small amount of resin is heated with 5% ninhydrin ethanol solution at 110°C for 3 minutes. The resin turns dark blue, indicating that Fmoc has been removed, and is directly used for the next reaction.

[0169] Coupling: Dissolve Fmoc-Ile-OH (1g, 3mmol, 3eq) and 2-(1H-benzotriazolyl L-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (0.96g, 3mmol, 3eq) in DMF (15mL), add DIEA (1mL, 6mmol, 6eq) to the reaction solution and stir for activation for 10 minutes under ice bath. Add the activation solution to the resin after Fmoc removal, react at room temperature for 1h, take a small amount of resin, add 5% ninhydrin ethanol solution and heat at 110℃ for 3 minutes) The resin becomes colorless. Drain the reaction solution and wash it with DMF (10mL) 3 times. The obtained resin is directly used for the next reaction.

[0170] The coupling cycle was repeated, and the above operation was performed to couple amino acids Fmoc-Aib-OH (0.97 g, 3 mmol, 3 eq), Fmoc-Asp(OtBu)-OH (1.23 g, 3 mmol, 3 eq), Fmoc-Asn(Trt)-OH (1.79 g, 3 mmol, 3 eq), Fmoc-PEG4-OH (0.73 g, 1.5 mmol, 1.5 eq), Fmoc-Val-OH (1 g, 3 mmol, 3 eq), Fmoc-Pro-OH (1 g, 3 mmol, 3 eq), Fmoc-Asp(OtBu)-OH (1.2 g, 3 mmol, 3 eq), Fmoc-PEG3-OH (0.66 g, 1.5 mmol, 1.5 eq), and DOTA(tBu)3 (1 g, 2 mmol, 2 eq). Use 10 mL of DCM and MeOH respectively, wash alternately for 3 times, drain, transfer to a vacuum oven, and dry in vacuum at 35°C for 2 hours to obtain 3.4 g of DOTA(OtBu)3-PEG3-Asp(OtBu)-Pro-Val-PEG4-Asn(Trt)-Asp(OtBu)-Aib-Ile-Asn(Trt)-resin, which is directly used in the next reaction.

[0171] Step 3:

[0172] Synthesis of DOTA-PEG3-Asp-Pro-Val-PEG4-Asn-Asp-Aib-Ile-Asn-OH(TM1)

[0173] Add cleavage solution (17 mL, 10 mL / g resin, TFA:TIS:H2O volume ratio of 95:2.5:2.5) to 1.7 g resin, react for 2.5 hours, filter, and wash the resin with cleavage solution (1 mL). Add methyl tert-butyl ether (MTBE) (50 mL) dropwise to the combined filtrate, settle in an ice bath for 1 hour, and centrifuge. Wash with methyl tert-butyl ether (40 mL) three times to obtain a white solid. Transfer the solid to a vacuum drying oven and vacuum dry at 35°C for 2 hours to obtain 690 mg of crude peptide. Purify by Pre-HPLC to obtain a purified solution, concentrate and freeze-dry to obtain 340 mg of a white solid with a purity of 97.6%, as shown in FIG. Figure 1 As shown, the yield is 40%.

[0174] The product prepared in Example 1 was subjected to mass spectrometry detection; the detection result was: MS (ESI): m / z [M+2H] 2+ / 2=847.6,[M+3H] 3+ / 3=565.5.

[0175] According to the operation method similar to that described in Example 1, the compounds (TM2-TM12) with the following structures were synthesized.

[0176] TM2 compounds

[0177]

[0178] TM3 compounds

[0179]

[0180] TM4 compounds

[0181]

[0182] TM5 compounds

[0183]

[0184] TM6 compounds

[0185]

[0186] TM7 compounds

[0187]

[0188] TM8 Compounds

[0189]

[0190] TM9 compounds

[0191]

[0192] TM10 Compound

[0193]

[0194] TM11 Compound

[0195]

[0196] TM12 Compound

[0197]

[0198] Example 2 Synthesis of TM13 Compound

[0199] The structural formula of TM13 compound is as follows:

[0200]

[0201] Step 1: Synthesis of Fmoc-Asn(Trt)-resin (M1)

[0202] 2-CTC Resin (1 g, 1 mmol) was placed in a peptide synthesis tube and swelled with DCM (10 mL) for 15 minutes at room temperature, and the solvent was drained. Fmoc-Asn(Trt)-OH (715 mg, 1.2 mmol), DCM (10 mL) and DIEA (310 mg, 2.4 mmol) were added, and the reaction was purged with nitrogen for 2 hours at room temperature, and the solvent was drained. The resin was washed with DCM (10 mL) three times. A mixed solution of MeOH and DIEA in DCM (15 mL, V DCM :V MeOH :V DIEA =75:25:5) and continued to react for 15 minutes, drained the reaction solution, washed three times with DCM (5 mL), and finally washed three times with N,N-dimethylformamide (DMF) (5 mL), drained the solvent to obtain Fmoc-Asn(Trt)-resin (M1), which was directly used in the next reaction.

[0203] Step 2: Synthesis of Fmoc-PEG3-Asp(OtBu)-Pro-Val-Asn(Trt)-Asp(OtBu)-Aib-Ile-Asn(Trt)-resin (M2)

[0204] Removal of Fmoc protecting group: Add piperidine in DMF solution (10 mL, V 哌啶 :V DMF =1:4), react at room temperature for 5 minutes, drain, and add piperidine DMF solution (10 mL, V 哌啶 :VDMF =1:4) at room temperature for 10 minutes. After the reaction is completed, the reaction solution is drained and washed with DMF (10 mL) 3 times, and the solvent is drained. A small amount of resin is heated with 5% ninhydrin ethanol solution at 110°C for 3 minutes. The resin turns dark blue, indicating that Fmoc has been removed, and is directly used for the next reaction.

[0205] Coupling: Dissolve Fmoc-Ile-OH (1g, 3mmol, 3eq) and 2-(1H-benzotriazolyl L-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (0.96g, 3mmol, 3eq) in DMF (15mL), add DIEA (1mL, 6mmol, 6eq) to the reaction solution and stir for activation for 10 minutes under ice bath. Add the activation solution to the resin after Fmoc removal, react at room temperature for 1h, take a small amount of resin, add 5% ninhydrin ethanol solution and heat at 110℃ for 3 minutes) The resin becomes colorless. Drain the reaction solution and wash it with DMF (10mL) 3 times. The obtained resin is directly used for the next reaction.

[0206] The coupling cycle was repeated, and the above operation was performed to couple amino acids Fmoc-Aib-OH (0.97 g, 3 mmol, 3 eq), Fmoc-Asp(OtBu)-OH (1.23 g, 3 mmol, 3 eq), Fmoc-Asn(Trt)-OH (1.79 g, 3 mmol, 3 eq), Fmoc-Val-OH (1 g, 3 mmol, 3 eq), Fmoc-Pro-OH (1 g, 3 mmol, 3 eq), Fmoc-Asp(OtBu)-OH (1.2 g, 3 mmol, 3 eq), and Fmoc-PEG3-OH (0.86 g, 2 mmol, 2 eq) one by one. The mixture was washed alternately three times with 10 mL of DCM and MeOH, dried, transferred to a vacuum oven, and dried in vacuo at 35°C for 2 hours to obtain 2.9 g of Fmoc-PEG3-Asp(OtBu)-Pro-Val-Asn(Trt)-Asp(OtBu)-Aib-Ile-Asn(Trt)-resin (M2).

[0207] Step 3: Synthesis of NH2-Ph-NH-CO-PEG3-Asp(OtBu)-Pro-Val-Asn(Trt)-Asp(OtBu)-Aib-Ile-Asn(Trt)-resin (M3)

[0208] Take 1.5g of the above resin and perform Fmoc removal in a peptide synthesis tube. After washing, add DMF solution (5mL) of N,N'-disuccinimidyl carbonate (DSC) (0.64g, 2.5mmol, 5eq) and DIEA (0.87mL, 5mmol, 10eq) to the peptide resin. After reacting for 2 hours under nitrogen bubbling, wash with DMF 3 times and drain. Add p-diphenylamine (0.27g, 2.5mmol, 5eq) and DIEA (0.87mL, 5mmol, 10eq) to the peptide resin, react for 2 hours under nitrogen bubbling, wash with DMF 3 times and drain.

[0209] Step 4: Synthesis of DOTA-XX-PEG3-Asp-Pro-Val-Asn-Asp-Aib-Ile-Asn-OH (M4)

[0210] DOTA(tBu)3 (0.57 g, 1 mmol, 2 eq) and TBTU (0.32 g, 1 mmol, 2 eq) were dissolved in DMF (15 mL). DIEA (1 mL, 6 mmol, 6 eq) was added to the reaction solution and stirred for activation for 10 minutes under an ice bath. The activation solution was added to the resin after Fmoc removal and reacted at room temperature overnight. A small amount of the resin was added with 5% ninhydrin ethanol solution and heated at 110°C for 3 minutes. The resin was colorless. The reaction solution was drained and washed with DMF (10 mL) 3 times. DCM and MeOH were used to shrink the solution alternately to obtain 1.7 g of resin (M4).

[0211] Step 5: Synthesis of DOTA-XX-PEG3-Asp-Pro-Val-Asn-Asp-Aib-Ile-Asn-OH (TM13)

[0212] To 1.7 g of the above resin, add lysis solution (17 mL, 10 mL / g resin, TFA:TIS:H2O volume ratio of 95:2.5:2.5), react for 2.5 hours, filter, and wash the resin with lysis solution (1 mL). Add methyl tert-butyl ether (MTBE) (80 mL) dropwise to the combined filtrate, settle in an ice bath for 1 hour, and centrifuge. Wash with methyl tert-butyl ether (40 mL) 3 times to obtain a white solid. Transfer the solid to a vacuum drying oven and vacuum dry at 35°C for 2 hours to obtain 594 mg of crude peptide, which is purified by Pre-HPLC to obtain a purified solution, which is concentrated and freeze-dried. 126 mg of a white solid is obtained with a purity of 96.3%, as shown in FIG. Figure 2 . Yield: 16%.

[0213] The product prepared in Example 2 was subjected to mass spectrometry detection; the detection result was: MS (ESI): m / z [M+2H + ] / 2=791.0, [M+3H +] / 3=527.9.

[0214] In this embodiment

[0215] According to the operation method similar to that described in Example 2, the compounds (TM14-TM18) with the following structures were synthesized.

[0216] TM14 Compound

[0217]

[0218] TM15 Compound

[0219]

[0220] TM16 Compound

[0221]

[0222] TM17 compounds

[0223]

[0224] TM18 Compound

[0225]

[0226] TM19 compounds

[0227]

[0228] Synthesis of Peptide-like Complexes Example 3 Synthesis of Ga-TM2 The synthesis route is as follows:

[0229]

[0230] Weigh TM2 (150 mg, 0.1 mmol) into a reaction tube, add ultrapure water (1 mL) to dissolve, add to GaCl3 solution (0.5 mL, 0.2 M), add NaOAc aqueous solution (1 M) to adjust the pH to 4-6. After stirring for 1 hour, take 1 drop of the reaction solution, dilute and filter, and send to HPLC for control. After the reaction of the raw material is completed, filter and send to purification. After freeze-drying, 107 mg of white solid was obtained with a purity of 98.8% HPLC, as shown in FIG. Figure 3 As shown. LC-MS results showed m / z: [M+2H + ] / 2=757.6 is the target molecule.

[0231] According to the similar operation method as described in Example 3, the compound with the following structure was synthesized.

[0232] Ga-TM3 compound

[0233]

[0234] LC-MS results showed m / z: [M+2H + ] / 2=741.8; 15 mg; 98.2% HPLC purity.

[0235] Ga-TM9 compound

[0236]

[0237] LC-MS results showed m / z: [M+2H + ] / 2=780.3; 21 mg; 96.6% HPLC purity.

[0238] Ga-TM1 compound

[0239]

[0240] LC-MS results showed m / z: [M+2H + ] / 2=873.4; 7 mg; 92.7% HPLC purity.

[0241] Ga-TM7 compound

[0242]

[0243] LC-MS results showed m / z: [M+2H + ] / 2=778.8; 67 mg; 93.5% HPLC purity.

[0244] Ga-TM17 compounds

[0245]

[0246] LC-MS results showed m / z: [M+2H + ] / 2=857.8; 21 mg; 97.8% HPLC purity.

[0247] Ga-TM16 compounds

[0248]

[0249] LC-MS results showed m / z: [M+2H + ] / 2=830.8; 17 mg; 98.7% HPLC purity.

[0250] Ga-TM13 compound

[0251]

[0252] LC-MS results showed m / z: [M+2H + ] / 2=823.8; 15 mg; 91.5% HPLC purity.

[0253] Ga-TM18 compound

[0254]

[0255] LC-MS results showed m / z: [M+2H + ] / 2=947.4; 8 mg; 95.8% HPLC purity.

[0256] Ga-TM19 compound

[0257]

[0258] LC-MS results showed m / z: [M+2H + ] / 2=954.4; 67 mg; 99.3% HPLC purity.

[0259] Gd-TM8 compounds

[0260]

[0261] LC-MS results showed m / z: [M+2H + ] / 2=796.3; 23 mg; 99.3% HPLC purity.

[0262] Lu-TM19 compound

[0263]

[0264] LC-MS results showed m / z: [M+2H + ] / 2=1007.4; 16 mg; 96.5% HPLC purity.

[0265] Test Example 1 Target Affinity Test

[0266] The affinity of the example compounds to the target protein integrins α5β1, αvβ3, αvβ5, and αvβ6 was tested using the surface plasmon resonance (SPR) technique. Specifically, the following steps were performed:

[0267] The recombinant Integrin α5β1, αvβ3, αvβ5, and αvβ6 proteins were fixed on a CM5 chip (Biacore), and an SPR instrument (Biacore T200) was used to test the binding constants (Ka) and dissociation constants (Kd) of the compounds with Integrin α5β1, αvβ3, αvβ5, and αvβ6 under the conditions of an injection volume of 30 μL of the test solution, a flow rate of 30 μL / min, and 25°C. The affinity constant KD between the compound and the target protein Integrin α5β1, αvβ3, αvβ5, and αvβ6 was calculated according to the formula KD=Kd / Ka (the lower the KD value, the higher the affinity of the example compound to the target protein).

[0268] The in vitro affinity data are shown in Table 1:

[0269] Table 1 KD values ​​of compounds for integrin α5β1, αvβ3, αvβ5 or αvβ6

[0270] Compound No. / Target α5β1(uM) αvβ3(uM) αvβ5(uM) αvβ6(uM) TM1 0.35 -- 1.24 0.88 Ga-TM1 1.35 -- 3.66 0.68 Ga-TM2 1.28 -- 1.35 12.7 Ga-TM3 35.5 -- 55.7 23.2 Ga-TM7 9.87 25.7 3.55 56.6 Ga-TM9 33.8 33.2 46.7 -- Ga-TM13 0.12 -- 0.32 -- Ga-TM16 55.3 -- -- -- Ga-TM17 34.2 -- -- -- Ga-TM18 0.25 -- 0.72 1.5 Ga-TM19 23.8 -- 67.6 -- Gd-TM8 4.40 -- 16.8 -- Lu-TM19 21.9 -- 32.6 --

[0271] Experimental Example 2 Radioactive compound labeling experiment

[0272] Radioactivity of compound TM1 68 Ga labeling

[0273] Add TM1 (20 μg) aqueous solution into the prepared 68 The GaCl3 solution is adjusted to pH 3-5 with sodium acetate aqueous solution and acetic acid, and reacted at 70-95°C for 15 minutes. After the reaction is completed, it is purified to obtain the labeled 68 Solution of Ga-TM1.

[0274] All compounds in the examples of the present invention 68 The Ga labeling method is the same as the above method. Continue labeling as described above to obtain 68 Ga-TM2, 68 Ga-TM13, 68 Ga-TM18.

[0275] PET / CT experiments

[0276] 1) Evaluation of lung adenocarcinoma model

[0277] M-NSG mice inoculated with H1975 were injected intravenously with about 100 μCi of the above 68 The Ga-labeled compound solution was injected and PET / CT imaging was performed 1 h and 2 h later. The experimental data in Table 2 were obtained through image post-processing.

[0278] Table 2 PET / CT experimental results

[0279]

[0280]

[0281] The results of the animal experiment in the above table show that there is obvious enrichment in the tumor of M-NSG mice inoculated with H1975. In the uptake values ​​at 1h and 2h, except for the kidney (the kidney is the main clearance pathway for the compound), the uptake values ​​of TM1, TM2, TM13, and TM18 in the tumor are the highest, and in the imaging data of 1h and 2h, the tumor / tissue (except tumor / kidney) is greater than 2, that is, the drug targets specific tumor sites. The uptake values ​​of the drug in various tissues (except tumors and kidneys) at 1h are all lower than 0.5% ID / g, that is, the drug can be quickly cleared in various tissues. At the same time, from Figure 4 The 1-hour imaging effect demonstrated that the drug is mainly enriched in the tumor, bladder and kidney. The image is clear and meets the conditions for PET / CT diagnosis.

[0282] The present invention lists 68 Ga chelated TM1, TM2, TM13, TM18 compounds were used for PET / CT imaging in a mouse model of lung adenocarcinoma. The data showed that they were specifically taken up in the tumor site and had low uptake in normal tissues. The above data show that the compounds mentioned in the present invention have tumor targeting specificity and can be used for 177 Lu, 64 Cu, 111 In、Al 18 F. 211 At 225 Ac, 90 Y. 213 Targeted compounds of radioactive substances such as Bi and Gd or their isotopes are expected to be used in the diagnosis and / or treatment of various tumors such as lung adenocarcinoma, breast cancer, pancreatic cancer, melanoma, malignant primary neuroendocrine prostate cancer and its lung metastatic lesions, breast cancer, ovarian cancer, gastrointestinal tumors, etc.

[0283] The results of PET / CT imaging animal experiments show that the peptoid compounds prepared by the present invention and their complexes can directly target tumor cells and can be used as targeting carriers to accurately deliver cytotoxins, radionuclides, etc. to tumor cells.

[0284] The results of in vitro enzymology data experiments show that the peptoid compounds prepared by the present invention and their complexes can be used for the diagnosis and / or treatment of various tumors such as lung adenocarcinoma, breast cancer, pancreatic cancer, melanoma, malignant primary neuroendocrine prostate cancer and its lung metastatic lesions, breast cancer, ovarian cancer, gastrointestinal tumors, etc.

[0285] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A peptoid compound, and its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, wherein the compound has the following structural formula: ZT-PD, or ZT-Linker-PD; in, The ZT structure is one of ZT1 to ZT4: na is an integer selected from 1 to 8; PD is a polypeptide compound, a compound and / or its derivatives prepared by amino condensation of one or more of the compounds of formula 1 to formula 6: In Formulae 1 to 6, m, n, and n1 are independently selected from integers between 0 and 5; R is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group; R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, hydrocarbon or substituted hydrocarbon, olefin or olefin derivative, alkynyl or alkynyl derivative, aryl and substituted aryl, heteroaryl or substituted heteroaryl; wherein the substituent is selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or selenium), haloalkylthio (or selenium), thiol (or selenium), alkylthio (or selenium) ether, arylthio (or selenium) ether, hydroxyl, cyano, nitro, carboxyl derivative, aryloxy, amide, acylamine, amino alkyl, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, halogenated alkylsulfonyl, sulfonic acid, sulfonamide, phosphoric acid, phosphate ester, unsubstituted aryl, aryl heterocyclic group, monocyclic heterocyclic group, N, O, S, Se, hydrogen, carboxyl, methyl thio (or seleno) ether group, ethyl thio (or seleno) ether group, -SOMe, -SO2Me, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, p-toluenesulfonamide, sulfonic acid ester; When R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y, and Z are absent; When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y, and Z are independently selected from hydrogen, amino, carboxyl, thiol, -SMe, -SEt, phosphate, nitro, -F, -Cl, -Br, -I, -CHF2, -CF3, -NHOH, -SO3H, -SOMe, -SO2Me, -SOEt, -SO2Et, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, -SeMe, -SeEt, p-toluenesulfonamide, phosphate, sulfonic acid Ester group, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), thiol (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, carboxyl derivative group, aryloxy, amide, acylamine, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester group, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphoric acid, unsubstituted aryl, aryl heterocyclic group, monocyclic heterocyclic group, methylthio (or seleno), ethylthio (or seleno), -NHOH. The Linker structure is as follows: X L Selected from N-alkyl substituted D- or L-amino acid, or one of the structures X1-X8: LL is selected from one of the following structures: LR does not exist or is selected from one of the following structures: m and n are independently selected from integers between 0 and 16; R 1L is selected from hydrogen, hydrocarbon or substituted hydrocarbon, alkene or alkene derivatives, alkynyl or alkynyl derivatives, aryl and substituted aryl, heteroaryl or substituted heteroaryl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno) group, haloalkylthio (or seleno) group, thiol (or seleno) group, alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl , ester group, sulfonyl group, alkylsulfonyl group, halogenated alkylsulfonyl group, sulfonic acid group, sulfonamide group, phosphoric acid group, phosphate ester group, unsubstituted aromatic group, aromatic heterocyclic group, monocyclic heterocyclic group, carboxyl group, -CHF2, -CF3, -NHOH, -SO3H, -SOMe, -SO2Me, -SOEt, -SO2Et, -CONH2, -COOMe, -COOEt, -NHOCH, -NHOCCH3, -NHSO2Me, p-toluenesulfonamide group, sulfonic acid ester group. R 2L Selected from -OH, -NH2, -NHMe, -N(Me)2, -N(Et)2; Y L Selected from one of the structures Y1-Y4: Z L With Y L The urea structure formed by coupling is selected from one of Z1-Z4:

2. The peptoid compound according to claim 1, and its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, characterized in that: The Linker structure is shown in L1 to L10: m, n, R 1L , R 2L , X L , Y L , Z L The group is as described in claim 1.

3. The peptoid compound according to claim 1, and its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, characterized in that: Linker is selected from the structure shown below:

4. The peptoid compound according to claim 1, and its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, characterized in that: The compounds of Formulas 1 to 6 in the PD structure are selected from one or more of Gln, Glu, Asn, Asp, homoaspartic acid, homoasparagine, homoglutamine, homoglutamic acid, Arg-Gly-Asp, Gly, Ala, Leu, Val, Leu, Phe, Ser, Thr, Phe, Tyr, Tyr(OMe) and Tyr(OEt); the amino acids in the compounds of Formulas 1 to 6 include one or both of L-configuration and D-configuration structures.

5. The peptoid compound according to claim 4, and its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, characterized in that: PD is formed by condensing five compounds in Formulae 1 to 6, forming four amide bonds, sulfonamide bonds and / or sulfenamide bonds. The left end of the amino acid or amino acid-like structure is the nitrogen end, and the right end is the carbon end.

6. The peptoid compound according to claim 5, and its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, characterized in that: PD is selected from one of the compounds of formula II to formula VII: In formula II, m, n, n1, n2, n3, n4, m1, m2, m3, and m4 are selected from integers between 0 and 5; R1 is selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp amino acid, amine derivative group, hydrocarbon group or substituted hydrocarbon; R2 is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group, an acyl derivative group, a sulfonyl derivative group, X5-Arg-Gly-Asp-; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 independently selected from hydrogen, hydrocarbon or substituted hydrocarbon, heteroatom substituted hydrocarbon, alkene or alkene derivative, alkynyl or alkynyl derivative, aryl and substituted aryl, heteroaryl or substituted heteroaryl; X, X1, X2, X3, X4, and X5 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon; In formula III, k1 and k2 are independently selected from integers between 0 and 16; R', R'1, R'2 and R'3 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon; X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon; AA1 is selected from one of the structures of Formula 7 to Formula 12: In Formulae 7 to 12: the acyl end of the general formula AA3 is coupled to the nitrogen end of the main chain; m, n, and n1 are independently selected from integers between 0 and 5; R, Z' are independently selected from hydrogen, -OH, -NH2, hydrocarbon or substituted hydrocarbon, acyl derivative groups, sulfonyl derivative groups; R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, hydrocarbon or substituted hydrocarbon, olefin or olefin derivatives, alkynyl or alkynyl derivatives, aryl and substituted aryl, heteroaryl or substituted heteroaryl; When R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y, and Z are absent; When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y, and Z are independently selected from hydrogen, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphoric acid, phosphoric acid ester, unsubstituted aryl, aryl heterocyclic group, and monocyclic heterocyclic group; In formula IV, k1 and k2 are independently selected from integers between 0 and 16; R', R'1, R'2 and R'3 are independently selected from hydrogen, hydroxyl, hydrocarbon or substituted hydrocarbon; X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl; X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon; AA2 is selected from one of the structures of Formula 13 to Formula 18: In Formulae 13 to 18: the acyl end of the general formula AA2 is coupled to the nitrogen end of the main chain, and the acyl end of the main chain is coupled to the nitrogen end of the general formula AA2; m, n, n1 are independently selected from 0 to 5; R is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group; R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, hydrocarbon or substituted hydrocarbon, olefin or olefin derivatives, alkynyl or alkynyl derivatives, aryl and substituted aryl, heteroaryl or substituted heteroaryl; When R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y, and Z are absent; When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y, and Z are independently selected from hydrogen, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphoric acid, phosphoric acid ester, unsubstituted aryl, aryl heterocyclic group, and monocyclic heterocyclic group; In formula V, k, k1 and k2 are independently selected from integers between 0 and 16; R', R'1, R'2 and R'3 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon; X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl; X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon; The selection range of AA3 is consistent with the selection range of AA2 in Formula III described in the above technical solution; In Formula VI, k, k1 and k2 are independently selected from integers between 0 and 16; R', R'1, R'2 and R'3 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon; X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl; X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon; The selection range of AA4 is consistent with the selection range of AA2 in formula III described in the above technical solution; In Formula VII, k and k1 are independently selected from integers between 0 and 16; R', R'1, R'2 are independently selected from hydrogen, hydroxyl, amino, hydrocarbon or substituted hydrocarbon; X' is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl; X1, X2 and X3 are independently selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form lipid derivative groups, amine derivative groups, Z 1 , Z 2 independently selected from alkyl, Z 3 Selected from hydrogen, hydroxyl, amino, ester derivative group formed with the carbon end of Asp, amine derivative group, hydrocarbon group or substituted hydrocarbon; AA5 is selected from one of the structures of Formula 19 to Formula 24: In Formulas 19 to 24: the main chain acyl end is coupled to the general nitrogen end of AA5; m, n, and n1 are independently selected from integers between 0 and 5; R is selected from hydrogen, -OH, -NH2, a hydrocarbon group or a substituted hydrocarbon group; R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, hydrocarbon or substituted hydrocarbon, olefin or olefin derivatives, alkynyl or alkynyl derivatives, aryl and substituted aryl, heteroaryl or substituted heteroaryl; When R1, R2, R3, R4, R5, and R6 are selected from hydrogen substitution, X, Y, and Z are absent; When R1, R2, R3, R4, R5, and R6 are selected from non-hydrogen substitutions, X, Y, and Z are independently selected from hydrogen, halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio (or seleno), haloalkylthio (or seleno), mercapto (or seleno), alkylthio (or seleno) ether, arylthio (or seleno) ether, hydroxyl, cyano, nitro, carboxyl derivative group, aryloxy, amide, acylamine, amino, hydroxylamine, alkylamine, dialkylamine, trifluoroalkoxy, trifluoromethyl, ester, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, phosphoric acid, phosphoric acid ester, unsubstituted aryl, aryl heterocyclic group, and monocyclic heterocyclic group; R x Selected from -H, -OH, -NH2, -NHNZ 1 Z 2 、-NHZ 1 、-NZ 1 Z 2 、-OZ 1 、-NHOZ 1 , -SH, -SeH, -SZ 1 、-SeZ 1 ,-Arg-Gly-Asp-Z 3 , connected with the carbonyl group to form a lipid derivative group, an amine derivative group, an olefin group or an olefin derivative, an alkynyl group or an alkynyl derivative, an aryl group and a substituted aryl group, a heteroaryl group or a substituted heteroaryl group, Z 1 , Z 2 independently selected from alkyl, Z 3 It is selected from hydrogen, hydroxyl, amino, an ester derivative group formed with the carbon end of Asp, an amine derivative group, a hydrocarbon group or a substituted hydrocarbon.

7. The peptoid compound according to claim 5, and its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs, characterized in that: The PD compound has the following structure:

8. A complex of a peptoid compound, the complex being formed by reacting the peptoid compound according to any one of claims 1 to 7, and its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs with a metal; the metal being selected from rare earth elements, Cu, Ga, In, Bi, Al 18 One of F, At, Ac, Bi or an isotope thereof.

9. A pharmaceutical composition comprising the peptidomimetic compound according to any one of claims 1 to 7, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs thereof and / or complexes of the peptidomimetic compound according to claim 8.

10. Use of a peptidomimetic compound according to any one of claims 1 to 7, and pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites and prodrugs thereof, and / or a complex of the peptidomimetic compound according to claim 8, and / or a pharmaceutical composition according to claim 9 in the preparation of drugs for diagnosing and / or treating diseases associated with integrin αvβ5, and / or integrin α5β1, and / or integrin αvβ3, and / or integrin αvβ6.

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