CN111662270A

CN111662270A - Iodine isotope labeled benzyl phenyl ether derivative, preparation method, pharmaceutical composition and application thereof

Info

Publication number: CN111662270A
Application number: CN201910165548.4A
Authority: CN
Inventors: 冯志强; 杨阳
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2019-03-05
Filing date: 2019-03-05
Publication date: 2020-09-15

Abstract

The invention discloses iodine radioisotope labeled benzyl phenyl ether derivatives, a preparation method thereof, a pharmaceutical composition and application. In particular to benzyl phenyl ether derivatives shown in a general formula I, medicinal salts thereof, stereoisomers thereof and preparation methods thereof, a composition containing one or more radioactive compounds, and the radioactive compounds used as a PD-L1 tracer in human or animal bodies for diagnosis, treatment and PD-1/PD-L1 signal channel related diseases such as cancer, infectious diseases, and autoimmune diseases.

Description

Iodine isotope labeled benzyl phenyl ether derivative, preparation method, pharmaceutical composition and application thereof

Technical Field

The invention discloses iodine radioisotope labeled benzyl phenyl ether derivatives, a preparation method thereof, a pharmaceutical composition and application. In particular to benzyl phenyl ether derivatives shown in a general formula I, medicinal salts thereof, stereoisomers thereof, a preparation method thereof, a composition containing one or more radioactive compounds and application of the radioactive compounds in human or animal bodies as PD-L1 tracers in diagnosis and treatment of diseases related to PD-1/PD-L1 signal pathways, such as cancers, infectious diseases and autoimmune diseases.

Background

With the deep research on tumor immunity, people find that the tumor microenvironment can protect tumor cells from being recognized and killed by the immune system of the body, and the immune escape of the tumor cells plays a very important role in the occurrence and development of tumors. The Science journal of 2013 lists tumor immunotherapy as the first major breakthrough, and once again, immunotherapy becomes the focus of the tumor therapy field. The activation or inhibition of immune cells in the body is regulated by positive signals and negative signals, wherein programmed death molecule 1 (PD-1) ligand (PD-1 ligand, PD-L1) is a negative immune regulation signal, inhibits the immune activity of tumor-specific CD8+ T cells, and mediates immune escape.

The tumor cells have the ability to evade the immune system by binding the PD-L1 protein produced on their surface to the PD-1 protein of T cells. The tumor microenvironment in the body can induce infiltrated T cells to highly express PD-1 molecules, and the tumor cells can highly express ligands PD-L1 and PD-L2 of PD-1, so that PD-1 channels in the tumor microenvironment are continuously activated, and the function of the T cells is inhibited, so that the tumor cannot be found, and the treatment which needs to attack the tumor and kill the tumor cells cannot be sent to the immune system. The PD-1 antibody is an antibody protein directed against PD-1 or PD-L1, such that the first two proteins cannot bind, blocking this pathway, partially restoring T cell function, allowing these cells to continue killing tumor cells.

Immunotherapy based on PD-1/PD-L1 is a new generation immunotherapy which is currently spotlighted, aims to resist tumors by utilizing the human body's own immune system, induces apoptosis by blocking the PD-1/PD-L1 signal pathway, and has the potential of treating various types of tumors. Recently, a series of surprising research results prove that the PD-l/PD-Ll inhibitory antibody has strong antitumor activity on various tumors and is particularly attractive. Currently, 2 PD-1 mab drugs (Nivolumab and Pembrolizumab), 3 PD-L1 mab drugs (Atezolizumab, Durvalumab and Avelumab) are successively approved on the market [3], show excellent and relatively long-lasting efficacy in various malignancies such as lymphoma, melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, etc., prolong the overall survival of patients, improve quality of life, and even enable individual patients to achieve cure [4], although immunotherapy is considered as a breakthrough therapy against cancer, and immune checkpoint inhibitors represented by PD-1/PD-L1 antibodies have become "star drugs" for cancer immunotherapy. However, the PD-1/PD-L1 antibody also has a number of disadvantages, mainly low response rates, such as: the overall response rate of PD-1/PD-L1 inhibitors is currently only 20-30% [5 ]. Still 70-80% of patients do not benefit, resulting in a waste of money, manpower and time. How to accurately screen effective tumor patients, how to accurately and effectively realize early diagnosis of tumors, effectively perform personalized treatment on the tumors, and simultaneously can minimize side effects of diagnosis and treatment, is a medical diagnosis and treatment method expected by people, namely accurate diagnosis and treatment, and the achievement of accurate medical treatment is an important subject of clinical research at present. The novel molecular diagnosis and treatment agent integrating diagnosis and treatment functions is one of the most effective solutions for realizing the aim of accurate diagnosis and treatment.

The precise diagnosis and treatment needs to adopt a high-sensitivity molecular imaging probe and an imaging technology to realize the rapid and precise diagnosis of a certain specific disease, and the targeted transportation and the controllable release of the medicine are adopted to ensure that the medicine can directly reach the focus without influencing normal organs. Around the important requirements of accurate imaging diagnosis, accurate treatment and prognosis evaluation of tumors, the key technologies of molecular imaging probes, targeted drugs and the like with high sensitivity, high specificity and high resolution are developed, and the key problems of accurate molecular image identification of tumor cells, accurate targeted tumor administration and molecular image evaluation are researched and solved. Single-Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) are two CT techniques of nuclear medicine, and are collectively called Emission Computed Tomography (ECT) because they image gamma rays emitted from a patient. At present, single SPECT imaging is gradually replaced by SPECT/CT, and the SPECT/CT becomes one of the most advanced medical imaging devices of human beings at present, and is an ideal tool for diagnosing living diseases and researching and developing new drugs. Advanced medical devices can measure biological activities of cells and molecules by using a SPECT principle, such as a SPECT system of GE company, and a composite imaging device SPECT & CT and PET & CT system combining diagnosis-level multi-layer CT, and can accurately locate the position, the nature and the degree of a lesion. SPECT imaging plays an important role clinically, and a three-dimensional image is obtained through tomography. The PET detection system has the advantages of high sensitivity, high resolution, tissue accumulation which can be properly quantified and the like, and can be combined with the anatomical image of CT or MR to display the biomolecular metabolism, the receptor ligand specific binding, the nerve medium activity and the like in vitro in a noninvasive, quantitative and dynamic manner.

The development of a molecular imaging probe with high sensitivity, high specificity and high resolution is a prerequisite for accurate diagnosis and treatment. The immunotherapy based on PD1/PD-L1 has low response rate, how to accurately screen effective tumor patients, and the acquisition of PD-L1 radioligand with high sensitivity, high specificity and high resolution is very important as a molecular imaging probe for monitoring the expression state of PD-L1 in tumor tissues. Currently, the evaluation of PD-L1 expression is usually performed by immunohistochemical method on tumor tissue biopsy specimens, which is very likely to result in inaccurate results and long time due to tumor tissue heterogeneity, and may cause local tissue damage and even tumor spread. The detection by the PD-L1 radioactive ligand through SPECT-CT is a non-invasive systemic detection means, can carry out tandem imaging on in-situ tumors, metastatic tumors and other PD-L1 expression tissues, and can timely monitor the dynamic change of PD-L1 expression in the tumor environment before, during and after the administration of the immune checkpoint regulator. In addition, several classes of molecular imaging agents based on antibody targeting to PD-L1 have been reported that provide sufficient affinity and specificity to PD-L1 to maximize the background ratio of signal, visualizing molecular targets within the tumor microenvironment. However, a drawback of antibody-based targeted PD-L1 imaging agents is slow clearance in vivo, particularly where elimination of the antibody imaging agent through the hepatobiliary system takes days to weeks, affecting imaging of adjacent organs such as the lung. As a result, it may take days to adequately clear the target tissue or adjacent tissue for imaging. An ideal PD-L1 radioligand for imaging requires high uptake in PD-L1 expressing tumors, but low background signal in non-PD-L1 expressing tissues, and should enable imaging of patients on the same day for clinical study design flexibility. Therefore, the PD-L1 radioligand based on small molecule targeting is probably an ideal imaging agent and has not been reported at present.

Disclosure of Invention

The invention aims to provide an iodine radioisotope labeled benzyl phenyl ether derivative which can be combined with PD-Ll and has a structural general formula I, a stereoisomer and a pharmaceutically acceptable salt thereof, a preparation method thereof, a radiopharmaceutical composition and application thereof in preparation of medicines for diagnosing and treating diseases related to PDl/PD-Ll signal channel. In order to solve the technical problem, the invention provides the following technical scheme:

the first aspect of the technical proposal of the invention provides iodine radioisotope labeled benzyl phenyl ether derivatives as shown in a general formula I, stereoisomers and medicinal salts thereof,

in the formula

R₁Selected from:

R₂selected from: phenyl, pyridylmethylene, substituted pyridylmethylene, the substituents selected from cyano, methylsulfonyl, acetylamino, carbamoyl, dimethylaminoyl, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclo-1-yl, the substituents being selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidino, sulfonamido, sulfamoyl, methylsulfonylamino, hydroxycarbamoyl, C1-8 alkoxycarbonyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, amino, mercapto, nitro, thiazolyl, oxazolyl, nitro, amino, sulfonyl, amino,

The takingThe substituent group comprises mono-substitution, di-substitution, tri-substitution and tetra-substitution;

x is selected from: fluoro, chloro, bromo, C1-4 alkyl, cyano, vinyl, trifluoromethyl, methoxy;

y is selected from: iodine radioisotope (I)^*) Including but not limited to iodine-125, iodine-131, iodine-123, iodine-124, iodine-129.

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are of formula (IA):

in the formula

The substituent comprises mono-substitution, di-substitution, tri-substitution and tetra-substitution;

x is selected from: fluorine, chlorine, bromine, C1-4 alkyl, cyano, vinyl, trifluoromethyl, methoxy.

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are of formula (IA 1):

in the formula

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IA 1-1):

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azepin-1-yl, the substituents being selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidino, sulfonamido, sulfamoyl, methylsulfonylamino, hydroxycarbamoyl, C1-8 alkoxycarbonyl, mercaptoamino, and mercaptoamino,Imidazolyl, thiazolyl, oxazolyl, tetrazolyl,

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IA 1-2):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IA 1-3):

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azepin-1-ylThe substituent is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidino, ureidoamino, guanidino, sulfonamido, sulfamoyl, methylsulfonylamino, hydroxycarbonyl, C1-8 alkoxycarbonyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, amino, cyano, amino, sulfonyl, sulfamoyl, amino,

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are of formula (IA 2):

in the formula

y is selected from: iodine radioisotope (I)^*)，Including but not limited to iodine-125, iodine-131, iodine-123, iodine-124, iodine-129.

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IA 2-1):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IA 2-2):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IA 2-3):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are of formula (IA 3):

in the formula

R₂Selected from: phenyl, pyridylmethylene, substituted pyridylmethylene, the substituents being selected from cyano, methanesulfonyl, acetylamino, carbamoyl, di-basicMethylamine formyl, trifluoromethyl, C1-5 alkyl, C1-5 alkoxy;

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IA 3-1):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IA 3-2):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IA 3-3):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are of formula (IA 4):

in the formula

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IA 4-1):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IA 4-2):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IA 4-3):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are of formula (IB):

in the formula

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclo-1-yl, wherein the substituents are selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidino, ureidoamino, guanidino, sulfonamido, etcSulfamoyl, methylsulfonylamino, hydroxycarbamoyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, thiazolyl, or thiazolyl,

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are of formula (IB 1):

in the formula

y is selected from: iodine radioisotope (I)^*) Including but not limited to iodine-125, iodine-131, iodine-123, iodine-124, iodine,Iodine-129.

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IB 1-1):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IB 1-2):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IB 1-3):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are of formula (IB 2):

in the formula

R₂Selected from: phenyl, pyridylmethylene, substituted pyridylmethylene, the substituents selected from cyano, methylsulfonyl, acetylamino, carbamoyl, dimethylaminoyl, trifluoromethyl, C1-5 alkyl, C1-5 alkoxyA group;

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IB 2-1):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IB 2-2):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IB 2-3):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are of formula (IB 3):

in the formula

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IB 3-1):

R₃selected from: getSubstituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclo-1-yl, the substituents being selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidino, sulfonamido, sulfamoyl, methylsulfonylamino, hydroxycarbamoyl, C1-8 alkoxycarbonyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, amino, mercapto, nitro, thiazolyl, oxazolyl, nitro, amino,

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IB 3-2):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IB 3-3):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are of formula (IB 4):

in the formula

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azepin-1-yl, the substituents being selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidino, sulfonamido, sulfamoyl, methylsulfonylamino, hydroxycarbamoyl, C1-8 alkoxy, amino, guanidino, sulfonamido, guanidino, C1-8 alkoxy, and aminoFormyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, thiazolyl, tetrazolyl,

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IB 4-1):

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IB 4-2):

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substitutedThe substituent of (C2-6) azacyclo-1-yl is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidino, ureido, guanidino, sulfonamido, sulfamoyl, methylsulfonylamino, hydroxycarbamoyl, C1-8 alkoxycarbonyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, guanidino, sulfonamido, guanidino, thiabendazole, guanidino, guanidin,

Preferred benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compounds are represented by formula (IB 4-3):

Preferred benzyl phenyl ether derivatives of the above general formula, and stereoisomers and pharmaceutically acceptable salts thereof, wherein R3 is selected from the group consisting of:

Most preferred are benzyl phenyl ether derivatives and stereoisomers thereof and pharmaceutically acceptable salts thereof, selected from the group consisting of:

(S) -N- [2- (2-cyanopyridine-4-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] proline

N- [2- (2-cyanopyridine-4-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo ] cyclopropylimine-2-carboxylic acid

(S, S) -N- [2- (2-cyanopyridine-4-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] -4-hydroxyproline

(S) -N- [2- (2-cyanopyridine-4-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] piperidine-2-carboxylic acid

(S) -N- [2- (2-cyanopyridine-4-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] serine

N- [2- (2-cyanopyridine-4-methyleneoxy) -4- (2-methyl-3-phenylbenzyloxy) -5-iodo-benzyl ] -2-methylserine

N- [2- (2-cyanopyridine-4-methyleneoxy) -4- (2-chloro-3-phenylbenzyloxy) -5-iodo-benzyl ] threonine

(S) -N- [2- (5-cyanopyridine-3-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] piperidine-2-carboxylic acid

N- [2- (5-cyanopyridine-3-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] -2-methylserine

(S) -N- [2- (5-cyanopyridine-3-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] serine

(S) -N- [2- (5-cyanopyridine-3-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] proline

N- [2- (5-cyanopyridine-3-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] threonine

(S) -N- [2- (5-cyanopyridine-3-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] alanine

(S) -N- [2- (2-cyanopyridine-4-methyleneoxy) -4- (2-bromo-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] serine

(S) -N- [2- (2-cyanopyridine-4-methyleneoxy) -4- (2-bromo-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] piperidine-2-carboxylic acid

(S) -N- [2- (5-cyanopyridine-3-methyleneoxy) -4- (2-bromo-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] serine

(2S) -2- [2- (5-cyanopyridine-3-methyleneoxy) -4- (2-methyl-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] amino-3-hydroxybutyric acid

(S) -N- [2- (3-cyanopyridine-5-methyleneoxy) -4- (2-bromo-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] piperidine-2-carboxylic acid

(2S, 4S) -N- [2- (3-cyanopyridine-5-methyleneoxy) -4- (2-bromo-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] pyrrolidine-2-carboxylic acid

(2S) -N- [2- (3-cyanopyridine-5-methyleneoxy) -4- (2-methyl-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] pyrrolidine-2-carboxylic acid

(S) -N- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] serine

(2S) -2- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] amino-3-hydroxybutyric acid

2- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] amino-2-methyl-3-hydroxypropionic acid

(2S) -2- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] aminopropionic acid

(S) -N- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] piperidinecarboxylic acid

(S) -N- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] proline

(2S, 4S) -N- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3- (3, 4-ethylenedioxyphenyl) benzyloxy) -5-iodo-benzyl ] -4-hydroxyproline

(2S, 4S) -N- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] -4-hydroxyproline

(2S) -N- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] proline

(2S) -N- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] piperidinecarboxylic acid

(2S) -N- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] serine

2- [2- (pyridine-3-methyleneoxy) -4- (2-cyano-3-phenylbenzyloxy) -5-iodo-benzyl ] amino-2-methyl-3-hydroxypropionic acid

2- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo ] benzyl ] amino-3-hydroxybutyric acid

2- [2- (pyridine-3-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo-benzyl ] aminopropionic acid

The benzyl phenyl ether derivative and the stereoisomer and the pharmaceutically acceptable salts thereof are characterized in that the pharmaceutically acceptable salts comprise salts formed by combining inorganic acid, organic acid, alkali metal ions, alkaline earth metal ions or organic base capable of providing physiologically acceptable cations and ammonium salts.

Further the inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, lycic acid, tartaric acid maleate, fumaric acid, citric acid or lactic acid; the alkali metal ions are selected from lithium ions, sodium ions and potassium ions; the alkaline earth metal ions are selected from calcium ions and magnesium ions; the organic base capable of providing a physiologically acceptable cation is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris (2-hydroxyethyl) amine.

In a second aspect of the present invention, there is provided a process for preparing a compound of the first aspect:

in order to prepare the compound shown in the general formula I, according to the structure shown in the general formula I, the compound shown in the general formula I is prepared by taking a substituted phenyl tin derivative 1 as a raw material according to the following reaction;

phenyl tin derivative 1 reacts with radioactive sodium iodide under the action of chloramine T to generate a compound shown in a general formula I, wherein trimethyl tin or tributyltin can be selected for substitution in the phenyl tin derivative 1, and the radioactive sodium iodide can be selected from Na¹²⁵I、Na¹³¹I、Na¹²³I、Na¹²⁴I、Na¹²⁹I；

Said R₁、R₂、R₃Y, X, as defined in any one of claims 1 to 35.

In addition, the starting materials and intermediates in the above reactions are readily available, and the reactions in each step can be readily synthesized according to reported literature or by conventional methods in organic synthesis to those skilled in the art. The compounds of formula I may exist in the form of solvates or non-solvates, and crystallization using different solvents may give different solvates. Pharmaceutically acceptable salts according to formula I include the different acid addition salts, such as the acid addition salts of the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, lycinic acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid. The pharmaceutically acceptable salts of formula I also include salts of various alkali metal (lithium, sodium, potassium), alkaline earth metal (calcium, magnesium) and ammonium salts, and salts of organic bases which provide physiologically acceptable cations, such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris (2-hydroxyethyl) amine. All such salts within the scope of the present invention may be prepared by conventional methods. During the preparation of the compounds of formula I and solvates and salts thereof, different crystallization conditions may occur as polycrystals or co-crystals.

In a third aspect of the present invention, a pharmaceutical composition is provided

The pharmaceutical composition comprises the iodine radioisotope labeled benzyl phenyl ether derivative as an effective component, and stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable carriers or excipients, auxiliaries and diluents thereof.

The invention also relates to a pharmaceutical composition using the compound as an active ingredient. The pharmaceutical composition may be prepared according to art-recognized methods. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.

The pharmaceutical compositions of the present invention may optionally further comprise additional components, such as antimicrobial preservatives, pH adjusting agents or fillers. Antimicrobial preservatives refer to agents that inhibit the growth of potentially harmful microorganisms such as bacteria, yeast or mold. Antimicrobial preservatives may also exhibit some bactericidal properties, depending on the dosage. The primary effect of the antimicrobial preservative of the present invention is to inhibit the growth of any such microorganisms in the radiopharmaceutical composition. Suitable antimicrobial preservatives include parabens, i.e. methyl, ethyl, propyl or butyl parabens or mixtures thereof; benzyl alcohol; phenol; cresol; cetrimide and thimerosal. A preferred antimicrobial preservative is paraben. A pH modifier refers to a compound or mixture of compounds that can be used to ensure that the pH of the radiopharmaceutical composition is within acceptable limits (about pH 40 to 8.5) for administration to humans or lactating animals. Suitable such pH adjusting agents include pharmaceutically acceptable buffers such as tricine, phosphate buffer or TRIS [ i.e. TRIS (hydroxymethyl) aminomethane ], and pharmaceutically acceptable bases. Bulking agents refer to pharmaceutically acceptable bulking agents that can facilitate handling of the starting material during product preparation, suitable bulking agents include inorganic salts such as sodium chloride, and water soluble sugars or sugar alcohols such as sucrose, maltose, mannitol, or trehalose.

Where the iodine radioisotope bonded phenyl group has one or more activating groups, to prevent deiodination, the pharmaceutical composition of the present invention may therefore require a stabilizing agent. A stabilizer refers to a compound that inhibits decomposition reactions such as redox reactions by trapping highly reactive free radicals such as oxygen-containing radicals generated by the radiolysis of water. The stabiliser of the invention is suitably selected from classical radical scavengers such as ascorbic acid or gentisic acid.

In addition, the biocompatible carrier medium is a fluid, especially a liquid, in which the labeled synthetic compound is suspended or dissolved so that the composition is physiologically tolerable, i.e., can be administered to a mammalian body without toxicity or undue discomfort. Biocompatible carrier media are injectable carrier liquids, such as sterile, pyrogen-free water for injection;aqueous solutions such as physiological saline (which may preferably be a balanced solution so that the final injectable product is isotonic or non-hypotonic); an aqueous solution of one or more tonicity-adjusting substances (e.g., salts of plasma cations with biocompatible counterions), sugars (e.g., prodrug sugars or sucrose), sugar alcohols (e.g., sorbitol or mannitol), glycols (e.g., glycerol), or other non-ionic polyol substances (e.g., polyethylene glycol, propylene glycol, etc.). The biocompatible carrier medium may also comprise a biocompatible organic solvent such as ethanol. Such solvents can be used to solubilize more lipophilic compounds or formulations. Preferably, the biocompatible carrier medium is pyrogen-free water for injection, isotonic saline or aqueous ethanol. Such an aqueous ethanol solution may have a range of compositions, but preferably 5-10% ethanol for the dry final composition, as described above, the pH of the biocompatible carrier medium for intravenous injection is suitably 4.0 to 10.5 for the present invention¹²³The ph of the I-labelled radiopharmaceutical, the biocompatible carrier medium, is suitably from 4.5 to 8.5, preferably from 4.6 to 8.0, most preferably from 5.0 to 7.5.

The radiopharmaceutical compositions of the present invention are provided in a clinical grade syringe or container equipped with a seal (e.g., a screw-on septum cap) suitable for single or multiple punctures with a hypodermic needle while maintaining sterile integrity, such containers may include single or multiple doses. Suitable containers include sealed containers that allow for maintaining sterility integrity and/or radiological safety while allowing for entry and withdrawal of solutions through a syringe, with preferred containers being septum-sealed vials in which an air-tight cap is screwed on with a overseal (typically aluminum). An additional advantage of such a container is that the closure can withstand a vacuum if desired, for example to change headspace gas or degassed solution. When the radiopharmaceutical is provided in a multi-dose container, it is preferred that such container comprises a single volume vial (e.g. a 10 to 30cm3 volume vial). The vial contains sufficient radiopharmaceutical for multiple patient doses. Unit patient doses can therefore be drawn into clinical grade syringes at various time intervals during the life of the bulk vial formulation to accommodate the clinical condition.

Thus, a radiopharmaceutical syringe designed to contain a single human dose or "unit dose" is preferably a disposable syringe or other syringe suitable for clinical use. Such syringes may optionally be equipped with a syringe shield to protect the operator from the radioactive dose. Such radiopharmaceutical syringe shields are known in the art and are commercially available in a variety of designs, preferably comprising lead or tungsten.

The fourth aspect of the technical scheme of the invention provides an application of iodine radioisotope labeled benzyl phenyl ether derivatives, stereoisomers and pharmaceutically acceptable salts thereof in preparation of medicines for diagnosing and treating diseases related to PD-1/PD-L1 signal pathways.

The diagnosis and treatment comprises diagnosis and treatment, wherein the diagnosis refers to that the iodine radioisotope-labeled benzyl phenyl ether derivative is used as a PD-L1 protein probe, and the SEPCT, PET or SEPCT-CT and PET-CT instruments are used for detecting or monitoring the expression states of lesion tissues and normal tissues PD-L1 in a patient body, so that the diagnosis and treatment system is applied to disease diagnosis, patient screening, treatment prognosis evaluation and disease progress, the metabolism condition in the drug body is observed, and reliable information is provided for the effective treatment of diseases by the drug; the treatment refers to that the iodine radioisotope labeled benzyl phenyl ether derivative is a PD-L1 inhibitor and is also a tumor immunotherapy agent, the radioactivity of the iodine radioisotope labeled benzyl phenyl ether derivative can kill tumor cells while being combined with PD-L1 in tumor tissues, and the tumor immunotherapy effect can be improved if the iodine radioisotope labeled benzyl phenyl ether derivative and the PD-L1 can be cooperated with immunotherapy.

The diseases related to the PD-1/PD-L1 signal channel are selected from cancers, infectious diseases and autoimmune diseases. The cancer is selected from skin cancer, lung cancer, urinary system tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, and head and neck cancer. The infectious diseases are selected from bacterial infection and virus infection. The autoimmune disease is selected from organ-specific autoimmune diseases and systemic autoimmune diseases, wherein the organ-specific autoimmune diseases comprise chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis and acute idiopathic polyneuritis, and the systemic autoimmune diseases comprise rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease and autoimmune hemolytic anemia.

The beneficial technical effects are as follows:

the iodine radioisotope labeled benzyl phenyl ether derivative has high inhibitory activity on the interaction of PD-1/PD-L1 and strong binding capacity with PD-L1 protein; and has a longer physiological half-life in vivo and higher stability in plasma; the preparation method has short synthesis time and high radiochemical yield; in the application aspect, the PD-L1 protein micromolecule probe has high sensitivity and specificity, and can be used for detecting or monitoring the expression states of lesion tissues and normal tissues PD-L1 in a patient body by utilizing SEPCT, PET or SEPCT-CT and PET-CT instruments and equipment, is applied to disease diagnosis, patient screening, treatment prognosis evaluation and disease progress, observes the metabolism condition in the body of a medicament, and provides reliable information for the medicament to effectively treat diseases; the iodine radioisotope labeled benzyl phenyl ether derivative is a PD-L1 inhibitor and is also a tumor immunotherapy agent, the radioactivity of the derivative has a killing effect on tumor cells, and radiotherapy and immunotherapy are synergistic, so that the tumor immunotherapy effect can be improved. Therefore, the iodine radioisotope labeled benzyl phenyl ether derivative can be used as a small molecule imaging agent of PD-L1 protein with integrated diagnosis and treatment.

Drawings

FIG. 1: a, b and c are high performance liquid chromatograms of examples 4, 5 and 8, respectively. Chromatographic conditions are as follows: phase B (methanol) phase A (water) (90%: 10%) and isocratic elution.

FIG. 2: a and b are the high performance liquid chromatograms of examples 6 and 7, respectively.

FIG. 3: uptake of tumor tissue in uninhibited nude mice by SPECT imaging technique¹²⁵I]Study of the condition of prodrug A. The left image is a transverse section image, the middle image is a longitudinal section image, and the right image is a coronal section image.

FIG. 4: uptake of tumor tissue in nude mice in the inhibition group by SPECT imaging technique¹²⁵I]Study of prodrug a. The left image is a transverse section image, the middle image is a longitudinal section image, and the right image is a coronal section image.

Detailed Description

The present invention will be further illustrated with reference to the following examples, but the scope of the present invention is not limited thereto.

The measuring instrument: NMR spectroscopy was performed using a Vaarian Mercury 300 NMR spectrometer. Mass spectra were obtained on ZAD-2F and VG300 mass spectrometers.

Example 1: (S) -N- (2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzyl) serine isopropyl ester

2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzaldehyde:

weighing 2-hydroxy-4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzaldehyde (720mg, 1.414mmol), completely dissolving in 25ml DMF (N, N-dimethylformamide), adding cesium carbonate (1.38g, 4.24mmol), stirring at room temperature for 10min, adding 3-chloromethylpyridine hydrochloride (348mg, 2.12mmol), heating to 76 ℃, reacting for 3.5h, (TLC detection, complete reaction of raw materials), adding water and ethyl acetate, extracting for three times, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, and separating by silica gel column chromatography to obtain an off-white solid (830 mg).¹H NMR(400MHz,DMSO-d6)10.09(s,1H,-CHO),8.70(s,1H,-ArH),8.53(d,J＝6.2Hz,1H,-ArH),8.02(s,1H,-ArH),7.93(m,1H,-ArH),7.71(dd,J＝7.6,1.7Hz,1H,-ArH),7.54–7.48(m,1H,-ArH),7.47–7.39(m,4H,-ArH),7.38–7.36(m,2H,-ArH),7.36–7.34(m,1H,-ArH),7.09(s,1H,-ArH),5.40(s,2H,-CH₂-),5.39(s,2H,-CH₂-).MS：[M+H]⁺:600。

(S) -N- (2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzyl) serine isopropyl ester

Weighing 2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzaldehyde (600mg, 1mmol)Dissolving in 10ml DMF, adding L-serine isopropyl ester hydrochloride (367mg, 2mmol), measuring glacial acetic acid (180mg, 3mmol), dropwise adding into the reaction system, stirring at room temperature for 20min, adding sodium cyanoborohydride (126mg, 2mmol), reacting at 25 ℃ overnight, stopping the reaction, adding water and ethyl acetate, extracting and separating for 3 times, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating under reduced pressure, separating by silica gel column chromatography to obtain a nitrogen-boron complex which is a colorless oily substance (TLC shows that the product is few and the majority is the nitrogen-boron complex), refluxing the nitrogen-boron complex with 30ml isopropanol for 12h, and performing silica gel column chromatography to obtain 328mg of the colorless oily substance.¹H NMR(400MHz,DMSO-d₆)8.68(s,1H,-ArH),8.55(dd,J＝4.8,1.4Hz,1H,-ArH),7.89(d,J＝7.9Hz,1H,-ArH),7.72(d,J＝7.7Hz,1H,-ArH),7.69(s,1H,-ArH),7.56–7.45(m,3H,-ArH),7.45–7.34(m,5H,-ArH),6.94(s,1H,-ArH),5.27(s,2H,-CH₂-),5.25(s,2H,-CH₂-),4.85(p,J＝6.2Hz,1H,-CH-),4.79(t,J＝5.7Hz,1H,-OH),3.69(d,J＝14.1Hz,1H,-CH₂-a),3.57(d,J＝14.1Hz,1H,-CH2-b),3.53(t,J＝5.6Hz,2H,-CH₂-),3.18(t,J＝4.7Hz,1H,-CH-),1.13(dd,J＝6.2,3.5Hz,6H,-2CH₃).MS：[M+H]⁺:731。

Example 2: (S) -N- (2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzyl) serine

(S) -N- (2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzyl) serine isopropyl ester (186mg, 0.254mmol) was weighed out and dissolved in 6ml MeOH/H₂And stirring the mixture at room temperature, adding lithium hydroxide monohydrate (43mg, 1.018mmol), reacting at room temperature for 2 hours, concentrating under reduced pressure, adding 1.5ml of distilled water, adjusting the pH to 6 with glacial acetic acid under the ice bath condition, precipitating a solid, standing, and performing suction filtration to obtain 128mg of an off-white solid.¹H NMR(400MHz,DMSO-d₆)8.69(s,1H,-ArH),8.51(d,J＝4.0Hz,1H,-ArH),7.94(d,J＝7.8Hz,1H,-ArH),7.78(s,1H,-ArH),7.68(d,J＝9.0Hz,1H,-ArH),7.51-7.45(m,1H,-ArH),7.45–7.41(m,2H,-ArH),7.41–7.32(m,5H,-ArH),6.96(s,1H,-ArH),5.30-5.20(m,4H,-2CH₂-),3.91(s,2H,-CH₂-),3.70-3.55(m,2H,-CH₂-),3.15(t,J＝4.9Hz,1H,-CH-).MS：[M+H]⁺:689。

Example 3: (S) -N- (2- (2-cyanopyridin-4-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzyl) serine isopropyl ester

2- (2-cyanopyridine-4-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzaldehyde

Weighing 2-hydroxy-4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzaldehyde (731mg, 1.44mmol), completely dissolving in 8ml of DMF (dimethyl formamide) in a 50ml single-neck bottle, adding potassium carbonate (597mg, 4.32mmol), stirring at room temperature for 10min, adding 3ml of DMF solution of 4-bromomethyl-2 cyanopyridine (425mg, 2.16mmol), reacting at room temperature for 12h, detecting by TLC (thin layer chromatography), completely reacting raw materials, adding appropriate amount of water, precipitating a large amount of white solid, performing suction filtration, washing with water, and drying to obtain 678mg of white solid.¹H NMR(500MHz,DMSO-d₆)10.26(s,1H,-CHO),8.78(d,J＝5.0Hz,1H,-ArH),8.22(s,1H,-ArH),8.10(s,1H,-ArH),7.88(d,J＝5.1Hz,1H,-ArH),7.73(d,J＝7.6Hz,1H,-ArH),7.56-7.46(m,3H,-ArH),7.46–7.35(m,4H,-ArH),7.02(s,1H,-ArH),5.54(s,2H,-CH₂-),5.40(s,2H,-CH₂-).MS:[M+H]⁺:625。

(S) -N- (2- (2-cyanopyridin-4-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzyl) serine isopropyl ester

Weighing 2- (2-cyanopyridine-4-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzaldehyde (100mg, 0.161mmol) and dissolving in 5ml DMF, adding L-serine isopropyl ester hydrochloride (59mg, 0.321mmol), measuring glacial acetic acid (58mg, 0.963mmol), dropwise adding into the reaction system, stirring at room temperature for 30min, adding sodium cyanoborohydride (21mg, 0.321mmol), reacting at room temperature for 2h, TLC showing that the raw material is basically reacted completely, stopping the reaction, adding water and ethyl acetate to extract liquid separation x 3, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating under reduced pressure, and performing silica gel column chromatography (DCM-DCM: MeOH)100:1- -40:1- -20:1) to give 48mg of an off-white solid.¹H NMR(500MHz,DMSO-d₆)8.78(d,J＝5.0Hz,1H,-ArH),8.15(s,1H,-ArH),7.84(d,J＝5.1Hz,1H,-ArH),7.75-7.70(m,2H,-ArH),7.56-7.49(m,3H,-ArH),7.48–7.37(m,4H,-ArH),6.88(s,1H,-ArH),5.39(s,2H,-CH₂-),5.26(s,2H,-CH₂-),4.92(m,1H,-CH-),4.83(d,J＝5.8Hz,1H,-OH),3.81(d,J＝13.7Hz,1H,-CH₂-a),3.66(d,J＝13.6Hz,1H,-CH₂-b),3.59(t,J＝5.5Hz,2H,-CH₂-),3.26(t,J＝5.3Hz,1H,-CH-),1.18(t,J＝5.8Hz,6H,-2CH₃).MS:[M+H]⁺:756。

Example 4: (S) -N- (2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5- (trimethyl -yl) benzyl) serine isopropyl ester

2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5- (trimethyl yl) benzaldehyde:

weighing 2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzaldehyde (300mg, 0.5mmol), dissolving in 10ml dioxane, adding palladium tetratriphenylphosphine under protection of inert gas, sucking 0.134ml hexamethylditin (virulent, attention to protection) by using an injector, heating to reflux, reacting for 5h, detecting by TLC that the reaction is complete, cooling to room temperature, stopping the reaction, filtering by using kieselguhr, washing by EA, evaporating the solvent, and directly performing silica gel column chromatography to obtain a light yellow oily substance (300 mg).¹HNMR(400MHz,DMSO-d₆)10.25(s,1H,-CHO),8.76–8.72(m,1H,-ArH),8.57(dd,J＝4.8,1.6Hz,1H,-ArH),8.02–7.91(m,1H,-ArH),7.68(s,1H,-ArH),7.62–7.58(m,1H,-ArH),7.54–7.50(m,1H,-ArH),7.50–7.48(m,1H,-ArH),7.47(s,1H,-ArH),7.46-7.43(m,1H,-ArH),7.43–7.35(m,4H,-ArH),7.05(s,1H,-ArH),5.43(s,2H,-CH₂-),5.35(s,2H,-CH₂-),0.14(s,9H,-3H₃).MS:[M+H]⁺:638,640。

(S) -N- (2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5- (trimethyl -yl) benzyl) serine isopropyl ester:

weighing 2- (pyridine-3)-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5- (trimethyl yl) benzaldehyde (300mg, 0.471mmol) was dissolved in 5-8ml of isopropanol, L-serine isopropyl ester hydrochloride (130mg, 0.706mmol) and 0.1ml of glacial acetic acid were added, after stirring at room temperature for 30min, sodium triacetoxyborohydride (198mg, 0.942mmol) was added, reaction was carried out at room temperature for 12h, water and ethyl acetate were added to extract and separate the solution 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and chromatography on C-18 reverse phase silica gel column gave a colorless oil.¹H NMR(500MHz,DMSO-d₆)8.68(s,1H,-ArH),8.57–8.47(m,1H,-ArH),7.88(d,J＝7.4Hz,1H,-ArH),7.53(d,J＝7.2Hz,1H,-ArH),7.50-7.44(m,3H,-ArH),7.43-7.38(m,2H,-ArH),7.38-7.32(m,3H,-ArH),7.18(s,1H,-ArH),6.85(s,1H,-ArH),5.23(s,2H,-CH₂-),5.18(s,2H,-CH₂-),4.88-4.82(m,1H,-CH-),4.76(s,1H,-OH),3.71(d,J＝13.3Hz,1H,-CH₂-(A)),3.59(d,J＝13.3Hz,1H,-CH₂-(B)),3.51(s,2H,-CH₂-),3.18(t,J＝5.4Hz,1H,-CH-),1.15-1.05(m,6H,-2CH₃),0.13(s,9H,-3CH₃).MS:[M+H]⁺:769。

Example 5: (S) -N- (2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo¹²⁵Benzyl serine isopropyl ester ([ 2 ])¹²⁵I]-prodrug A)

Radioactivity¹²⁵Marking I:

radioactive Radio-HPLC on-line detector (model: Gabi Star, No: 30960, manufacturer: GLYSIA); high performance liquid chromatograph (model: SPD-20A, manufactured by SHIMADZU Shimadzu Japan).

(S) -N- (2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo¹²⁵Benzyl) serine isopropyl ester:

35mg of isopropyl (S) -N- (2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5- (trimethyl -yl) benzyl) serine was dissolved in 200. mu.L of absolute ethanol, 20. mu.L was diluted to 500. mu.L, 100. mu.L was put in a penicillin vial (0.7mg), 100. mu.L of chloramine T aqueous solution (2mg/mL) was added, and 2. mu.L was addedL Na¹²⁵I (268. mu. Ci) was shaken by Vortex, left at room temperature for 15min, and Na was added₂S₂O₅After being dissolved in 100. mu.L of absolute ethanol, the mixture is filtered through a 0.22um microfiltration membrane, and the labeling rate of the label is identified and separated and purified by HPLC. Collecting the product containing¹²⁵I]-eluent of prodrug a component, blow-drying the component with a nitrogen blow-dryer. The marking rate is more than 95 percent.

Example 6: (S) -N- (2- (2-cyanopyridin-4-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5- (trimethyl -yl) benzyl) serine isopropyl ester

2- (2-cyanopyridin-4-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5- (trimethyl yl) benzaldehyde:

weighing 2- (2-cyanopyridine-4-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodobenzaldehyde (313mg, 0.5mmol), dissolving in 15ml dioxane, adding palladium (57mg, 0.05mmol) of tetratriphenylphosphine under the protection of argon, sucking (245mg, 0.75mmol) of hexamethylditin (strong toxicity, attention to protection) by using a syringe, heating to reflux, reacting for 6h, detecting by TLC (the product is basically consistent with the polarity of a raw material point and cannot be distinguished), cooling to room temperature, stopping the reaction, filtering by using kieselguhr, washing by EA, evaporating the solvent, and directly performing silica gel column chromatography to obtain a light yellow oily substance, 102 mg.¹H NMR(500MHz,Acetone-d₆)10.46(s,1H,-CHO),8.77(d,J＝5.1Hz,1H,-ArH),8.13(s,1H,-ArH),7.89(d,J＝5.1Hz,1H,-ArH),7.86(s,1H,-ArH),7.57(d,J＝7.6,1H,-ArH),7.53–7.46(m,3H,-ArH),7.45–7.37(m,4H,-ArH),6.95(s,1H,-ArH),5.58(s,2H,-CH₂-),5.38(s,2H,-CH₂-),0.23(s,9H,-Sn(CH₃)₃).MS:[M+H]⁺:663.02。

(S) -isopropyl N- (2- (2-cyanopyridin-4-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5- (trimethyl -yl) benzyl) serine:

2- (2-cyanopyridin-4-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5- (trimethyl yl) benzaldehyde (90mg, 0.136mmol) was weighed out and dissolved in 5ml of DMF, followed by addition of L-silkIsopropyl amino acid hydrochloride (50mg, 0.272mmol) and glacial acetic acid (24mg, 0.408mmol) are stirred at room temperature for 30min, sodium triacetoxyborohydride (17mg, 0.272mmol) is added, after reaction at room temperature for 1.5h, TLC detection is carried out to complete the reaction, water and ethyl acetate are added for extraction and liquid separation for 3 times, an organic phase is washed by saturated saline solution, dried by anhydrous sodium sulfate, filtered, decompressed and evaporated to dryness, and silica gel column chromatography is carried out to obtain 70mg of light yellow oily substance which is semi-prepared by HPLC (conditions: isocratic elution: 95% methanol/5% water), so as to obtain 35mg of colorless oily substance.¹H NMR(500MHz,Acetone-d₆)8.72(d,J＝4.9Hz,1H,-ArH),8.11(s,1H,-ArH),7.86(d,J＝4.4Hz,1H,-ArH),7.54(d,J＝7.4Hz,1H,-ArH),7.51-7.45(m,3H,-ArH),7.45-7.38(m,3H,-ArH),7.37-7.33(m,2H,-ArH),6.79(s,1H,-ArH),5.41(s,2H,-CH₂-),5.23(s,2H,-CH₂-),5.03-4.95(m,1H,-CH-),4.05(q,J＝7.1Hz,1H,-OH),3.94(d,J＝12.8Hz,1H,-CH₂-a),3.81(d,J＝12.8Hz,1H,-CH₂-b),3.76–3.60(m,2H,-CH₂-),3.37(t,J＝5.1Hz,1H,-CH-),1.20(t,J＝6.5Hz,6H,-2CH₃),0.23(s,9H,-3CH₃).LC-MS:[M+H]⁺:794.12。

Example 7: (S) -N- (2- (2-cyanopyridin-4-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo¹²⁵Benzyl serine isopropyl ester ([ 2 ])¹²⁵I]-prodrug B)

Radioactivity¹²⁵Marking I:

35mg of isopropyl (S) -N- (2- (pyridin-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5- (trimethyl -yl) benzyl) serine was dissolved in 200. mu.L of absolute ethanol, 20. mu.L was diluted to 500. mu.L, 100. mu.L was put in a penicillin vial (0.7mg), and 100. mu.L of chloramine T water was addedSolution (2mg/mL), 2. mu.L Na was added¹²⁵I (268. mu. Ci) was shaken by Vortex, left at room temperature for 15min, and Na was added₂S₂O₅After being dissolved in 100. mu.L of absolute ethanol, the mixture is filtered through a 0.22um microfiltration membrane, and the labeling rate of the label is identified and separated and purified by HPLC. Collecting the product containing¹²⁵I]-elution of prodrug B fraction by blow drying the fraction with a nitrogen blow dryer. The marking rate is more than 95 percent.

Example 8: (S) -N- (2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo¹²⁵Benzyl serine ([ alpha ])¹²⁵I]-technical A)

50ul of (S) -N- (2- (pyridine-3-methoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-iodo was aspirated¹²⁵Benzyl) isopropyl serine ammonia solution in methanol, 50ul sodium hydroxide solution, in 0.5ml EP tube and sealing, put in 200ml round flask, through magnetic stirring, make EP tube shake 4 hours in flask fully at room temperature, add acetic acid aqueous solution 100ul, the liquid turns turbid this moment, swirl, after standing for 10min at room temperature, add 200ul ethyl acetate to extract, swirl and shake fully; after standing and clarifying, 100ul of the ethyl acetate phase at the upper layer is absorbed, 100ul of methanol is added for dilution, and HPLC separation (mobile phase methanol: 0.1% formic acid aqueous solution ═ 7: 3, isocratic elution) is carried out to obtain (S) -N- (2- (pyridine-3-methoxy) -4- (2-bromo-3-phenyl benzyloxy) -5-iodine)¹²⁵Benzyl) serine.

Example 9: [¹²⁵I]Prodrug A and [2 ]¹²⁵I]Characterization of technical A

The characterization method comprises the following steps: under Radio-HPLC conditions, the column: ODS-C18,4.6um 250 mm; mobile phase: methanol, water (90%: 10%) and flow rate 1 min/mL. Structural characterization was performed by comparing the retention time of the radiolabel under the radioactive Radio-detector to that of the control under the UV detector and calculating the radiochemical purity (RCP) of the radiolabel under the Radio-detector. The number of batches of labeled samples and the results of the labeling characterization are shown in table 1 below:

TABLE 1 sample labeling and characterization results

Radioactivity [ alpha ]¹²⁵I]Prodrug A and [2 ]¹²⁵I]Radio-HPLC characterization of prodrug a is shown in figure 1.

Radioactivity [ alpha ]¹²⁵I]Radio-HPLC characterization of prodrug B is shown in figure 2.

Example 10:[¹²⁵I]-prodrug AIs/are as followsSPECT/CT imaging of tumor-bearing mice

Tumor tissue blocks of NCI-H460 with low expression of PD-L1 and NCI-H1650 with high expression of PD-L1 are inoculated to the left and right armpits of BALB/C nude mice respectively and used for experiments when the tumor tissue blocks grow to 1-1.5 cm.

The experimental process comprises the following steps:

1) 6 tumor-bearing mice are sampled and divided into two groups (n is 3) of inhibition groups and non-inhibition groups, wherein the non-inhibition groups are directly administrated with 4-5 MBq by tail vein; the inhibition group takes a constant PD-L1 targeted drug as an inhibitor for early intragastric administration, and then 4-5 MBq is administered to the tail vein.

2) SPECT/CT imaging was performed under isoflurane gas anesthesia for 4 consecutive hours.

3) Reconstructing the image data to obtain a whole body image of each mouse, performing ROI encirclement on the tumor part, and calculating the tumor uptake ratio

4) And taking the key reconstructed image, and displaying the transverse, longitudinal and coronal dissection layer images of the optimal tumor part.

5) Representative image: the non-inhibited group is shown in FIG. 3, and the inhibited group is shown in FIG. 4.

And (3) data processing results:

1)[¹²⁵I]prodrug a has significant radioactive uptake in the liver, gastrointestinal tract, etc. of tumor-bearing mice, suggesting that it may be metabolized primarily by the liver.

2) For the non-inhibited set [2 ]¹²⁵I]Prodrug a had significant uptake in PD-L1-highly expressed NCI-H1650 tumors, lower uptake in less expressed NCI-H460, with an uptake ratio of 4.44 30min after administration. Tumor tissue pair of NCI-H1650 highly expressed in PD-L1¹²⁵I]Significant uptake of prodrug AHigher than NCI-H460 with low expression of PD-L1.

3) For the inhibition group, both tumor uptake was reduced after gastric feeding of PD-L1 inhibitor in advance, whether the tumor tissue of NCI-H460 with low expression of PD-L1 or NCI-H1650 with high expression of PD-L1. Indicating that PD-L1 is expressed in the tumor tissue as para 2¹²⁵I]The specificity of the uptake of prodrug a.

Claims

1. Benzyl phenyl ether derivatives shown in a general formula I, stereoisomers and pharmaceutically acceptable salts thereof,

in the formula

R₁Selected from:

y is selected from: iodine radioisotopesElement I^*Comprises iodine-125, iodine-131, iodine-123, iodine-124 and iodine-129.

2. The benzyl phenyl ether derivative according to claim 1, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA):

in the formula

y is selected from: iodine radioisotope I^*Comprises iodine-125, iodine-131, iodine-123, iodine-124 and iodine-129.

3. The benzyl phenyl ether derivative according to claim 2, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 1):

in the formula

4. The benzyl phenyl ether derivative and its stereoisomers and pharmaceutically acceptable salts thereof according to claim 3, wherein said compound is represented by formula (IA 1-1):

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azepin-1-yl, the substituents being selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidino, sulfonamido, sulfamoyl, methylsulfonylamino, hydroxycarbamoyl, C1-8 alkoxycarbonyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazoylAn azolyl group,

5. The benzyl phenyl ether derivative and its stereoisomers and pharmaceutically acceptable salts thereof according to claim 3, wherein said compound is represented by formula (IA 1-2):

6. The benzyl phenyl ether derivative according to claim 3, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 1-3):

7. The benzyl phenyl ether derivative according to claim 2, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 2):

in the formula

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azepin-1-yl, the substituents being selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidino, sulfonamido, sulfamoyl, methylsulfonylamino, hydroxylFormyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, thiazolyl, or the like,

8. The benzyl phenyl ether derivative according to claim 7, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 2-1):

9. The benzyl phenyl ether derivative and its stereoisomers and pharmaceutically acceptable salts thereof according to claim 7, wherein said compound is represented by formula (IA 2-2):

10. The benzyl phenyl ether derivative according to claim 7, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 2-3):

11. The benzyl phenyl ether derivative according to claim 2, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 3):

in the formula

12. The benzyl phenyl ether derivative according to claim 11, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 3-1):

13. The benzyl phenyl ether derivative according to claim 11, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 3-2):

14. The benzyl phenyl ether derivative according to claim 11, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 3-3):

15. The benzyl phenyl ether derivative according to claim 2, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 4):

in the formula

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclo-1-ylThe substituent is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidino, ureidoamino, guanidino, sulfonamido, sulfamoyl, methylsulfonylamino, hydroxycarbamoyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, amino, cyano, amino, sulfonyl, amino,

16. The benzyl phenyl ether derivative according to claim 15, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 4-1):

17. The benzyl phenyl ether derivative according to claim 15, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 4-2):

18. The benzyl phenyl ether derivative according to claim 15, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IA 4-3):

19. The benzyl phenyl ether derivative according to claim 1, and stereoisomers and pharmaceutically acceptable salts thereof, wherein the compound is represented by formula (IB):

in the formula

20. The benzyl phenyl ether derivative according to claim 19, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 1):

in the formula

21. The benzyl phenyl ether derivative according to claim 20, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 1-1):

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclo-1-yl, wherein the substituent is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6Alkylamino, acetylamino, cyano, ureido, guanidino, ureidoamino, guanidinoamino, sulfonamido, sulfamoyl, methylsulfonylamino, hydroxycarbamoyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, and the like,

22. The benzyl phenyl ether derivative according to claim 20, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 1-2):

23. The benzyl phenyl ether derivative according to claim 20, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 1-3):

24. The benzyl phenyl ether derivative according to claim 19, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 2):

in the formula

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azepin-1-yl, the substituents being selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidino, sulfonamido, sulfamoylMethylsulfonylamino, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, and the like,

25. The benzyl phenyl ether derivative according to claim 24, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 2-1):

26. The benzyl phenyl ether derivative according to claim 24, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 2-2):

27. The benzyl phenyl ether derivative according to claim 24, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 2-3):

28. The benzyl phenyl ether derivative according to claim 19, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 3):

in the formula

29. The benzyl phenyl ether derivative according to claim 28, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 3-1):

30. The benzyl phenyl ether derivative according to claim 28, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 3-2):

31. The benzyl phenyl ether derivative according to claim 28, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 3-3):

32. The benzyl phenyl ether derivative according to claim 19, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 4):

in the formula

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino,Substituted C2-6 azacyclo-1-yl with substituents selected from hydrogen, fluorine, chlorine, bromine, hydroxy, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, ureido, guanidino, ureidoamino, guanidino-amino, sulfonamido, sulfamoyl, methanesulfonamido, hydroxycarbamoyl, C1-8 alkoxycarbonyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, and the like,

33. The benzyl phenyl ether derivative according to claim 32, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 4-1):

34. The benzyl phenyl ether derivative according to claim 32, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 4-2):

35. The benzyl phenyl ether derivative according to claim 32, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is represented by formula (IB 4-3):

R₃selected from: substituted C1-8 saturated alkylamino, substituted C2-6 unsaturated alkylamino, substituted C2-6 azacyclo-1-yl, wherein the substituents are selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-5 alkyl, C1-5 alkoxy, amino, C1-6 alkylamino, acetamido, cyano, carbamido, guanidino, carbamido, sulfoaminoAmido, sulfamoyl, methylsulfonamido, hydroxyformyl, C1-8 alkoxyformyl, mercapto, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, and the like,

36. The benzyl phenyl ether derivative and stereoisomers thereof and pharmaceutically acceptable salts thereof according to any one of claims 1-35, wherein R3 is selected from the group consisting of:

37. The benzyl phenyl ether derivative according to claims 1-35, and stereoisomers and pharmaceutically acceptable salts thereof, wherein said compound is selected from the group consisting of:

38. The benzyl phenyl ether derivative and its stereoisomers and pharmaceutically acceptable salts thereof according to claim 1, wherein the pharmaceutically acceptable salts include salts formed in combination with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or organic bases capable of providing physiologically acceptable cations, and ammonium salts; preferably, the inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, lycic acid, tartaric acid maleate, fumaric acid, citric acid or lactic acid; the alkali metal ions are selected from lithium ions, sodium ions and potassium ions; the alkaline earth metal ions are selected from calcium ions and magnesium ions; the organic base capable of providing a physiologically acceptable cation is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris (2-hydroxyethyl) amine.

39. A process for the preparation of a benzylphenyl ether derivative according to any one of claims 1 to 38, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

in order to prepare the compound shown in the general formula I, according to the structure shown in the general formula I, substituted phenyl tin derivative 1 is used as a raw material to prepare the compound shown in the general formula I according to the following reaction;

Said R₁、R₂、R₃Y, X is as defined in any one of claims 1 to 38.

40. A radiopharmaceutical composition which comprises as active ingredient the benzyl phenyl ether derivative and its stereoisomers as well as pharmaceutically acceptable salts thereof according to any one of claims 1 to 38 and one or more pharmaceutically acceptable adjuvants, excipients or diluents.

41. The use of a benzyl phenyl ether derivative according to any one of claims 1-38, and stereoisomers and pharmaceutically acceptable salts thereof, for the manufacture of a medicament or medicament for the diagnosis and/or treatment of diseases associated with the PD-1/PD-L1 signaling pathway.

42. The use of claim 41, wherein the disease associated with the PD-1/PD-L1 signaling pathway is selected from the group consisting of cancer, infectious disease, autoimmune disease; preferably, the cancer is selected from skin cancer, lung cancer, urinary tumor, hematological tumor, breast cancer, glioma, digestive tumor, reproductive tumor, lymphoma, nervous system tumor, brain tumor, head and neck cancer; the infectious diseases are selected from bacterial infection and viral infection; the autoimmune disease is selected from organ-specific autoimmune diseases and systemic autoimmune diseases, wherein the organ-specific autoimmune diseases comprise chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis and acute idiopathic polyneuritis, and the systemic autoimmune diseases comprise rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease and autoimmune hemolytic anemia.

43. Use of a benzyl phenyl ether derivative according to any one of claims 1-38, and stereoisomers and pharmaceutically acceptable salts thereof, for the manufacture of a radiopharmaceutical for use in an in vivo imaging method.

44. Use of the benzyl phenyl ether derivatives and stereoisomers and pharmaceutically acceptable salts thereof according to any one of claims 1-38, for the preparation of in vivo tracer PD-L1.

45. A method of generating images of the human or animal body by administering a benzyl phenyl ether derivative of any one of claims 1-38, and stereoisomers and pharmaceutically acceptable salts thereof, to said body and using SPECT or PET to generate an image of at least a portion of said body expressing PD-L1, or said body to which said compound has distributed, wherein said compound is a tracer for PD-L1 in said body.

46. A method of monitoring the effect of a medicament for the treatment of a disease associated with PD-L1 in a human or animal body by administering to said body a benzyl phenyl ether derivative or a stereoisomer thereof according to any one of claims 1 to 38 and pharmaceutically acceptable salts thereof, monitoring the distribution of said compound in the body, the absorption of said compound by cellular receptors, or monitoring the effect of a medicament for the treatment of a disease associated with PD-L1 in a human or animal body.