Creation of a novel aging tracer

Abstract

This invention relates to compounds useful for visualizing cellular senescence in vitro and in vivo, the preparation of such compounds, and the use thereof. Specifically, this invention relates to novel glycosides for use as senescence tracers in vitro and in vivo.

Description

[Technical Field]

[0001] This invention relates to compounds useful for visualizing cellular senescence in vitro and in vivo, the preparation of such compounds, and the use thereof. Specifically, this invention relates to novel glycosides for use as senescence tracers in vitro and in vivo. [Background technology]

[0002] Cellular senescence is a biological process in which cells deviate from their proliferation cycle. Cellular senescence was first characterized in fibroblasts, which were observed to be able to passage only a limited number of times before their proliferation permanently ceased. This phenomenon, known as the Hayflick limit, can explain the physiological process of aging. Cellular senescence involves clear changes in metabolic pathways (Roninson, EB, Tumor Cell Senescence in Cancer Treatment, Cancer Res., 2003, 63:2705-2715).

[0003] Senescent cells exhibit aging-related secretory phenotypes, including pro-inflammatory cytokines and growth factors. Under certain circumstances, removing senescent tissue from patients can provide significant benefits. Furthermore, aging is recognized to play a crucial role in cancer treatment and treatment resistance. Inducing aging through treatment can establish stable clinical endpoints and thus may serve as a criterion for the success of chemotherapy. In addition, detecting senescent cells in diagnostic tests may enable the detection of preneoplastic lesions (Roninson, EB, Tumor Cell Senescence in Cancer Treatment, Cancer Res., 2003, 63:2705-2715; and Campisi, J. and d'Adda di Fagagna, F., Cellular Senescence: when bad things happen to good cells, Nature Reviews Molecular Cell Biology, 2007, 8:729-740).

[0004] The most widely used surrogate marker for senescent cells is senescence-related β-galactosidase (Roninson, EB, Tumor Cell Senescence in Cancer Treatment, Cancer Res., 2003, 63:2705-2715). However, substrates for such β-galactosidases have the drawback that they can only be used to track β-galactosidase expression ex vivo and in vitro.

[0005] In recent years, β-galactosidase-specific PET (positron emission tomography) tracers for in vivo imaging of tumor aging have been reported. For example, the PET tracer [ 18 [F]FPyGal enables non-invasive imaging of β-galactosidase as a surrogate marker for aging. However, this compound has the disadvantage of having a short retention time. [Overview of the project] [Problems that the invention aims to solve]

[0006] This invention aims to solve the above-mentioned problems related to compounds in the prior art.

[0007] There is a need for novel compounds that can act as tracers for cellular senescence, which may be used simultaneously in vitro and in vivo. There is also a need for radiotracers for cellular senescence with extended intracellular retention times. Furthermore, there is a need for radiotracers for senescent cells that accumulate in localized areas within senescent cells. In addition, there is a need for improved methods to obtain high-resolution / improved imaging at low and / or the same radiation dose in the treatment of disorders associated with cellular senescence (e.g., cancer). Furthermore, the present invention aims to provide an alternative method for selectively eliminating senescent cells in vivo. Furthermore, the present invention aims to provide an alternative means for measuring the efficiency of cancer treatment. [Means for solving the problem]

[0008] This invention is based on the finding that several types of radioactive tracers can be retained within cells by utilizing various mechanisms, specifically by self-destructive mechanisms that may involve chemical binding or sorption processes to cellular components. This allows for the proactive extension of the retention time of radiolabeled hexose derivatives within senescent cells, thereby enabling and facilitating the labeling and detection of senescent cells both in vitro and in vivo.

[0009] Therefore, the present invention is Formula: GSL (In the formula, G is a glycoside, a substituted or unsubstituted C1-C5 alkyl derivative thereof, and / or a substituted or unsubstituted N-acetyl derivative thereof, having a glycosidic bond to S; * indicates the binding site between G and S; S is

Chem.

Chem.

[0010] Surprisingly, the compounds of the present invention were found to be selectively and highly concentrated in senescent cells. While we do not wish to be bound by any particular theory, it is hypothesized that, based on their binding mechanism, the compounds of the present invention accumulate in localized areas within senescent cells, such as organelles. Such localized concentration within cells facilitates in vivo targeting and elimination of cells (especially tumors). Furthermore, generally speaking, using the radiolabeling of the present invention offers the advantage of significantly improved sensitivity compared to conventional labeling methods. This is partly due to the high tissue penetration of gamma photons emitted from the radiolabeling and the very high sensitivity of the radiation detector used. Thus, the compounds of the present invention enable quantitative, selective, and sensitive in vivo detection of senescent cells (especially tumors). It is believed that the highly selective concentration of the compounds of the present invention, using detectable radiolabeling or therapeutic radioresidues, in senescent cells can be utilized to diagnose or treat age-related diseases.

[0011] Another advantage is that tumors can be treated using non-invasive methods. For example, when a compound of the present invention having a therapeutic radioactive residue is administered, the tumor can be treated because almost all of the compound is taken up by the tumor tissue. A further advantage of using the compounds of the present invention is their flexibility. For example, the compounds of the present invention can be easily provided with detectable radiolabels or therapeutic radioactive residues, so they can be easily adapted to various changing needs in the clinical field.

[0012] A further advantage is that radiolabeling can be performed in the final synthesis step, and this radiolabeling can be carried out using a relatively simple method. This makes it possible to perform the final synthesis step at or near the site where the compound of the present invention is administered, such as in a hospital. As a result, 18 F 64 This allows for the administration of compounds with relatively short half-lives, such as Cu. Furthermore, a fully equipped laboratory for the initial synthesis of the compounds of the present invention is not required in the facility where the compounds of the present invention are administered.

[0013] The compounds of the present invention may exist in the form of stereoisomers (enantiomers, diastereomers), depending on their structure. Therefore, the present invention also encompasses enantiomers or diastereomers, and mixtures thereof. Stereoisomerically homogeneous components can be isolated from mixtures of enantiomers and / or diastereomers by known methods. If the compounds of the present invention are produced in the form of tautomers, the present invention encompasses all tautomers. Tautomers are structural isomers of the compounds of the present invention that can be readily converted to each other. Furthermore, the compounds of the present invention may exist in the form of prodrugs. Prodrugs are pharmacologically inactive compounds of the present invention that are metabolized into pharmacologically active drugs after ingestion.

[0014] A salt suitable for the purposes of the present invention is a pharmaceutically acceptable salt of the compound of the present invention. However, the present invention also includes salts that are not suitable for pharmaceutical use but can be used, for example, for the isolation or purification of the compound of the present invention.

[0015] Generally, salts are electrically neutral because they consist of a specific number of cations and a corresponding number of anions. In the preparation of a particular salt, a counterion corresponding to that salt is used, and it is not considered necessary to explicitly state such counterions here.

[0016] The pharmaceutically acceptable salts and their preparations are well known in the art. For types and preparations of such pharmaceutically acceptable salts, see Stahl, PH and Wermuth, CG, Handbook of Pharmaceutical Salts Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH, 2011, and Gupta D., et al., Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations, Molecules. 2018 Jul; 23(7): 1719, the contents of which are incorporated herein by reference in their entirety.

[0017] Examples of pharmaceutically acceptable salts of the compound of the present invention include inorganic salts such as ammonium salts, alkali metal salts, and alkaline earth metal salts; organic salts; or salts with basic amino acids. Furthermore, salts with inorganic acids or acidic amino acids are also examples.

[0018] The compounds of the present invention and their salts may exist in the form of solvates. In such cases, the compounds of the present invention or their salts (particularly pharmaceutically acceptable salts) exist in a solid or liquid state in which solvent molecules coordinate to form complexes. A hydrate is a specific form of solvate in which water is coordinated.

[0019] A "glycoside" generally refers to a molecule in which a sugar is attached to another residue or group via a glycosidic bond or glycosidic linkage. Glycosides include hexoses, and examples of hexoses include aldohexoses such as allose, altrose, glucose, mannose, growth, idose, galactose, and talose, and ketohexoses such as psicose, fructose, sorbose, and tagatose. The glycoside of the present invention is preferably a D isomer. A particularly preferred example of a glycoside is β-D-galactosidase.

[0020] The glycosides of the present invention can exist as substituted or unsubstituted C1-C5 alkyl derivatives and / or substituted or unsubstituted N-acetyl derivatives. Therefore, one or more hydroxyl groups may be unmodified, modified with substituted or unsubstituted C1-C5 alkyl residues as described later, or substituted with substituted or unsubstituted N-acetyl residues. Thus, it can be easily understood that a variety of glycoside derivatives exist, including, for example, substituted or unsubstituted C1-C5 alkyl derivatives having one substituted or unsubstituted C1-C5 alkyl residue at the terminal hydroxyl group, and substituted or unsubstituted N-acetyl derivatives having one substituted or unsubstituted N-acetyl substitution near the glycosidic bond. Furthermore, glycoside derivatives having one or more substituted or unsubstituted C1-C5 alkyl residues and / or substituted or unsubstituted N-acetyl residues are also included.

[0021] When the glycoside of the present invention is a substituted or unsubstituted C1-C5 alkyl derivative and / or a substituted or unsubstituted N-acetyl derivative, the compound of the present invention is expected to have a longer retention time compared to the unmodified glycoside because it inhibits enzymatic cleavage. Therefore, the compound of the present invention may be present in high concentrations in senescent cells.

[0022] The term "alkyl" generally refers to branched or linear alkyl groups, C1-C 18 Alkyl, for example, C1-C 16 Alkyl, C1-C14 Alkyl, C1-C 12 Alkyl, C1-C 10 The alkyl, C1-C8 alkyl, or C1-C6 alkyl is preferred, and C1-C5 alkyl is more preferred. Examples of C1-C5 alkyl include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbuta-2-yl, 2-methylbuta-2-yl, and 2,2-dimethylpropyl.

[0023] The term "alkenyl" generally refers to a partially saturated or fully saturated branched or linear alkyl residue. Therefore, an alkenyl residue has at least one CC double or CC triple bond.

[0024] The term "aryl" refers to a substantially aromatic monocyclic or polycyclic ring containing carbon and hydrogen atoms. The aromatic ring may preferably satisfy Hückel's rule. The aryl group is preferably a monocyclic or bicyclic ring, more preferably a monocyclic ring, which contains 4 to 8 carbon atoms. The molecular weight of the aryl residue is more preferably 500 g / mol or less, for example, 400 g / mol or less, 300 g / mol or less, or 200 g / mol or less.

[0025] The term "heteroaryl" refers to a substantially aromatic monocyclic or polycyclic ring containing a carbon atom, a hydrogen atom, and at least one heteroatom, preferably containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, for example, 3 heteroatoms, 2 heteroatoms, or 1 heteroatom. Therefore, it is preferable that the heteroaryl satisfies Hückel's rule. The heteroaryl group is preferably a monocyclic or bicyclic ring, more preferably a monocyclic ring, which contains 2 to 6 carbon atoms and 1 to 3 heteroatoms. The molecular weight of the heteroaryl residue is preferably 500 g / mol or less, for example, preferably 400 g / mol or less, 300 g / mol or less, or 200 g / mol or less.

[0026] In this specification, the term “substitution” means modification of a carbon chain by the attachment of one or more residues to an alkyl group such as a C1-C5 alkyl, cycloalkyl, or heterocycloalkyl group, and / or the introduction of one or more heteroatoms (e.g., N, S, or O). Furthermore, the residues may be selected from the group consisting of fluorine, chlorine, bromine, and iodine; methyl groups; ethyl groups; and functional groups such as hydroxyl groups, amino groups, O-alkyl groups (especially C1-C5O-alkyl), nitro groups, and carboxyl groups. The total molecular weight of the residues attached to a specific alkyl group such as a C1-C5 alkyl moiety, cycloalkyl moiety, or heterocycloalkyl moiety is preferably 250 g / mol or less, and more preferably 150 g / mol or less or 100 g / mol or less. Preferred substituents for the C1-C5 alkyl residues include compounds such as CH2-O-CH2, C2H4-O-CH2, CH2-O-CH2-O-CH2, CH2-O-CH2-O-CH2, C2H4-O-CH2-O-CH2, CH2-O-C2H4-O-CH2, C2H4-O-C2H4-O-CH2-O-C2H4, CH2-O-CH2-O-CH2-O-CH2, C2H4-O-CH2-O-CH2-O-CH2, and CH2-O-C2H4-O-CH2-O-CH2.

[0027] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine, and is preferably fluorine, chlorine, or bromine. In some embodiments, the term "halogen" or "halo" is: 76 Br, 75 Br, 19 F and 18 It is preferable to refer to F.

[0028] The term "methylhalogen" refers to a methyl group having one fluorine, chlorine, bromine, or iodine atom, or a methyl group having two or three halogens independently selected from fluorine, chlorine, bromine, and iodine. In some embodiments, the methylhalogen is 76 Br, 75 Br, 19 F or 18 It is preferable that it has F.

[0029] The term "detectable radioactive label" is, for example, 11 C, 40 K, 13 N, 15 O, 18 F, 75 Br, 76 Br, 82 Rb, 68 Ga, 64 Cu, 62 Cu, 89 Zr, 123 I, 124 I, 125 I, 131 I, 210 At, 211 At and 111 It contains In. Detectable radioactive labels include: 11 C, 18 F, 68 Ga, 64 Cu and 124 I is preferred. Detectable radiolabeling enables quantitative and / or qualitative evaluation of senescent cells, as well as identification of their localization, particularly in vivo. Senescent tissue may be appropriately identified and, for example, surgically removed with high selectivity. 18F is particularly preferred because, when it decays, it does not generate non-radioactive elements, and the compound of the present invention can be decomposed in vivo, allowing the compound to be removed from the cell without causing further damage to the cell itself or the organism to which the cell belongs.

[0030] Alternatively, complexes coordinated to such atoms are included. In this case, the complex may be called a chelating agent coordinated to a detectable radioactive label. A (coordination) complex has an atom or ion (usually a metal atom or metal ion) at its center, with ligands or complexing agents arranged around it. The central atom or ion is usually a detectable radioactive label. Therefore, the Z residue includes the central atom or ion and the ligands or complexing agents arranged around it. Specific examples of such chelating agents coordinated to detectable radioactive labels are well known to those skilled in the art. Such chelating agents are preferably amino acids, and preferably amino acids that make up proteins / natural amino acids (e.g., histidine). Other examples of suitable chelating agents include DOTA, NOTA, NODAGA, and desferrioxamine (e.g., desferrioxamine B).

[0031] In this specification, the term "therapeutic radioactive residue" is defined as follows: 32 P, 60 Co, 89 Sr, 186 Re, 153 This refers to atoms such as Sm. Other examples of therapeutic radioactive residues include the previously mentioned examples of detectable radiolabels. 125 I and 131 I was mentioned, and also, 86 Y, 111 In, 177 Lu and 67Cu is an example. Alternatively, complexes coordinated to such atoms are included. In this case, the complex may be called a chelating agent coordinated to a therapeutic radioactive residue. In the treatment of cellular aging disorders (especially cancer), the use of the compounds of the present invention having therapeutic residues allows for the combination of the target selectivity of the compounds of the present invention with systemic effects such as chemotherapy, and can be used as part of a therapeutic strategy aimed at cure or control and mitigation of disease.

[0032] In particular, it has already been demonstrated that β-galactosidases derived from humans or animals can tolerate glycosides to which large residues are bound without affecting their enzymatic activity, even if such large residues are bound to the glycoside. Therefore, it can be reasonably predicted that the compounds of the present invention having bulky therapeutic radioactive residues can be converted by β-galactosidases derived from humans or animals.

[0033] It is understood that therapeutic radioactive residues may be prepared and bound to the compound of the present invention in the same manner as detectable radiolabels. Preferably, the therapeutic residues and the detectable labels are the same, thereby enabling the diagnosis and treatment of cellular aging-related disorders (especially cancer).

[0034] In the above formula, the ends of the bonded parts of the group represented by G, marked with an asterisk (*), are not carbon atoms or CH2 groups, but rather the parts that constitute the bond to the atom to which G is bonded.

[0035] In the above formula, the ends of the bonds of the group represented by S, marked with * or #, are not carbon atoms or CH2 groups, but rather the parts that constitute the bond to the atom to which S is bonded.

[0036] In the above formula, the end of the bond of the group represented by L, marked with a #, is not a carbon atom or a CH2 group, but rather the part that constitutes a bond to the atom to which L is bonded.

[0037] In this invention, the terms “having / including” or “having / including” are open-ended terms and do not exclude any other elements other than those explicitly stated.

[0038] In this invention, the terms "consisting of" or "making up" are closed-end terms that exclude any elements other than those explicitly stated.

[0039] In the present invention, the terms "substantially consisting of" or "substantially consisting of" are partially closed-end terms and refer to preparations having additional components other than those described, to the extent that they do not significantly alter the properties of the preparation according to the present invention.

[0040] In the present invention, when a preparation is described using the terms "having" or "having," it clearly includes a preparation comprising the said components, or a preparation substantially comprising the said components.

[0041] As used herein, radiation medicine refers to any type of equipment or device that can detect the Z residues of the present invention, namely, detectable radioactive labels, therapeutic radioactive residues, chelating agents coordinated with detectable radioactive labels, or chelating agents coordinated with therapeutic radioactive residues, and generate visual signals or images. Preferably, the device can identify the location of Z residues in the body of a mammal. Specific examples of radiation medicine include, but are not limited to, positron emission tomography (PET) that can create three-dimensional images or maps of the functional processes in the body. This system detects gamma-ray pairs indirectly emitted from a radioactive isotope that emits positrons and is bound to a metabolic active molecule (i.e., a substrate of β-galactosidase) and introduced into the body. Next, through computer analysis, the spatial location of metabolic activity is reconstructed as an image, and this image is supplemented with a CT X-ray scan performed on the patient with the same device, preferably simultaneously, in the same examination, to obtain a three-dimensional image capable of identifying the location of tissues enriched with the prodrug. In positron emission, a proton is converted into a neutron, a positron, and a neutrino by the weak force. Isotopes that have undergone so-called β+ decay emit positrons. Suitable positron-emitting radionuclides for this purpose include 11 C, 40 K, 13 N, 15 O, 18 F, 75 Br, 76 Br, 89 Zr, 82 Rb, 68 Ga, 62 Cu and 64 Cu, among which 11 C and 18 F are preferred. Other useful radionuclides include 123 I, 124 I, 125 I, 131 I, 210 At, 211 At and 111In is one example. Furthermore, the compounds of the present invention may be labeled with technetium and rhenium isotopes using known chelate complexes. Methods for preparing radionuclides and radiolabeling compounds are well known to those skilled in the art. US2007 / 0273308 and WO2007 / 122488 (the contents of these documents are incorporated herein by reference in their entirety) relate, for example, to the preparation of radionuclides. Radiolabeling is outlined, for example, in WO2007 / 148089 and WO2007 / 148083 (the contents of these documents are incorporated herein by reference in their entirety).

[0042] PET is preferably connected to a computed tomography (CT) scanner. Such a PET / CT system enables quantitative detection of signals and allows the detected signals to be attributed to specific tissues, that is, the localization of the radionuclide used, i.e., the prodrug bound to it, to be identified. The functions, procedures, and equipment of PET / CT are well known to those skilled in the art. Other suitable methods include single-photon emission computed tomography (SPECT) and methods based on nuclear magnetic resonance (NMR) that detect the quantum mechanical magnetic properties of atomic nuclei.

[0043] The radiomedical equipment used is preferably a PET scanner, and more preferably a PET / CT scanner or a PET / MR scanner. [Brief explanation of the drawing]

[0044] [Figure 1] This section presents a model experiment to verify the self-destructive mechanism. [Figure 2] This shows an experiment involving uptake in galactosidase-overexpressing cells. [Figure 3] This shows an uptake experiment in a senescent cell model. [Figure 4] This shows a dynamic PET scan of Amp19 tumor-bearing mice using [18F]TFPBGal. [Figure 5][18F] Autoradiography of cyclophore-treated (aging) Amp19 tumors and control Amp19 tumors after PIPGal administration. [Figure 6] Ex vivo immunohistochemical analyses of CX-treated (aging) Amp19 tumors and solvent-treated (control) Amp19 tumors are shown. [Modes for carrying out the invention]

[0045] According to one preferred embodiment, The substituted or unsubstituted C1-C5 alkyl derivatives of the glycoside of the present invention are substituted or unsubstituted 5-(C1-C5 alkyl) glycosides; The substituted or unsubstituted N-acetyl derivatives of the glycoside of the present invention are substituted or unsubstituted 2-(N-acetyl)glycosides, substituted or unsubstituted 3-(N-acetyl)glycosides, or substituted or unsubstituted poly(N-acetyl)glycosides; The glycoside of the present invention is selected from the group consisting of α-D-glucofuranoside, α-D-mannofuranoside, α-D-fructofuranside, α-D-glucopyranoside, α-D-mannopyranoside, α-D-galactopyranoside, α-D-fructopyranoside, β-D-glucofuranoside, β-D-mannofuranoside, β-D-fructofuranside, β-D-glucopyranoside, β-D-mannopyranoside, β-D-galactopyranoside, and β-D-fructopyranoside; R 3 Z is Z, [(CH2) m O(CH2) n ] o Z, [(CH2) m CO(CH2) n ] o Z, and NR 4 (CH2) n Selected from the group consisting of Z, R 4 is H, methyl or ethyl, and m, n and o are each independently integers from 1 to 5; and / or S is [ka] That is the case.

[0046] According to another preferred embodiment, L is [ka] Preferably, [ka] and; R 1 Each of them operates independently, (CH2) n Z and O(CH2) n A selection is made from the group consisting of Z, where n is 1 to 3, and preferably # is in the meta or para position relative to *; B is independently H, F, Cl, Br, I, NO2, OR 4 , NR 4 R 5 and selected from the group consisting of unsubstituted C1-C5 alkyl groups, provided that at least three H atoms are present; R 4 and R 5 Each of these is independently selected from the group consisting of H, methyl, and ethyl.

[0047] According to yet another preferred embodiment, L is #-CH2OR 2 Alternatively, #-CH2OOCNHR 2 Preferably, L is in the ortho or para position relative to *; R 2 is a substituted or unsubstituted C1-C8 alkyl group, or a substituted or unsubstituted aryl group, preferably a substituted naphthyl, substituted biphenyl, or substituted benzyl group; B is independent of R 3 Selected from the group consisting of Z, H, F, Cl, Br, I, NO2 and substituted or unsubstituted C1-C5 alkyl groups, provided that at least one R is included. 3 There exist Z and at least two H; R 3 Z is -Z, -[(CH2)m O(CH2) n ] o Z, -[(CH2) m CO(CH2) n ] o Z, and -NH(CH2) n Selected from the group consisting of Z, where m, n, and o are each independent integers from 1 to 4, preferably R 3 Z is in the para position relative to * or #; and / or R 4 and R 5 Each of these is independently selected from the group consisting of H and substituted or unsubstituted C1-C3 alkyl groups.

[0048] When L is in the ortho or para position relative to *, quinone methide formation is promoted.

[0049] According to one preferred embodiment, the compound of the present invention is [ka] Compound [ 18 F]20((Sa-)PIPGal, 18 F]PIPGal (also called PIPGaL), [ka] Compound [ 18 F]9((SA-)NO2-ADBGal or [ 18 (also known as F]NO2ADBGal), [ka] Compound [ 18 F]29((SA-)TFPBGal or [ 18 F]TFPBGal (also called F), or [ka] Compound [ 18 F]14((SA-)ADTFPBGal or [ 18 It is also called F]ADTFPBGal).

[0050] According to another preferred embodiment of the present invention, the detectable radioactive label is 11 C, 40 K, 13 N, 15 O, 18 F, 75 Br, 76 Br, 82 Rb, 68 Ga, 64 Cu, 62 Cu, 89 Zr, 123 I, 124 I, 125 I, 131 I, 210 At, 211 At and 111 Selected from the group consisting of In, 11 C, 18 F, 68 Ga, 64 Cu and 124 It is preferable to select from the group consisting of I. 18 It is more preferable that it be F.

[0051] According to yet another preferred embodiment of the present invention, the therapeutic radioactive residue is 32 P, 60 Co, 64 Cu, 89 Sr, 90 Y, 177 Lu, 186 Re and 153 Selected from the group consisting of Sm.

[0052] According to one preferred embodiment of the present invention, the compounds of the present invention are intended for use in surgical procedures. The compounds of the present invention are preferably used in combination with at least one inert and non-toxic pharmaceutically appropriate additive.

[0053] According to one preferred embodiment of the present invention, the compounds of the present invention are intended for use as pharmaceuticals. The compounds of the present invention are preferably used in combination with at least one inert and non-toxic pharmaceutically appropriate additive.

[0054] According to another preferred embodiment of the present invention, the compounds of the present invention are for use in a method for detecting cellular senescence.

[0055] According to another preferred embodiment of the present invention, the compound of the present invention is intended for use in a method for measuring the effectiveness of cancer treatment.

[0056] The cancers diagnosed and / or treated using the compounds of the present invention may be selected from prostate cancer, colorectal cancer, breast cancer, lung tumors, male or female genitourinary tract tumors, malignant melanoma, pharyngeal and neck tumors / cervical tumors, malignant lymphoma, hematopoietic malignancies, and musculoskeletal tumors.

[0057] According to yet another preferred embodiment of the present invention, the method for detecting cellular senescence includes contacting cells with the compound of the present invention.

[0058] According to yet another preferred embodiment of the present invention, the method for measuring the efficiency of cancer treatment includes contacting cells with the compound of the present invention.

[0059] According to yet another preferred embodiment of the present invention, the method is carried out in vivo.

[0060] According to yet another preferred embodiment of the present invention, the method is carried out in vitro.

[0061] The above method can be performed both in vivo and in vitro. A specific example of performing it in vivo is monitoring the efficiency of cancer treatment in human patients, while a specific example of performing it in vitro is screening for new drugs.

[0062] The compounds of the present invention are preferably administered parenterally.

[0063] In parenteral administration routes, the compounds of the present invention may be administered in an appropriate dosage form. Parenteral administration can be carried out by methods that do not involve an absorption step (e.g., intravenous, intra-arterial, intracardiac, intrathecal, or intralumbar), or by methods that do involve an absorption step (e.g., intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). Suitable dosage forms for parenteral administration include injectable and intravenous formulations in the form of liquids, suspensions, emulsions, lyophilized products, or sterile powders.

[0064] The compounds of the present invention may be formulated into the above-described dosage forms. This formulation can be carried out by mixing with inert and non-toxic pharmaceutically acceptable additives by methods known to the present. Such additives include, in particular, carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, e.g., ascorbic acid), colorants (e.g., inorganic pigments, e.g., iron oxide), and flavoring agents and / or odoring agents.

[0065] The compounds of the present invention are preferably configured to accumulate within cells. Intracellular accumulation is more preferably occurring in cells where the compounds of the present invention have been converted by senescence-related β-galactosidase (SABG). Furthermore, intracellular accumulation may be based on a self-destructive mechanism involving chemical bonding or sorption processes to cellular components. Moreover, intracellular accumulation is more preferably accompanied by bonding of the compounds of the present invention, for example, covalent and / or ionic bonding. For example, bonding to intracellular components such as proteins, for example, covalent and / or ionic bonding, may occur.

[0066] The basic principles of the present invention are schematically shown in the following schemes 1 and 2.

[0067] According to Scheme 1, for example, a radioactive tracer that is PIPGal is R 1 It contains a basic functional group in its vicinity, specifically a tertiary amine. In this respect, in particular, [ka] The compound showed good results, and this compound, [ka] It is preferable that this be the case. When the glucosidase moiety is cleaved by aging-related β-galactosidase (SABG) or β-galactosidase, R 1 Nitrogen adjacent to the residue can be readily protonated within the acidic lysosomes of the target cell and captured within these acidic lysosomes. This so-called pH capture is presumed to be due to the sorption (particularly adsorption) of ammonium groups to negatively charged cellular components, such as negatively charged amino acids of proteins. The radiolabeled alcohol accumulated and captured in the acidic lysosomes may be detected by radiomedical equipment such as PET / CT scanners.

[0068] [ka]

[0069] Scheme 2 illustrates a second method. In this method, the glucosidase portion is cleaved by aging-related β-galactosidase (SABG), and a structure that degrades into a quinone methide appears in the alcohol. This quinone methide reacts with amino acid residues (particularly cysteine ​​and lysine residues) of proteins present in the target cell (indicated by arrows) to form a secondary amine, creating a bond with these amino residues. In the secondary amine formed by this so-called quinone methide bond, one residue remains (still) bound to the protein, while the other residue is bound to the original radiolabeled tracer residue. This radiolabeled alcohol bound to the intracellular protein may be detected by radiomedical equipment such as a PET / CT scanner.

[0070] [ka]

[0071] The compounds of the present invention may be prepared as shown in the following schematic diagram.

[0072] [ka]

[0073] In the first step, a hexose precursor having bromine at the glycosidic bond position and having multiple acetylated hydroxyl groups is reacted with hydroxybenzaldehyde, preferably 2-hydroxybenzaldehyde, and a nitro group (e.g., 2-hydroxy-5-nitrobenzaldehyde) to form glycoside 1. The aldehyde group is converted to alcohol 3, in which the nitro group is protected with, for example, a tert-butyloxycarbonyl (Boc) protecting group, and in which 4, for example, a methylsulfonyl (MS) group is introduced to the alcohol. This converts the alcohol to a suitable leaving group, generating an alkylating agent. This method allows for the introduction of aryl leaving groups necessary for the self-destructive reaction and the generation of quinone methides.

[0074] [ka]

[0075] The methylsulfonyl-activated hydroxyl group of the Boc-protected methylsulfonyl-substituted precursor 4 is converted to ether 5 or ether 10. In the next step, the Boc protecting group is converted to a secondary amine 6 or secondary amine 11 having a hydroxyl moiety, and this amine is further converted to a mesyl group 7 or mesyl group 12 and activated, enabling radiofluorination in a later step.

[0076] [ka]

[0077] The Boc protecting group of ether 5 or ether 10 in scheme 4 is converted to a secondary amine having a fluorine moiety. Next, the acyl group of the hexose moiety is removed to obtain non-radioactive standard 9 or non-radioactive standard 14.

[0078] [ka]

[0079] In the first step, a brominated and acetylated hexose derivative (e.g., acetobromogalactose) is converted using the protected 4-(piperazin-1-yl)phenol derivative 15, and then deprotected to obtain a Boc-protected glycoside 16, which is further converted to a mesylate ester 18. A non-radioactive standard may also be synthesized by reacting an acetylated hexose derivative (e.g., acetobromogalactose) with the protected 4-(piperazin-1-yl)phenol derivative 15, followed by alkylation 19 and deprotection 20.

[0080] [ka]

[0081] As shown in Scheme 7, the hexose derivative is converted using a substituted (iodine-substituted or bromine-substituted) orthosalicylaldehyde to obtain compound 21, and then this compound is converted with NaBH4 to obtain alcohol 22. In 23, the alcohol is mesylated and then converted to tetrafluorophenyl ether 24. Next, the iodine substituent or bromine substituent is reacted to obtain compound 25.

[0082] [ka]

[0083] The hexose derivative is reacted with fluorine-substituted orthosalicylaldehyde to obtain compound 26, which is then converted with NaBH4 to obtain alcohol 27. Next, this alcohol is converted to tetrafluorophenyl ether 28 and deacetylated.

[0084] The compounds of the present invention exhibit unexpected and beneficial pharmacological effects. These compounds can label senescent cells in vitro and in vivo. Specifically, labeling senescent cells with the compounds of the present invention in vivo allows for clear identification of senescent cells during surgical procedures, making it possible to target and eliminate senescent cells (especially cancer cells).

[0085] The foregoing description is illustrative only and not limiting. Those skilled in the art will readily be able to implement numerous embodiments by examining the foregoing description. For example, the present invention primarily describes the synthesis of tracer 9 and diagnostic use thereof. It goes without saying that any suitable detection labels and therapeutic residues of any kind may be synthesized and conjugated to the compounds of the present invention. Therefore, the scope of the present invention is not defined by the foregoing description, but should be defined by the entire scope equivalent to the appended claims and assertions.

[0086] Unless otherwise stated, in the following tests and examples, percentages are expressed in weight percentages, and parts are expressed in parts by weight. Solvent ratios, dilution ratios, and liquid / solution concentrations are all based on volume. The notation "w / v" means "weight / volume." Therefore, for example, "10 w / v%" means that 10 g of the substance is contained in 100 ml of solution or suspension. [Examples]

[0087] General method [ 18 [F] fluoride was prepared using a PETtrace 890 cyclotron (GE Healthcare, Uppsala, Sweden) and delivered directly to the module. This fluoride was collected in a QMA cartridge, eluted into the reactor using Kryptofix solution or TBAOTf solution, and then the solvent was removed by distillation at high temperature.

[0088] For standard nucleophilic radiofluorination, Sep-Pak Plus Light QMA carbonate cartridges were conditioned with NaHCO3 (10 mL), air (10 mL), H2O (10 mL), and air (10 mL). For copper-catalyzed radiofluorination (TFPBGal), Sep-Pak QMA carbonate light cartridges were conditioned with 10 mL of KOTf2 solution (90 mg / mL), air (10 mL), H2O (10 mL), and air (10 mL). Sep-Pak Light C18 cartridges were conditioned with EtOH (10 mL) and H2O (10 mL). Alumina N cartridges were conditioned with H2O (5 mL).

[0089] The Kryptofix eluate used in all nucleophilic radiofluorination processes contained Kryptofix (9.5 mg), K2CO3 (1.7 mg), H2O (80 μL), and CH3CN (1.92 mL). For fluoride elution in copper-catalyzed radiofluorination, a solution of TBAOTf (5 mg) in MeOH (1 mL) was used.

[0090] All tracers were verified to identify the respective reference compounds using radio-HPLC, utilizing their retention times. Radio-HPLC analysis data was collected using an Agilent HPLC (1260 Infinity series with automated sample injector) connected to an inline radiation detector [NaI(Tl)].

[0091] [ 18 F]9([ 18 F]ADNO 2 BGal) and [ 18 F]14([ 18 Automatic synthesis of F]ADTFPBGal) The selected precursor (compound 7 or compound 12, 3.00 mg, 4.13 μmol or 3.98 μmol) was dissolved in DMF (500 μL). After adding the precursor solution and heating at 150°C for 10 minutes to obtain the acetylation product, deprotection was performed by adding 0.1 M aqueous NaOH solution. The reaction mixture was neutralized with 0.1 M aqueous NaH2PO4 solution and transferred to preparative HPLC. Purification of the product was performed using an Elixys Pure / Form module (Sofie Bioscience, Culver City, California, USA) equipped with a Luna 5 μm C18(2) 100 Å 250 × 10 mm column (Phenomenex, Torrance, California, USA), with a stepwise gradient at a flow rate of 6 mL / min. 18 F]9 step gradient: 10%B at 0.0-7.0 min, 60%B at 7.0-13.0 min, 100%B at 13.0-15.0 min; Solvent A: H2O, Solvent B: MeCN; Retention time: approximately 11.5 min. 18 F]14-step gradient: 10%B at 0.0-6.5 mins, 40%B at 6.5-18.0 mins, 100%B at 18.0-20.0 mins; Solvent A: H2O, Solvent B: MeCN; Retention time: approximately 16.5 mins.

[0092] The product peak was collected, diluted with water (50.0 mL), collected in a C18 cartridge, eluted into a product vial with EtOH (0.50 mL), and formulated with phosphate-buffered saline (4.50 mL). Quality control was performed by analytical HPLC. Quality control was performed using an analytical radioHPLC equipped with a Luna 5 μm C18(2) 100 Å 250 × 4.6 mm column (Phenomenex, Torrance, California, USA) with the following gradient: 0-2 min (5% B), 2-17 min (5% → 100% B), 17-23 min (100% B), 23-28 min (100% → 5% B), 28-29 min (5% B); Solvent A: 0.1% TFA aqueous solution, Solvent B: MeCN; 1 mL / min. 18 The holding time for F]6 is approximately 10.7 minutes, 18 The holding time for F]11 was set to approximately 11.0 minutes.

[0093] [ 18 F]PIPGal([ 18 F]20) and [ 18 F]TFPBGal([ 18 Automatic synthesis of F]29) 18 Automated synthesis of F-tracers was performed using the GE FX N Pro synthesis module (GE Healthcare, Münster, Germany) with TRACERlab (GE) control and user interface software.

[0094] The performance of the radiochemical reaction was monitored by radio-TLC using a 0.20 mm Polygram SIL G / UV254 (silica gel 60) TLC plate. The radio-TLC plate was developed with an appropriate running buffer / solvent mixture. Radio-TLC data were acquired using the Cyclone Plus storage phosphor imaging system (PerkinElmer, Waltham, Massachusetts, USA).

[0095] [ 18 F]PIPGal's automatic compositing (FX N Pro) Precursor 18 (10 mg) dissolved in DMSO (500 μL) was added to a reactor containing azeotropically dried fluoride and heated at 150°C for 15 minutes. Next, the reactor was cooled to 40°C, and 0.1 M NaOH (1.0 mL) was added. The reaction mixture was stirred at 40°C for 2 minutes, and then 0.1 M NaH2PO4 (2.0 mL) was added. The mixture was purified using semi-preparative HPLC (Luna 5 μm C18(2) 100 Å 250 × 4.6 mm, Phenomenex) at a flow rate of 6 ml / min with phosphate-buffered saline (PBS) containing 10% EtOH. Based on the radioactive signal (13-14 minutes), the product was collected and transferred to a product vial. Quality control was performed by HPLC using an ABZ+ column (90% 25 mM ammonium formate in CH3CN solution, 1 mL / min). Purity was evaluated by radio-TLC (35% acetone, 35% 1-butanol, 10% acetic acid, and 20% H2O).

[0096] [ 18 F] Automatic compositing of TFBB Gal (FX N Pro) To the dried fluoride, a DMA (700 μL) solution containing 25 mg of precursor, 3.26 μL of pyridine, and 3.7 mg of Cu(OTf)2 was added. The reaction mixture was heated at 120°C for 20 minutes and then cooled to 40°C. Deprotection was performed by adding 1 mL of 2 M NaOH and reacting at 40°C for 10 minutes. Next, 500 μL of 0.3 M HCl was added to the reaction mixture. This mixture was passed through an alumina N cartridge and diluted with a solution containing 500 μL of 4 M HCl and HPLC eluent (2 mL). The mixture was then purified by semi-preparative HPLC (Luna 5 μm C18(2) 100 Å 250 × 4.6 mm, Phenomenex) using an eluent containing a 0.1% TFA aqueous solution of 35% MeCN at a flow rate of 6 mL / min. Based on the radioactive signal (10-15 minutes), the product was collected and transferred to a dilution reservoir containing water (50 mL). The product was fixed by passing this solution through a SepPak C18 cartridge, washed with water (5.0 mL), and then eluted into a product vial containing PBS (4.5 mL) using EtOH (0.5 mL). Purity was evaluated by radio-TLC using ethyl acetate.

[0097] Biological experimental methods Cells were cultured at 37°C under 5% CO2 in a wet incubator (Binder, Tuttlingen, Germany). Fetal bovine serum (FBS, Sigma, a subsidiary of Merck) was inactivated by heating at 57°C for 30 minutes and used as a cell culture additive. For in vitro uptake experiments, cells were rinsed with DPBS, collected with a cell scraper, and then centrifuged. Next, the cell pellet was washed with DPBS, resuspended in DPBS, and the cell count was measured. 1 × 10⁻⁶ 6 0.74 MBq of tracer was added to a 1 mL DPBS suspension containing 2480 cells and incubated at 37°C for 40 minutes under 5% CO2. After the prescribed incubation time, the suspension was centrifuged. The cell pellet was transferred to a new gamma counter tube (Sarstedt), washed twice with 1 mL of DPBS, and then resuspended in 1 mL of DPBS. The uptake rate was 2480 Wizard 2 The measurement was performed using an automated gamma counter (PerkinElmer).

[0098] X-gal staining was performed to confirm senescence in vitro. For X-gal staining, cells were fixed at room temperature for 15 minutes in a DPBS solution of 0.25% glutaraldehyde (Sigma-Merck, a subsidiary of Merck) and 2% formaldehyde (Sigma-Merck, a subsidiary of Merck). Next, the cells were washed twice with a DPBS solution of 1 mM magnesium chloride (MgCl2, Sigma-Merck, a subsidiary of Merck) (pH 6.0) and incubated at 37°C. A freshly prepared staining solution, which had been warmed and filtered beforehand, was added. The staining solution contained 1 mg / mL of 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside (X-gal, PEQLAB / VWR from Avantor), 5 mM potassium hexacyanoferrate(III) [K3Fe(CN)6, Sigma-Merck], and 5 mM potassium hexacyanoferrate(II) [K4Fe(CN)6, Merck] in a 1 mM MgCl2 / DPBS solution (pH 6.0). Each sample was wrapped in aluminum foil to protect it from light and prevent evaporation. Next, each sample was washed twice with a 1 mM MgCl2 / DPBS solution (pH 6.0) and then observed under an optical microscope (Axiovert 200 equipped with AxioCam and AxioVision, Carl Zeiss, Oberkochen, Germany).

[0099] The animal manipulation was approved by the local government (Regierungspraesidium Tübingen, Germany) and carried out in accordance with the German Animal Welfare Act. The mice used were 6-7 weeks old. The tumors measured 0.5 × 10⁻⁶. 6 The cells were subcutaneously administered and transplanted into the right flank of SCID beige mice. The majority of the tumor was 100 mm. 3 At the point when the mice reached a certain stage (approximately 3 weeks after vaccination), they were randomly divided into two groups. Each group received intraperitoneal administration of 25 mg / kg / day of CX-5461 (AdooQ BioScience, Irvine, California, USA) or a solvent [50 mM monosodium phosphate (Sigma-Merck, a subsidiary of Merck, Darmstadt, Germany), pH 4.5] for 5 consecutive days.

[0100] Anatomical imaging was performed using a 7 Tesla small animal MRI scanner equipped with a rat-specific whole-body coil and Paravision® software (Bruker, Billerica, Massachusetts, USA). To ensure accurate positioning, the rats were fixed and transferred to the PET scanner. After administering 12±1 MBq of tracer (measured with a CRC 15-R dosimeter) to the rats via a tail vein catheter, the catheter was flushed with 50 μL of heparinized saline. 57 Transmission scans were performed using an external point source of Co, and attenuation correction was applied. Static radiation scans were acquired 50-60 minutes after tracer administration.

[0101] The raw data in list format was histogrammed and reconstructed using the OSEM3D / SP-MAP algorithm implemented in Inveon Acquisition Workplace. The reconstructed PET images and their corresponding MRI images were imported into Inveon Research Workplace software (Siemens) and manually aligned. The target region was manually drawn based on anatomical references, and numerical values ​​(Bq / ml) were extracted from the corresponding PET images. Tracer uptake was calculated as the percentage of the injection volume per cubic centimeter (%ID / cc).

[0102] To perform autoradiography, tumors were embedded in an optimal cutting temperature compound (Tissue-Tech® OCT, Sakura FineTech, Netherlands, Alfen Ahn den Reing) and frozen at -20°C using a cryotome (Leica, Germany, Wetzlar). Next, 20 μm frozen sections were mounted on microscope slides (SuperFrost® Plus, R. Langenbrinck, Germany, Emendingen). The slides were exposed overnight to a fluorescence screen (Molecular Dynamics, a subsidiary of GE Healthcare). The fluorescence screen was then scanned with a fluorescence imager (Storm 840, Amersham, a subsidiary of GE Healthcare). The signal intensity of the sections was normalized based on the attenuated dose administered to rats using ImageJ, open-source software (National Institutes of Health, Bethesda, Maryland, USA).

[0103] Hematoxylin and eosin (H&E) staining was performed on autoradiographic sections using an automated staining system by staff from the dermatology department (University Hospital Tübingen, Germany).

[0104] Immunohistochemical analysis (IHC) was performed by staff from the Department of Pathology (University Hospital Tübingen, Germany) using an automated immunohistochemical staining system (Ventana Medical Systems, Roche) in accordance with the manufacturer's protocol.

[0105] Example 1 The synthesis of a precursor compound by reaction scheme 3 is disclosed in Example 1.

[0106] Synthesis of Compound 1 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(2-formyl-4-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetic acid, 1 [ka]

[0107] Under an argon atmosphere, 5.0 g, 12.2 mmol of acetobromogalactose and 2-hydroxy-5-nitrobenzaldehyde (2.2 g, 13.4 mmol) were cooled on ice and dissolved in CH3CN (50 mL). Diisopropylethylamine (7 mL) was added dropwise to this solution. The resulting mixture was stirred overnight while slowly raising the temperature to room temperature. After concentrating the mixture under reduced pressure, the resulting residue was diluted with ELISA (200 mL) and washed sequentially with 5% citric acid (3 × 100 mL), water (2 × 100 mL), saturated NaHCO3 aqueous solution (2 × 100 mL), and saline solution (100 mL). The organic layer was dried over Na2SO4 and then concentrated under reduced pressure to approximately 30 mL. The mixture was crystallized overnight at -20°C. The obtained crystals were collected, and the mother liquor was concentrated to obtain secondary crystals. The resulting colorless crystals were collected by filtration and dried (4.9 g, 81.1%). f : 0.5 (PE / Â 1:1); 1 H NMR (600 MHz, CDCl3) δ 10.30 (s, 1H), 8.66 (d, J = 2.9 Hz, 1H), 8.38 (dd, J = 9.2, 2.9 Hz, 1H), 7.34 - 7.18 (m, 1H), 5.58 (dd, J = 10.5, 7.8 Hz, 1H), 5.49 (d, J = 3.5 Hz, 1H), 5.31 (d, J = 7.9 Hz, 1H), 5.17 (dd, J = 10.5, 3.4 Hz, 1H), 4.22 - 4.14 (m, 3H), 2.18 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 2.00 (s, 4H).

[0108] Synthesis of Compound 2 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(2-(hydroxymethyl)-4-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 2 [ka]

[0109] Aldehyde 1 (2.1 g, 4.2 mmol) was dissolved in EtOH (40 mL). Na(CN)BH3 (2.7 g, 12.85 mmol) and Na(OAc)3BH (0.26 g, 3.4 mmol) were carefully added in small amounts to this solution. The reaction mixture was stirred at room temperature for 1 hour, after which water (30 mL) and siRNA (300 mL) were added sequentially. The organic layer was washed with water (2 × 100 mL) and saline solution (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The product was crystallized overnight at -20°C, and the mother liquor was concentrated to obtain secondary crystals. The obtained solid was recovered by filtration and dried under reduced pressure (1.79 g, 85%). f : 0.45 (PE / siRNA 1:1); 1 H NMR (600 MHz, CDCl3) δ 8.29 (d, J = 2.8 Hz, 1H), 8.16 (dd, J = 9.0, 2.8 Hz, 1H), 7.07 (d, J = 9.0 Hz, 1H), 5.53 (dd, J = 10.5, 7.8 Hz, 1H), 5.49 (d, J = 3.4 Hz, 1H), 5.20 - 5.15 (m, 2H), 4.67 (d, J = 1.9 Hz, 2H), 4.22 (td, J = 9.3, 5.3 Hz, 1H), 4.19 - 4.13 (m, 2H), 2.20 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H).

[0110] Synthesis of Compound 3 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((tert-butoxycarbonyl)amino)-2-(hydroxymethyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl,3 [ka]

[0111] A solution of the above compound 2 (2.3 g, 4.5 mmol) in EtOAc (5 mL) was added to a suspension of 5% Pd / C (0.74 g) in EtOAc. The resulting solution was degassed and stirred under a hydrogen atmosphere for 4 hours. After it was confirmed by TLC that the starting material had been completely consumed, the atmosphere was replaced with argon, and a solution of Boc2O (1.5 g, 4.5 mmol) in EtOAc (5 mL) was added through a septum. The reaction mixture was stirred at room temperature overnight and then filtered through celite. After removing the solvent under reduced pressure, the resulting residue was purified by silica gel flash chromatography (a PE solution of 5 - 100% EtOAc), and the product was obtained as a colorless oil (1.9 g, 73%). 1 H NMR (600 MHz, CDCl3) δ 7.30 (s, 1H), 5.48 (dd, J = 10.5, 7.9 Hz, 1H), 5.44 (dd, J = 3.5, 1.1 Hz, 1H), 5.十一 (dd, J = 10.5, 3.4 Hz, 1H), 4.98 (d, J = 8.0 Hz, 1H), 4.23 - 4.13 (m, 2H), 4.02 (ddd, J = 7.2, 5.9, 1.2 Hz, 1H), 2.04 (s, 4H), 6.九十六 (d, J = 8.7 Hz, 1H), 6.46 (s, 1H), 4.64 (d, J = 12.9 Hz, 1H), 4.51 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.10 (s, 3H), 2.01 (s, 3H), 1.50 (s, 9H).

[0112] Example 2 The synthesis of the precursor of the compound according to Reaction Scheme 1 is disclosed in Example 2.

[0113] Synthesis of Compound 4 Triacetate (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((tert-butoxycarbonyl)amino)-2-(((methylsulfonyl)oxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 4

Chemical Structure

[0114] Under an argon atmosphere, a solution of the above compound 3 (3.44 g, 6.04 mmol) in DCM (180 mL) was cooled to 0 °C, and Et3N (3.00 mL, 18.1 mmol) was added. MsCl (0.51 mL, 6.64 mmol) was added dropwise, and the resulting mixture was stirred at 0 °C for 45 minutes. The reaction was stopped with an aqueous NaHCO3 solution, extracted with DCM, and then washed with an aqueous citric acid solution and an aqueous NaHCO3 solution. The organic phase was dried over MgSO4, the solvent was distilled off, and the product was purified by flash chromatography (PE / EtOAc: 5 - 100% B) to obtain the product (3.03 g, 77%). R f : 0.62 (PE / EtOAc 1:2). 1 H NMR (600 MHz, DMSO-d6) δ 9.34 (s, 1H), 7.55 (s, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.06 (dd, J = 9.0, 2.7 Hz, 1H), 5.38 (dd, J = 7.9, 2.6 Hz, 1H), 5.35 (d, J = 3.5 Hz, 1H), 5.29 (dd, J = 10.6, 3.4 Hz, 1H), 5.23 (td, J = 10.3, 7.7 Hz, 1H), 5.10 (qd, J = 11.6, , 2.7 Hz, 2H), 4.42 (t, J = 6.5 Hz, 1H), 4.15 - 4.07 (m, 2H), 3.19 (s, 3H), 2.15 (s, 3H), 2.07 (s, 3H), 2.01 (s, 3H), 1.95 (s, 3H), 1.46 (s, 12H).<​​​​​​​​

[0116] Under an argon atmosphere, a mixture of compound 4 (1.57 g, 2.43 mmol) and 4-nitrophenol (670 mg, 4.85 mmol) was dissolved in MeCN. Cs2CO3 (1.74 g, 5.33 mmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with toluene. The organic phase was dried over MgSO4, the solvent was removed by distillation, and the mixture was purified by flash chromatography to obtain the product (1.58 g, 94%). 1 H NMR (600 MHz, CDCl3) δ 8.22 (d, J = 9.2 Hz, 2H), 7.41 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.05 - 7.02 (m, 2H), 7.00 (d, J = 8.9 Hz, 1H), 5.50 (dd, J = 10.5, 7.9 Hz, 1H), 5.47 (dd, J = 3.4, 1.1 Hz, 1H), 5.12 (dd, J = 10.5, 3.5 Hz, 1H), 5.10 (d, J = 3.3 Hz, 2H), 5.03 (d, J = 7.9 Hz, 1H), 4.22 (dd, J = 11.3, 7.0 Hz, 1H), 4.16 (t, J = 5.7 Hz, 1H), 4.09 - 4.05 (m, 1H), 2.19 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H), 1.95 (s, 3H), 1.50 (s, 9H).

[0117] Synthesis of Compound 6 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((3-hydroxypropyl)amino)-2-((4-nitrophenoxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl,6 [ka]

[0118] A solution of compound 5 (265 mg, 0.38 mmol) in DCM / TFA (1:1 v / v) (5.3 mL, 5.3 mL) was stirred at room temperature for 15 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in anhydrous MeCN (8.00 mL) under an argon atmosphere. NaI (23.5 mg, 0.16 mmol), Et3N (0.21 mL, 1.49 mmol), and 3-bromo-1-propanol (0.04 mL, 0.45 mmol) were added. The resulting mixture was heated overnight at 80°C. The reaction mixture was diluted with water and extracted with Â. The organic phase was dried over MgSO4, the solvent was removed, and the mixture was purified by flash chromatography (PE / Â: 16-100% B) to obtain the product (80.0 mg, 32%). 1 H NMR (600 MHz, CDCl3) δ 8.23 ​​- 8.19 (m, 2H), 7.07 - 7.03 (m, 2H), 6.98 (d, J = 8.8 Hz, 1H), 6.96 - 6.93 (m, 1H), 6.80 (d, J = 8.6 Hz, 1H), 5.48 (dd, J = 10.5, 7.9 Hz, 2H), 5.46 (dd, J = 3.5, 1.1 Hz, 1H), 5.14 - 5.11 (m, 1H), 5.10 (s, 2H), 4.98 (d, J = 7.9 Hz, 1H), 4.18 (ddd, J = 41.1, 11.6, 6.2 Hz, 3H), 4.05 (td, J = 6.6, 1.1 Hz, 1H), 3.81 (t, J = 5.7 Hz, 2H), 3.29 (t, J = 6.4 Hz, 2H), 2.19 (s, 3H), 2.06 (s, 4H), 2.01 (s, 3H), 1.97 (s, 3H), 1.89 (p, J = 6.1 Hz, 2H).

[0119] Synthesis of Compound 7 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((3-((methylsulfonyl)oxy)propyl)amino)-2-((4-nitrophenoxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl,7 [ka]

[0120] Under an argon atmosphere, a solution of compound 6 (80.0 mg, 0.12 mmol) in anhydrous DCM (6.00 mL) was cooled to 0°C, and Et3N (0.05 mL, 0.37 mmol) was added. MsCl (0.01 mL, 0.12 mmol) was added dropwise, and the resulting mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4, the solvent was removed by distillation, and the mixture was purified by flash chromatography (PE / Â: 16-100% B) to obtain the product (59.0 mg, 66%). 1 H NMR (600 MHz, DMSO-d6) δ 8.26 - 8.20 (m, 2H), 7.20 - 7.13 (m, 2H), 6.94 (d, J = 8.8 Hz, 1H), 6.64 (d, J = 2.8 Hz, 1H), 6.56 (dd, J = 8.9, 2.8 Hz, 1H), 5.56 (t, J = 5.8 Hz, 1H), 5.32 (dd, J = 3.5, 1.2 Hz, 1H), 5.26 (dd, J = 10.1, 3.6 Hz, 1H), 5.22 - 5.14 (m, 2H), 5.06 (q, 2H), 4.36 (ddd, J = 7.0, 5.3, 1.2 Hz, 1H), 4.28 (t, J = 6.3 Hz, 2H), 4.13 (dd, J = 11.3, 7.4 Hz, 1H), 4.06 (t, J = 5.4 Hz, 1H), 3.16 (s, 3H), 3.06 (q, J = 6.5 Hz, 2H), 2.14 (s, 3H), 2.01 (s, 3H), 1.92 (s, 3H), 1.92 (s, 3H), 1.89 (q, J = 6.6 Hz, 2H).

[0121] Example 3 The synthesis of a precursor compound by reaction scheme 5 is disclosed in Example 3.

[0122] Synthesis of compound 8 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((3-fluoropropyl)amino)-2-((4-nitrophenoxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 8 [ka]

[0123] A solution of compound 5 (140 mg, 0.20 mmol) in DCM / TFA (1:1 v / v) (2.8 mL, 2.8 mL) was stirred at room temperature for 15 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in anhydrous MeCN (5.30 mL) under an argon atmosphere. NaI (13.9 mg, 0.09 mmol), Et3N (0.12 mL, 0.88 mmol), and 3-fluoro-1-iodopropane (0.03 mL, 0.26 mmol) were added. The resulting mixture was heated overnight at 80°C. The reaction mixture was diluted with water and extracted with Â. The organic phase was dried over MgSO4, the solvent was removed, and the mixture was purified by flash chromatography (PE / Â: 16-100% B) to obtain the product (58.0 mg, 45%). 11H NMR (600 MHz, CDCl3) δ 8.21 (dt, J = 9.2, 2.1 Hz, 2H), 7.05 (dt, J = 9.3, 2.3 Hz, 2H), 6.97 (d, J = 8.7 Hz, 1H), 6.88 (s, 2H), 6.74 (s, 0H), 5.48 (dd, J = 10.5, 8.0 Hz, 2H), 5.46 (d, J = 3.5 Hz, 1H), 5.10 (s, 2H), 4.97 (d, J = 7.9 Hz, 1H), 4.55 (dt, J = 47.1, 5.5 Hz, 2H), 4.25 - 4.13 (m, 2H), 4.04 (t, J = 6.7 Hz, 1H), 3.29 (t, J = 6.9 Hz, 2H), 2.19 (s, 3H), 2.07 (s, 1H), 2.06 (s, 3H), 2.03 (s, 1H), 2.01 (s, 3H), 2.00 (s, 1H), 1.97 (s, 3H).

[0124] Synthesis of compound 9 (2S,3R,4S,5R,6R)-2-(4-((3-Fluoropropyl)amino)-2-((4-nitrophenoxy)methyl)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 9

Chemical formula

[0125] A solution of the above compound 8 (20.0 mg, 0.02 mmol) in MeOH / H2O / Et3N (10:1:1 v / v) (2.50 mL, 0.25 mL, 0.25 mL) was stirred at room temperature for 90 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by flash chromatography (DCM / MeOH: 2% - 20% B) to obtain the product (5.00 mg, 67%). 1H NMR (600 MHz, DMSO-d6) δ 8.20 (dt, J = 9.3, 2.2 Hz, 2H), 7.21 (dt, J = 9.4, 2.3 Hz, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 2.9 Hz, 1H), 6.49 (dd, J = 8.8, 2.8 Hz, 1H), 5.42 (t, J = 5.8 Hz, 1H), 5.29 (s, 2H), 5.23 (s, 1H), 4.83 (s, 1H), 4.65 (s, 1H), 4.56 - 4.52 (m, 2H), 4.49 (s, 1H), 4.47 (t, J = 5.9 Hz, 1H), 3.68 (s, 1H), 3.02 (td, J = 5.6, 1.5 Hz, 2H), 2.61 (p, J = 1.9 Hz, 1H), 1.87 (s, 2H).

[0126] Synthesis of compound 10 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((tert-butoxycarbonyl)amino)-2-((2,3,5,6-tetrafluorophenoxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 10 [ka]

[0127] Under an argon atmosphere, a mixture of compound 4 (3.00 g, 4.63 mmol) and 2,3,5,6-tetrafluorophenol (1.54 g, 9.26 mmol) was dissolved in MeCN. Cs2CO3 (3.32 g, 10.2 mmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with phenyl to obtain the product (3.20 g, 96%). f : 0.63 (PE / Depositphotos 1:1). 1H NMR (600 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.64 - 7.54 (m, 1H), 7.52 (s, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.03 (dd, J = 9.2, 2.5 Hz, 1H), 5.36 - 5.31 (m, 2H), 5.26 (dt, J = 10.5, 3.5 Hz, 1H), 5.23 (dd, J = 11.5, 2.5 Hz, 1H), 5.15 (td, 1H), 5.09 (d, J = 11.6 Hz, 1H), 4.41 (t, J = 6.4 Hz, 1H), 4.13 - 4.06 (m, 2H), 2.15 (d, J = 2.5 Hz, 3H), 2.01 (d, J = 2.5 Hz, 3H), 1.96 (d, J = 2.5 Hz, 3H), 1.94 (d, J = 2.4 Hz, 3H), 1.45 (d, J = 2.6 Hz, 9H).

[0128] Synthesis of compound 11 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((3-hydroxypropyl)amino)-2-((2,3,5,6-tetrafluorophenoxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 11 [ka]

[0129] A solution of compound 10 (3.15 g, 4.39 mmol) in DCM / TFA (1:1 v / v) (35 mL, 35 mL) was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in anhydrous MeCN (80.0 mL) under an argon atmosphere. NaI (229 mg, 1.53 mmol), Et3N (2.44 mL, 17.5 mmol), and 3-bromo-1-propanol (0.47 mL, 5.25 mmol) were added. The resulting mixture was heated overnight at 80°C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, the solvent was removed, and the mixture was purified by flash chromatography (PE / ethyl acetate: 5%~100% B) to obtain the product (244 mg, 8%). f : 0.18 (PE / Ifaldehyde 1:2). 1 H NMR (600 MHz, DMSO-d6) δ 7.59 (tt, J = 10.8, 7.2 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.98 - 6.83 (m, 2H), 5.32 (dd, J = 3.6, 1.2 Hz, 1H), 5.30 - 5.25 (m, 2H), 5.24 (d, J = 9.7 Hz, 1H), 5.15 (dd, J = 10.4, 7.9 Hz, 1H), 5.10 (d, J = 11.6 Hz, 1H), 4.38 (ddd, J = 7.0, 5.5, 1.2 Hz, 1H), 4.13 - 4.06 (m, 2H), 3.48 (t, J = 6.1 Hz, 2H), 3.11 (t, J = 7.2 Hz, 2H), 2.15 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H), 1.94 (s, 3H), 1.70 - 1.64 (m, 2H).

[0130] Synthesis of compound 12 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((3-((methylsulfonyl)oxy)propyl)amino)-2-((2,3,5,6-tetrafluorophenoxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 12 [ka]

[0131] Under an argon atmosphere, a solution of compound 11 (200 mg, 0.30 mmol) in anhydrous DCM (40.0 mL) was cooled to 0°C, and Et3N (0.12 mL, 0.89 mmol) was added. MsCl (0.02 mL, 0.30 mmol) was added dropwise, and the resulting mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4, the solvent was removed by distillation, and the mixture was purified by flash chromatography (PE / Â: 10%~100%B) to obtain the product (89.0 mg, 40%). f : 0.52 (PE / ₹1:3). 1 H NMR (600 MHz, DMSO-d6) δ 7.58 (tt, J = 10.8, 7.2 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.62 (d, J = 2.8 Hz, 1H), 6.57 (dd, J = 8.9, 2.9 Hz, 1H), 5.56 (t, J = 5.7 Hz, 1H), 5.30 (dd, J = 3.6, 1.1 Hz, 1H), 5.26 - 5.20 (m, 2H), 5.16 (d, J = 8.0 Hz, 1H), 5.12 (dd, J = 10.1, 8.0 Hz, 1H), 5.07 (d, J = 11.3 Hz, 1H), 4.34 (ddd, J = 7.0, 5.5, 1.2 Hz, 1H), 4.29 (t, J = 6.3 Hz, 2H), 4.13 - 4.05 (m, 2H), 3.16 (s, 3H), 3.06 (q, J = 6.5 Hz, 2H), 2.15 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.93 (s, 3H), 1.90 (p, J = 6.6 Hz, 2H).

[0132] Synthesis of compound 13 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4-((3-fluoropropyl)amino)-2-((2,3,5,6-tetrafluorophenoxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 13 [ka]

[0133] A solution of compound 10 (43.0 mg, 0.06 mmol) in DCM / TFA (1:1 v / v) (0.85 mL, 0.85 mL) was stirred at room temperature for 15 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in anhydrous MeCN (1.00 mL) under an argon atmosphere. NaI (4.08 mg, 0.03 mmol), Et3N (0.04 mL, 0.26 mmol), and 3-fluoro-1-iodopropane (0.01 mL, 0.08 mmol) were added. The resulting mixture was heated overnight at 80°C. The reaction mixture was diluted with water and extracted with Â. The organic phase was dried over MgSO4, the solvent was removed, and the mixture was purified by flash chromatography (PE / Â: 16%~100% B) to obtain the product (11.0 mg, 25%).

[0134] Synthesis of compound 14 (2S,3R,4S,5R,6R)-2-(4-((3-fluoropropyl)amino)-2-((2,3,5,6-tetrafluorophenoxy)methyl)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 14 [ka]

[0135] A solution of compound 13 (2.00 mg, 3.00 μmol) in MeOH / H2O / Et3N (10:1:1 v / v) (0.50 mL, 0.05 mL, 0.05 mL) was stirred at room temperature for 90 minutes. The solvent was removed under reduced pressure to obtain the product. 1H NMR (600 MHz, DMSO-d6) δ 7.57 (q, J = 8.9 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.63 (d, J = 2.9 Hz, 1H), 6.52 (dd, J = 8.8, 2.9 Hz, 1H), 5.45 (t, J = 5.9 Hz, 1H), 5.35 (d, J = 11.5 Hz, 1H), 5.29 (d, J = 11.6 Hz, 1H), 5.03 (d, J = 5.3 Hz, 1H), 4.79 (s, 1H), 4.61 (s, 1H), 4.57 (t, J = 5.9 Hz, 1H), 4.49 (t, J = 5.9 Hz, 1H), 4.44 (d, J = 7.8 Hz, 2H), 3.66 (t, J = 3.8 Hz, 2H), 3.28 (d, J = 4.8 Hz, 2H), 3.05 (q, J = 4.2, 3.2 Hz, 2H), 1.87 (dp, J = 25.8, 6.4 Hz, 2H).

[0136] Example 4 The synthesis of a precursor compound by reaction scheme 6 is disclosed in Example 4.

[0137] Synthesis of Compound 15 4-(4-hydroxyphenyl)piperazine-1-carboxylate tert-butyl, 15 [ka]

[0138] Under an argon atmosphere, a 5 mL solution of Boc2O (1.29 g, 5.9 mmol) in DCM was added dropwise to a 10 mL solution of 4-(piperazine-1-yl)phenol (1.0 g, 5.6 mmol) and Et3N (1.1 mL) in DCM. The reaction mixture was stirred overnight and slowly heated to room temperature. The reaction mixture was sequentially washed with 10% citric acid aqueous solution (3 × 20 mL), water (2 × 10 mL), and saline solution (10 mL), dried over MgSO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (10-100% ethyl acetate solution in PE) to obtain the product as a white solid (1.0 g, 64.3%). f : 0.50 (PE / Â 1:1); 1 H NMR (600 MHz, CDCl3) δ 6.94 - 6.87 (m, 2H), 6.81 - 6.76 (m, 2H), 3.64 - 3.55 (m, 4H), 3.02 (t, J = 5.1 Hz, 4H), 1.48 (s, 9H).

[0139] Synthesis of compound 16 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4(4-(tert-butoxycarbonyl)piperazine-1-yl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 16 [ka]

[0140] A solution of acetobromogalactose (3.0 g, 7.3 mmol), compound 15 (3.1 g, 10.8 mmol), and NaOH (430 mg, 10.8 mmol) in acetone / water (1:1) (48 mL) was stirred overnight at room temperature. The reaction mixture was diluted with toluene (150 mL) and washed with water (3 × 30 mL) and saline solution (30 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (PE solution of 10-80% toluene) to obtain the product as a colorless oil. f: 0.45 (PE / Ixate 1:1); MS (ESI): [M + H] + (theoretical value) = 608.2, measured value = 609.2

[0141] Synthesis of Compound 17 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4-(4-(3-hydroxypropyl)piperazine-1-yl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 17 [ka]

[0142] A solution of the above glycoside 16 (385 mg, 0.63 mmol) protected with N-Boc in TFA / DCM (1:1) (4 mL) was stirred at room temperature for 1 hour. TLC analysis confirmed that the starting material was consumed and a single polar product was formed. The solvent was removed under high pressure, and the resulting residue was dissolved in CH3CN (10 mL). To this solution, 3-bromopropan-1-ol (106 mg, 0.76 mmol), Et3N (335 μL), and a catalytic amount of NaI were added. The reaction mixture was refluxed under an argon atmosphere for 3 hours, and then the solvent was removed under reduced pressure. The resulting residue was dissolved in DCM (20 mL), washed with water (10 mL) and saline (10 mL), and dried over MgSO4. The product was purified by silica gel flash chromatography (0-10% MeOH / DCM) to obtain a colorless oil (210 mg, 58.7%). f : 0.45 (MeOH / DCM 1:9); HPLC single peak. MS (ESI): [M + H] + (Theoretical value) = 567.2, Measured value = 567.2.

[0143] Synthesis of compound 18 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4(4(3((methylsulfonyl)oxy)propyl)piperazine-1-yl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 18 [ka]

[0144] Under an argon atmosphere, a 1 mL solution of MsCl (43 μL, 0.56 mmol) in DCM was added dropwise to an ice-cold 4 mL solution of Alcohol 17 (210 mg, 0.37 mmol) and Et3N (234 μL) in DCM. After raising the reaction mixture to room temperature, 10 mL of saturated NaHCO3 aqueous solution was added. The resulting mixture was extracted with DCM (3 × 10 mL), washed with water (10 mL) and saline solution (10 mL), and dried over Na2SO4. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography (0-15% MeOH / DCM) to obtain the product as a colorless oil (200 mg, 83.8%). f : 0.5 (MeOH / DCM 1:9); HPLC single peak. MS (ESI): [M + H] + (Theoretical value) = 645.7, Measured value = 645.2.

[0145] Synthesis of compound 19 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(4-(4-(3-fluoropropyl)piperazine-1-yl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 19 [ka]

[0146] A solution of the above glycoside 16 (401 mg, 0.66 mmol) protected with N-Boc in TFA / DCM (1:1) (4 mL) was stirred at room temperature for 1 hour. TLC analysis confirmed that the starting material was consumed and a single polar product was formed. The solvent was removed under high pressure, and the resulting residue was dissolved in CH3CN (10 mL). To this solution, 3-fluoro-1-iodopropane (138 mg, 0.74 mmol) and Et3N (930 μL) were added. The reaction mixture was heated overnight at 50 °C under an argon atmosphere. The solvent was removed under reduced pressure. The resulting residue was dissolved in DCM (20 mL), washed with water (10 mL) and saline (10 mL), and dried over MgSO4. The product was purified by silica gel flash chromatography (0-10% MeOH / DCM) to obtain a colorless oil (31 mg, 8.3%). f : 0.45 (MeOH / DCM 1:9); HPLC single peak. MS (ESI): [M + H]+ (theoretical value) = 569.3, measured value = 569.3; 1 H NMR (600 MHz, DMSO) δ 7.02 - 6.97 (m, 2H), 6.97 - 6.86 (m, 2H), 5.34 - 5.26 (m, 3H), 5.18 (dd, J = 10.3, 7.9 Hz, 1H), 4.61 (t, J = 5.6 Hz, 1H), 4.53 (t, J = 5.7 Hz, 1H), 4.39 (ddd, J = 7.0, 5.6, 1.2 Hz, 1H), 4.15 - 4.06 (m, 2H), 3.73 (s, 1H), 3.62 (s, 1H), 3.19 (s, 2H), 3.12 (qd, J = 7.3, 4.6 Hz, 2H), 2.98 (d, J = 15.5 Hz, 2H), 2.15 (s, 3H), 2.05 (s, 2H), 2.02 (s, 2H), 1.95 (s, 2H), 1.20 (t, J = 7.3 Hz, 4H).

[0147] Synthesis of compound 20 (2S,3R,4S,5R,6R)-2-(4-(4-(3-fluoropropyl)piperazin-1-yl)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 20 [ka]

[0148] The protected glycoside 19 (50 mg, 0.09 mmol) was stirred in a mixed solution of Et3N / H2O / MeOH (1:1:8) at room temperature for 2 hours. The residue was purified by preparative HPLC and lyophilized to obtain a non-radioactive standard (28 mg, 78%). HPLC single peak. MS (ESI): [M + H] + (Theoretical value) = 401.2, Measured value = 401.3.

[0149] Example 5 The synthesis of precursor compounds according to reaction schemes 7 and 8 is disclosed in Example 5.

[0150] Synthesis of Compound 21 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(2-formyl-5-iodophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetic acid, 21 [ka]

[0151] Under an argon atmosphere, diisopropylethylamine (1.1 mL) was added dropwise to a CH3CN (15 mL) solution of ice-cold acetobromogalactose (1.0 g, 2.4 mmol) and 5-iodosalicyaldehyde (0.5 g, 2.0 mmol). The resulting mixture was stirred overnight while slowly raising the temperature to room temperature. After concentrating the mixture under reduced pressure, the resulting residue was diluted with alkyl hydroxide (100 mL) and washed sequentially with 5% citric acid (3 × 50 mL), water (2 × 50 mL), saturated NaHCO3 aqueous solution (2 × 50 mL), and saline solution (50 mL). The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The mixture was purified by silica gel flash chromatography (10-100% alkyl hydroxide / PE) to obtain the product as a colorless foam (1.0 g, 85.6%). 1 H NMR (600 MHz, CDCl3) δ 10.22 (s, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.56 (dd, J = 10.5, 7.9 Hz, 1H), 5.47 (dd, J = 3.4, 1.1 Hz, 1H), 5.16 - 5.09 (m, 2H), 4.25 - 4.07 (m, 3H), 2.19 (s, 3H), 2.06 (s, 3H) 2.05 (s, 3H), 2.02 (s, 3H).

[0152] Synthesis of compound 22 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(2-(hydroxymethyl)-5-iodophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetic acid, 22 [ka]

[0153] A solution of the above aldehyde 21 (0.8 g, 1.4 mmol) in DCM (18 mL) / isopropanol (6 mL) was prepared. Sodium borohydride (0.2 g, 5.3 mmol) was slowly added to this solution in small amounts. After stirring the reaction mixture at room temperature for 1 hour, 5% citric acid (10 mL) was added. The resulting mixture was extracted with DCM (3 × 20 mL), and the combined organic layers were sequentially washed with saturated NaHCO3 aqueous solution (2 × 15 mL), water (15 mL), and saline solution (10 mL). After drying over MgSO4, the mixture was concentrated under reduced pressure. The mixture was purified by silica gel flash chromatography (10-100% Â / PE) to obtain the product (430 mg, 54%). HPLC single peak. MS (ESI): [M + Na] + (Theoretical value) = 603.0, Measured value = 603.0.

[0154] Synthesis of compound 23 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(5-iodo-2-(((methylsulfonyl)oxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 23 [ka]

[0155] Under an argon atmosphere, a 10.0 mL solution of the above alcohol 22 (660 mg, 1.1 mmol) in anhydrous DCM was cooled to 0°C, and Et3N (0.5 mL) was added. A 1 mL solution of MsCl (156 mg, 1.4 mmol) in DCM was added dropwise, and the resulting mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with water and extracted with DCM (3 × 10 mL). The combined organic phase was dried over MgSO4, the solvent was removed by distillation, and the mixture was purified by flash chromatography (10-100% PE / Â) to obtain the mesylated product (540 mg, 72.6%). HPLC: Single peak. MS (ESI): [M + Na] + (Theoretical value) = 681.4, Measured value = 681.0.

[0156] Synthesis of Compound 24 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(5-iodo-2-((2,3,5,6-tetrafluorophenoxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 24 [ka]

[0157] The above mesylation intermediate 23 (202 mg, 0.3 mmol), Cs2CO3, and 2,3,5,6-tetrafluorophenol were added to CH3CN (10 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with RINKAN to obtain the product (160 mg, 71.7%). HPLC single peak. (ESI): [M + Na] + (Theoretical value) = 751.0, Measured value = 750.9.

[0158] Synthesis of Compound 25 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(2-((2,3,5,6-tetrafluorophenoxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 25 [ka]

[0159] Under an argon atmosphere, a solution of DMF (5 mL) containing the above iodide precursor 24 (160 mg, 0.2 mmol), potassium acetate (21.6 mg, 0.7 mmol), Pd(dppf)Cl2 (33 mg, 44 μmol), and B2pin2 (67 mg, 0.26 mmol) was stirred overnight at 80°C. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 × 10 mL). The combined organic layer was washed with water (10 mL) and saline solution (10 mL), and then dried over MgSO4. The product was purified by silica gel flash chromatography (10-100% PE / siRNA) to obtain a colorless oil (80 mg, 55.0%). 1 H NMR (600 MHz, CDCl3) δ 7.79 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.75 (tt, J = 9.9, 6.9 Hz, 1H), 5.49 (dd, J = 10.5, 7.9 Hz, 1H), 5.46 (d, J = 3.4 Hz, 1H), 5.37 (d, J = 11.5 Hz, 1H), 5.16 - 5.10 (m, 2H), 5.07 (d, J = 11.5 Hz, 1H), 4.22 - 4.07 (m, 4H), 2.19 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.32 (s, 12H).

[0160] Synthesis of Compound 26 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(5-fluoro-2-formylphenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetic acid, 26 [ka]

[0161] Under an argon atmosphere, diisopropylethylamine (930 μL) was added dropwise to a 10 mL solution of ice-cold acetobromogalactose (730 mg, 1.8 mmol) and 5-fluorosalicyaldehyde (820 mg, 5.8 mmol) in CH3CN (10 mL). The resulting mixture was stirred overnight while slowly increasing the temperature to room temperature. After concentrating the mixture under reduced pressure, the resulting residue was diluted with RINKAN (500 mL) and washed sequentially with 5% citric acid (3 × 25 mL), water (2 × 25 mL), saturated NaHCO3 aqueous solution (2 × 25 mL), and saline solution (25 mL). The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The resulting mixture was purified by silica gel flash chromatography to obtain the product (505 mg, 59.4%). (ESI): [M + Na] + (Theoretical value) = 493.1, Measured value = 493.1.

[0162] Synthesis of Compound 27 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(5-fluoro-2-(hydroxymethyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetic acid, 27 [ka]

[0163] Aldehyde 26 (200 mg, 430 μmol) was dissolved in a mixture of DCM (9 mL) and isopropanol (3 mL). NaBH4 (135 mg, 3.6 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 2 hours. To stop the reaction, 5% citric acid (10 mL) was added. This mixture was extracted with DCM (3 × 20 mL), and the combined organic layers were sequentially washed with saturated NaHCO3 aqueous solution (2 × 15 mL), water (15 mL), and saline solution (10 mL). The mixture was then dried over MgSO4 and concentrated under reduced pressure. The mixture was purified by silica gel flash chromatography (10-100% Â / PE) to obtain the product (110 mg, 55.0%). (ESI): [M + Na] + (Theoretical value) = 495.1, Measured value = 495.2.

[0164] Synthesis of compound 28 (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(5-fluoro-2-((2,3,5,6-tetrafluorophenoxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl, 28 [ka]

[0165] Under an argon atmosphere, a solution of alcohol 27 (200 mg, 360 μmol) in anhydrous DCM (10.0 mL) was cooled to 0°C, and Et3N (0.5 mL) was added. A solution of MsCl (100 mg, 872 μmol) in DCM (1 mL) was added dropwise, and the resulting mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with water and extracted with DCM (3 × 10 mL). The combined organic phase was dried over MgSO4, and the solvent was removed by distillation to obtain a mesylation intermediate (115 mg, 58.1%).

[0166] The above mesylation intermediate (115 mg, 209 μmol), Cs2CO3 (136 mg, 418 μmol), and 2,3,5,6-tetrafluorophenol (52.5 mg, 314 μmol) were added to CH3CN (10 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with RINKAN to obtain the product (92 mg, 41.1%). HPLC single peak. (ESI): [M + Na] + (Theoretical value) = 643.1, Measured value = 643.1.

[0167] Synthesis of compound 29 (2S,3R,4S,5R,6R)-2-(5-fluoro-2-((2,3,5,6-tetrafluorophenoxy)methyl)phenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 29 [ka]

[0168] The above acetylation intermediate 28 (65 mg) was stirred with a catalytic amount of NaOMe in MeOH (15 mL) at room temperature for 2 hours. Amberlite IR120 (1 g) was added, and the solution was filtered and concentrated under reduced pressure to obtain a non-radioactive standard (quantitative yield). HPLC: Single peak. MS (ESI): [M + H] + (Theoretical value) = 453.1, Measured value = 453.0.

[0169] Example 6 In Example 6, with reference to Figure 1, a model experiment using a non-radioactive tracer is disclosed to verify the self-destructive mechanism.

[0170] The model substrate shown on the left side of Figure 1A was incubated with β-galactosidase. The substrate was hydrolyzed by the enzyme to produce a primary metabolite, which then spontaneously decomposed to produce a quinone methide and a readily detectable colored metabolite (4-nitrophenol). More specifically, Figure 1A shows a schematic diagram of the enzymatic reaction. Figure 1B shows the HPLC of the unreacted substrate. Figure 1C shows the HPLC after incubation of the enzyme and substrate for 30 minutes, indicating that readily detectable p-nitrophenol (4NP) was obtained as a metabolite. Figure 1D shows the reference HPLC of 4NP. 4NP can be detected by measuring absorption at a wavelength of 320 nm.

[0171] Example 7 Figure 2 shows the uptake experiment in cells overexpressing β-galactosidase (BG).

[0172] In vitro experiments were performed by quantifying uptake using a gamma counter. In all experiments, 1 million cells of each cell line were treated with 20 μCi of the tracer. After incubation for 40 minutes, the cells were centrifuged, the supernatant was removed, and the cell pellet was resuspended in fresh PBS. Next, each sample was placed in a biodistribution tube and measured with a gamma counter. Each tracer was first tested using a β-galactosidase (LacZ) overexpression model of colorectal cancer cell lines (CT26-CL25) and wild-type cells (CT26) as a control (Figure 2A). Next, each tracer was tested in a senescent cell model, i.e., a hepatoma cell line (Amp19) treated with a ribosome checkpoint inhibitor (RCI) (Figures 2B and 2C).

[0173] Example 8 Example 8 shows an uptake experiment in a senescent cell model.

[0174] Referring to Figures 3A and 3B, the results of the in vitro evaluation of the novel tracer in the aging model are summarized in Table 1 below.

[0175] [Table 1]

[0176] In the in vivo experiment, aging was induced in in vivo Amp19 mouse xenografts by treatment with a ribosome checkpoint inhibitor. In the control group, mice were treated with a solvent (PBS). After induction of aging, a tracer (13 MBq) was intravenously injected, and dynamic PET and dynamic MRI scans were performed. Ex vivo tumor sections were subjected to autoradiography, X-Gal staining, and immunohistochemical analysis (H&E, p53, p21, and ki-67).

[0177] Example 9 In Example 9, [ 18Dynamic PET scans were performed on Amp19 tumor-bearing mice using F]TFPBGal (Figure 4). In CX-treated (senescent) tumors, [ 18 Dynamic uptake of [F]TFPBGal was higher at all time points compared to the untreated control. Uptake was stable in both treated and untreated tumors, reaching a maximum value and then plateauing, with no washout effect observed.

[0178] Referring to Figure 5, [ 18 Autoradiography of CX-treated (aging) Amp19 tumors and control Amp19 tumors after administration of F]PIPGal is shown. Amp19 tumor-carrying mice [ 18 Autoradiography was performed after administration of [F]PIPGal. Higher signal accumulation was observed in CX-treated (aging) tumors compared to non-aging controls.

[0179] Autoradiography of tumors (Figure 5) shows increased uptake in CX-treated (aging) tumors after PET scan compared to untreated controls.

[0180] Furthermore, the tumors were analyzed using conventional H&E staining. In addition, immunohistochemical analysis (IHC) for Ki67, activated caspase 3, p53, p21, and CD31 was performed on all samples.

[0181] According to the pathology report, the control tumors showed more necrosis, higher growth rate and apoptosis rate, fewer p21-positive and p53-positive cells, and more blood vessels compared to the aging tumors.

[0182] Ex vivo immunohistochemical analyses of CX-treated (aging) Amp19 tumors and solvent-treated (control) Amp19 tumors are shown in Figure 6 and Table 2.

[0183] [Table 2]

[0184] Furthermore, this disclosure includes examples as described in the following sections.

[0185] Section 1. Formula: GSL (In the formula, G is a glycoside, a substituted or unsubstituted C1-C5 alkyl derivative thereof, and / or a substituted or unsubstituted N-acetyl derivative thereof, having a glycosidic bond to S; * indicates the binding site between G and S; S is [ka] Selected from the group consisting of; Each A is independently selected from the group consisting of C, S, N, and O, provided that at least three carbon atoms are present; # indicates the junction site between S and L; L is [ka] #-CH2OR 2 , and #-CH2OOCNHR 2 Selected from the group consisting of; Each of E is independently selected from the group consisting of N, NH, C, CH, and CH2; B and R 1 Each of them is independent of R 3 Z, H, F, Cl, Br, I, NO2, OR 4 , NR 4 R 5 and selected from the group consisting of substituted or unsubstituted C1-C5 alkyl groups, provided that at least one R is included. 3 Z exists; R 2 This is selected from the group consisting of substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted aryls, and substituted or unsubstituted heteroaryls; R 3 Z is (CH2) m Z, [(CH2) m O(CH2) n ] oZ, [(CH2) m CO(CH2) n ] o Z, [(CH2) m OOC(CH2) n ] o Z, and [(CH2) m NR 4 (CH2) n ] o Selected from the group Z, m is between 0 and 5, and n and o are independent integers between 1 and 5; R 4 and R 5 Each of these is independently selected from the group consisting of H and substituted or unsubstituted C1-C5 alkyl groups; Z is a detectable radioactive label, a therapeutic radioactive residue, a chelating agent coordinated to a detectable radioactive label, or a chelating agent coordinated to a therapeutic radioactive residue. The compound represented by, or its stereoisomers, enantiomers, tautomers, prodrugs and / or pharmaceutically acceptable salts. Section 2. The substituted or unsubstituted C1-C5 alkyl derivative of the glycoside is a substituted or unsubstituted 5-(C1-C5 alkyl) glycoside; The substituted or unsubstituted N-acetyl derivative of the glycoside is a substituted or unsubstituted 2-(N-acetyl) glycoside, a substituted or unsubstituted 3-(N-acetyl) glycoside, or a substituted or unsubstituted poly(N-acetyl) glycoside; The glycoside is selected from the group consisting of α-D-glucofuranoside, α-D-mannofuranoside, α-D-fructofuranside, α-D-glucopyranoside, α-D-mannopyranoside, α-D-galactopyranoside, α-D-fructopyranoside, β-D-glucofuranoside, β-D-mannofuranoside, β-D-fructofuranside, β-D-glucopyranoside, β-D-mannopyranoside, β-D-galactopyranoside, and β-D-fructopyranoside; and / or R 3 Z is Z, [(CH2) m O(CH2) n ]o Z, [(CH2) m CO(CH2) n ] o Z, and NR 4 (CH2) n Selected from the group consisting of Z, R 4 However, H is either methyl or ethyl, and m, n, and o are each independent integers from 1 to 5. The compounds described in item 1.

[0186] Section 3. L is, [ka] Preferably, [ka] and; R 1 However, each operates independently, (CH2) n Z and O(CH2) n Selected from the group consisting of Z, where n is 1 to 3, and preferably # is in the meta or para position relative to *; B is independent of H, F, Cl, Br, I, NO2, OR 4 , NR 4 R 5 and selected from the group consisting of unsubstituted C1-C5 alkyl groups, provided that at least three H atoms are present; R 4 and R 5 However, each is independently selected from the group consisting of H, methyl, and ethyl. A compound described in any one of the preceding items.

[0187] Item 4.L is #-CH2OR 2 Or #-CH2OOCNHR 2 Preferably, L is in the ortho or para position relative to *; R 2 However, it is a substituted or unsubstituted C1-C8 alkyl, or a substituted or unsubstituted aryl, preferably a substituted benzyl; B, independently, R 3 Selected from the group consisting of Z, H, F, Cl, Br, I, NO2 and substituted or unsubstituted C1-C5 alkyl groups, provided that at least one R is included. 3 There exist Z and at least two H; R 3 Z is -Z, -[(CH2) m O(CH2) n ] o Z, -[(CH2) m CO(CH2) n ] o Z, and -NH(CH2) n Selected from the group consisting of Z, where m, n, and o are each independently integers from 1 to 4, preferably R 3 Z is in a para position relative to * or #; R 4 and R 5 However, each is independently selected from the group consisting of H and substituted or unsubstituted C1-C3 alkyl groups. A compound described in any one of paragraphs 1 to 3.

[0188] Section 5. The compound according to any one of the preceding sections, wherein the glycoside is a β-D-glucopyranoside.

[0189] Section 6. The compound according to any one of sections 1 to 4, wherein the glycoside is β-D-mannopyranoside.

[0190] Item 7. The compound according to any one of items 1 to 4, wherein the glycoside is β-D-galactopyranoside.

[0191] Item 8. The compound according to any one of items 1 to 4, wherein the glycoside is β-D-fructopyranoside.

[0192] Item 9. S is, [ka] The compound described in any one of the preceding items.

[0193] Item 10. L is, [ka] The compound described in any one of paragraphs 1 to 3 and paragraphs 5 to 9.

[0194] Section 11.R 1 R 3 The compound described in item 10, which is Z.

[0195] Item 12. A compound according to any one of the preceding items, wherein B is selected from the group consisting of H, F, Cl, Br, I, NO2, methyl, and ethyl.

[0196] Item 13. The compound described in item 12, wherein all but one B are H.

[0197] Item 14. The compound according to item 13, wherein one of the B is selected from the group consisting of F, Cl, Br, I, and methyl.

[0198] Item 15. The compounds described in item 12, wherein all B are H.

[0199] Section 16.R 1 (CH2) m A compound described in any one of the items 1 to 3 and 5 to 15, wherein Z is an integer between 1 and 5.

[0200] Article 17: The compound described in Article 16, wherein m is 2, 3, or 4.

[0201] Item 18: The compound described in item 16, wherein m is 3.

[0202] Section 19.R 1 (CH2) m O(CH2) n ] oA compound according to any one of the items 1 to 3 and 5 to 15, wherein Z is such that m is between 0 and 5, and n and o are each independent integers between 1 and 5.

[0203] Section 20.R 1 (CH2) m CO(CH2) n ] o A compound according to any one of the items 1 to 3 and 5 to 15, wherein Z is such that m is between 0 and 5, and n and o are each independent integers between 1 and 5.

[0204] Section 21.R 1 (CH2) m OOC(CH2) n ] o A compound according to any one of the items 1 to 3 and 5 to 15, wherein Z is such that m is between 0 and 5, and n and o are each independent integers between 1 and 5.

[0205] Section 22.R 1 (CH2) m NR 4 (CH2) n ] o Z is such that m is between 0 and 5, and n and o are independent integers between 1 and 5, and R 4 A compound according to any one of paragraphs 1 to 3 and 5 to 15, wherein the atom is H or methyl.

[0206] Article 23. A compound according to any one of articles 19 to 22, wherein m and o are each 1, and n is 1, 2, or 3.

[0207] Article 24. A compound described in any one of articles 19 to 22, wherein m, n, and o are each 1.

[0208] Item 25.B is R 3 Selected from the group consisting of Z, H, F, Cl, Br, I, NO2, methyl, and ethyl, provided that at least one R is included. 3A compound described in any one of the following items, 1, 2, and 4 through 10, in which Z is present.

[0209] Item 26. One B is R, not H. 3 The compound described in item 25, which is Z.

[0210] Section 27.R 3 The compound described in item 25 or 26, wherein Z is -Z.

[0211] Section 28.R 3 Z is NH(CH2) n The compound described in item 25 or 26, wherein Z is an integer between 1 and 4.

[0212] Item 29: The compounds described in item 28, wherein n is 2, 3, or 4.

[0213] Section 30.R 3 A compound according to any one of the following items: item 1, item 2, item 4-10, and item 25-29, wherein Z is in the para position relative to *.

[0214] Item 31. L is #-CH2OR 2 The compound described in any one of paragraphs 1, 2, 4-10, and 25-30.

[0215] Item 32. L is #-CH2OOCNHR 2 The compound described in any one of paragraphs 1, 2, 4-10, and 25-30.

[0216] Section 33.R 2 A compound according to any one of the following paragraphs, 1, 2, 4-10, and 25-32, wherein is an aryl or heteroaryl compound.

[0217] Paragraph 34. The aryl or heteroaryl is NO2 - At least one residue having an equivalent or greater -M effect, and / or I -The compound described in paragraph 33, which is substituted with at least one residue having an equivalent or greater -I effect.

[0218] Paragraph 35. The aryl is at least one NO2 - and / or F - The compound described in paragraph 33 or 34, which is substituted with.

[0219] Item 36. The compound according to any one of items 33 to 35, wherein the aryl is phenyl.

[0220] Item 37. The compound according to any one of items 33 to 36, wherein the aryl comprises one or two residues having a -M effect, and the residues are located in the ortho or para position relative to L.

[0221] 38. The compound according to any one of paragraphs 33 to 36, wherein the aryl comprises two or four residues having a -I effect, and the residues are located in the ortho or meta position relative to L.

[0222] Item 39. The compound according to any one of items 33 to 36, wherein the aryl comprises two residues having an -I effect located in the ortho position relative to L and one residue having an -M effect located in the para position relative to L.

[0223] Item 40. The compound according to any one of items 33 to 35 and 37 to 39, wherein the aryl is naphthyl.

[0224] Paragraph 41. The compound is [ka] The compound described in paragraph 1 or 2.

[0225] Section 42. A compound described in any one of the preceding sections, which is configured to accumulate in cells.

[0226] Item 43. The compound according to item 42, wherein the accumulation within the cell includes the binding of the compound.

[0227] Paragraph 44. The detectable radioactive label is 11 C, 40 K, 13 N, 15 O, 18 F, 75 Br, 76 Br, 82 Rb, 68 Ga, 64 Cu, 62 Cu, 89 Zr, 123 I, 124 I, 125 I, 131 I, 210 At, 211 At and 111 A compound selected from the group consisting of In, as described in any one of the preceding items.

[0228] Section 45. The detectable radioactive label is 11 C, 18 F, 68 Ga, 64 Cu and 124 A compound selected from the group consisting of I, as described in any one of the preceding items.

[0229] Section 46. The detectable radioactive label is 18 A compound that is F, as described in any one of the preceding items.

[0230] Section 47. The therapeutic radioactive residue is 32 P, 60 Co, 64 Cu, 89 Sr, 90 Y, 177 Lu, 186 Re and 153 A compound selected from the group consisting of Sm, as described in any one of items 1 to 39.

[0231] Section 48. The therapeutic radioactive residues 64A compound that is Cu, as described in any one of items 1 to 40.

[0232] Section 49. A compound described in any one of the preceding sections, for use in surgical procedures.

[0233] Section 50. Compounds described in any one of sections 1 to 46, for use in a method for detecting cellular senescence.

[0234] Section 51. Compounds described in any one of sections 1 to 46, for use in a method for measuring the effectiveness of cancer treatment.

[0235] Section 52. A method for detecting cellular senescence, comprising contacting cells with a compound described in any one of sections 1 to 46.

[0236] Paragraph 53. A method for measuring the effectiveness of cancer treatment, comprising contacting cells with a compound described in any one of paragraphs 1 to 46.

[0237] Paragraph 54. The method described in paragraph 52 or 53, performed in vivo.

[0238] Paragraph 55. The method described in paragraph 52 or 53, performed in vitro.

Claims

1. Formula: G-S-L (In the formula, G is a glycoside, and its substituted or unsubstituted C 1 ~C 5 Alkyl derivatives, and / or substituted or unsubstituted N-acetyl derivatives thereof, having a glycosidic bond to S; * indicates the bonding site between G and S; S is 【Chemistry 1】 Selected from the group consisting of; A is independently selected from the group consisting of C, S, N, and O, provided that at least three carbon atoms are present; # indicates the junction between S and L; L is 【Chemistry 2】 #-CH 2 Ure 2 , and #-CH 2 OOCNHR 2 Selected from the group consisting of; E is independently N, NH, C, CH, and CH 2 Selected from the group consisting of; B and R 1 are each independently, R 3 Z, H, F, Cl, Br, I, NO 2 , OR 4 , NR 4 R 5 and substituted or unsubstituted C 1 ~C 5 alkyl, provided that at least one R 3 Z is present; R 2 This is selected from the group consisting of substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted aryls, and substituted or unsubstituted heteroaryls; R 3 Z is (CH 2 ) m Z, (CH 2 ) m O(CH 2 ) n ] o Z, (CH 2 ) m CO(CH 2 ) n ] o Z, (CH 2 ) m OOC(CH 2 ) n ] o Z, and [(CH 2 ) m NR 4 (CH 2 ) n ] o Selected from the group Z, m is between 0 and 5, and n and o are independent integers between 1 and 5; R 4 and R 5 These are, independently, H and substituted or unsubstituted C. 1 ~C 5 Selected from the group consisting of alkyl groups; Z is a detectable radioactive label, a therapeutic radioactive residue, a chelating agent coordinated to a detectable radioactive label, or a chelating agent coordinated to a therapeutic radioactive residue. The compound represented by, or its stereoisomers, enantiomers, tautomers, prodrugs and / or pharmaceutically acceptable salts.

2. The substituted or unsubstituted C of the aforementioned glycoside 1 ~C 5 Alkyl derivatives are substituted or unsubstituted 5-(C 1 ~C 5 It is an alkyl glycoside; The substituted or unsubstituted N-acetyl derivative of the glycoside is a substituted or unsubstituted 2-(N-acetyl) glycoside, a substituted or unsubstituted 3-(N-acetyl) glycoside, or a substituted or unsubstituted poly(N-acetyl) glycoside; The glycoside is selected from the group consisting of α-D-glucofuranoside, α-D-mannofuranoside, α-D-fructofuranside, α-D-glucopyranoside, α-D-mannopyranoside, α-D-galactopyranoside, α-D-fructopyranoside, β-D-glucofuranoside, β-D-mannofuranoside, β-D-fructofuranside, β-D-glucopyranoside, β-D-mannopyranoside, β-D-galactopyranoside, and β-D-fructopyranoside; R 3 Z is Z, [(CH 2 ) m O(CH 2 ) n ] o Z, (CH 2 ) m CO(CH 2 ) n ] o Z, and NR 4 (CH 2 ) n Selected from the group consisting of Z, R 4 H is methyl or ethyl, and m, n and o are each independently integers from 1 to 5; and / or S 【Transformation 3】 The compound according to claim 1.

3. L, 【Chemistry 4】 Preferably, 【Transformation 5】 And; R 1 However, each is independent of the others, (CH 2 ) n Z and O(CH 2 ) n Selected from the group consisting of Z, where n is 1 to 3, and preferably, # is in the meta or para position relative to *; B is independently H, F, Cl, Br, I, NO 2 , OR 4 , NR 4 R 5 and unsubstituted C 1 ~C 5 Selected from the group consisting of alkyl groups, provided that at least three H atoms are present; R 4 and R 5 However, each is independently selected from the group consisting of H, methyl, and ethyl. The compound according to any one of the preceding claims.

4. L is #-CH 2 Ure 2 Or #-CH 2 OOCNHR 2 Preferably, L is in the ortho or para position relative to *; R 2 However, C is either substituted or non-substituted. 1 ~C 8 Alkyl, or substituted or unsubstituted aryl, preferably substituted benzyl; B, independently, R 3 Z, H, F, Cl, Br, I, NO 2 and substitution or non-substitution of C 1 ~C 5 Selected from the group consisting of alkyl groups, provided that at least one R is included. 3 There exists a Z and at least two H; R 3 Z is -Z, -[(CH 2 ) m O(CH 2 ) n o Z, -[(CH 2 ) m CO(CH 2 ) n o Z, and -NH(CH 2 ) n Z is selected from the group consisting of, m, n and o are each independently an integer from 1 to 4, preferably, R 3 Z is para to * or #;​​ R 4 and R 5 However, each is independent of H and substituted or unsubstituted C. 1 ~C 3 Selected from the group consisting of alkyl groups, The compound according to any one of claims 1 to 3.

5. The aforementioned compound, 【Transformation 6】 The compound according to claim 1.

6. A compound according to any one of the preceding claims, configured to accumulate inside a cell.

7. The detectable radioactive label is 11 C, 40 K, 13 N, 15 O, 18 F, 75 Br, 76 Br, 82 Rb, 68 Ga, 64 Cu, 62 Cu, 89 Zr, 123 I, 124 I, 125 I, 131 I, 210 At, 211 At and 111 Selected from the group consisting of In, preferably, 11 C, 18 F, 68 Ga, 64 Cu and 124 Selected from the group consisting of I, more 18 A compound according to any one of the preceding claims, wherein F.

8. The aforementioned therapeutic radioactive residue is 32 P, 60 Co, 64 Cu, 89 Sr, 90 Y, 177 Lu, 186 Re and 153 A compound according to any one of claims 1 to 6, selected from the group consisting of Sm.

9. A compound according to any one of the preceding claims, for use in surgical procedures.

10. A compound according to claims 1 to 7 for use in a method for detecting cellular senescence.

11. A compound according to any one of claims 1 to 7, for use in a method for measuring the efficiency of cancer treatment.

12. A method for detecting cellular senescence, comprising contacting cells with a compound according to any one of claims 1 to 7.

13. A method for measuring the efficiency of cancer treatment, comprising contacting cells with a compound according to any one of claims 1 to 7.

14. The method according to claim 12 or 13, performed in vivo.

15. The method according to claim 12 or 13, performed in vitro.

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