Quinoxaline derivative as well as preparation method and application thereof

Abstract

The quinoxaline derivative designed by the invention has the characteristics of high efficiency, low toxicity, prevention and treatment, stable quality, convenience in taking, effectiveness in oral injection and the like, can directly resist multi-system injury caused by radiation, effectively relieves symptoms of acute radiation sickness, and wins precious opportunity for subsequent comprehensive treatment.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a quinoxaline derivative, its preparation method and application. Background Art

[0002] In recent years, with the development of modern science and technology, the potential risk of people being damaged by radiation has increased significantly. Ionizing radiation (IR) can cause multi-system dysfunction, including the hematopoietic system, digestive system, reproductive system, etc. When the body is exposed to high-dose (>1GY) IR, symptoms such as nausea, vomiting, and dizziness will occur. Radiation mainly directly or indirectly destroys various cellular components such as DNA, proteins, and cell membrane structures in organisms, making biological macromolecules function abnormally or even fail, thereby triggering huge adverse reactions in the body. If the body cannot well cope with these changes in body functions caused by radiation, it will increase its own cancer risk, and it is very likely that the offspring will also carry related mutated genes, affecting the quality of life of the next generation. The tissue toxicity of ionizing radiation to normal human bodies also limits the further application of cancer radiotherapy.

[0003] Radiation protection drugs, namely radiation damage prevention drugs and / or radiation damage treatment drugs, can directly cope with the changes in body functions caused by radiation, reduce the impact on irradiated humans, and are beneficial to subsequent comprehensive treatment. As traditional anti-radiation drugs, free radical scavengers, superoxide dismutase and its analogs, nitrogen oxides, cytokines and other drugs generally have disadvantages such as low drug efficacy, large toxic and side effects, and high treatment costs. Therefore, it is particularly important and urgent to find anti-radiation drugs with high efficiency, low toxicity, economy and convenient use.

[0004] Ex-RAD (ON 01210.Na) is a small molecule radiation protectant developed jointly by the Armed Forces Radiobiology Research Institute of the US Army and Oncovir, Inc. of the United States. It acts on the ATM-p53 signaling pathway and is the sodium salt of trans-4-carboxystyryl-4-chlorobenzyl sulfone. Different from most radiation protectants, Ex-RAD is not a free radical scavenger and has nothing to do with cell cycle arrest. Existing experimental data show that Ex-RAD has a novel radiation protection mechanism, and its anti-radiation effect is related to the repair of DNA damage pathways. In in vivo and in vitro experimental studies, Ex-RAD has shown good anti-radiation activity. Summary of the Invention

[0005] The object of the present invention is to propose a quinoxaline derivative, or its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate compound in view of the technical defects existing in the prior art, and the formula I is as follows,

[0006]

[0007] Among them, R1 and R2 are each independently hydrogen or an electron-withdrawing group, for example, they can be halogen, cyano, -COR3, carboxyl, sulfonic acid group, nitro, halomethyl;

[0008] X is a thioether, sulfone or sulfoxide group;

[0009] R3 is hydrogen, a substituted or unsubstituted C1-C6 alkyl group, preferably a C1-C3 alkyl group; the substitution means that one or more (preferably 1, 2, 3 or 4) hydrogen atoms on the group are each independently substituted by substituents selected from the following group: halogen, -CN, hydroxyl, nitro, amino, C1-C6 alkyl, halogenated C1-C4 alkyl (such as -CF3), C3-C8 cycloalkyl or heterocycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester group.

[0010] In another alternative example, R1 and R2 are mono-substituted or multi-substituted (2, 3 or 4) on the ring (quinoline ring). Preferably, it is mono-substituted, and the substitution position is preferably the 6'-position.

[0011] In another alternative example, the quinoline N atom forms an N + -O - ionic bond.

[0012] In another preferred example, R1 is halogen or hydrogen; R2 is hydrogen, halogen, cyano or carboxyl.

[0013] In another alternative example, the substitution position of R2 is the 4'-position.

[0014] In another alternative example, the halogen is fluorine, chlorine, bromine or iodine.

[0015] The quinoxaline derivatives of the present invention optionally include any one of the following:

[0016] 6-bromo-2-[(4-methylbenzyl)thio]quinoxaline

[0017] 2-[(4-carboxybenzyl)thio]quinoxaline

[0018] 6-chloro-2-[(4-bromobenzyl)sulfonyl]quinoxaline

[0019] 6-chloro-2-[(4-carboxybenzyl)sulfonyl]quinoxaline

[0020] 2-[(4-fluorobenzyl)sulfonyl]quinoxaline

[0021] 2-[(4-bromobenzyl)sulfonyl]quinoxaline

[0022] 2-[(4-Cyanobenzyl)sulfonyl]quinoxaline

[0023] 6-Bromo-2-[(4-chlorobenzyl)sulfonyl]quinoxaline

[0024] 6-Bromo-2-[(4-bromobenzyl)sulfonyl]quinoxaline

[0025] 6-Bromo-2-[(4-methylbenzyl)sulfonyl]quinoxaline

[0026] 2-[(4-Methylbenzyl)sulfonyl]quinoxaline

[0027] 6-Chloro-2-[(4-bromobenzyl)sulfinyl]quinoxaline

[0028] 6-Chloro-2-[(4-carboxybenzyl)sulfinyl]quinoxaline

[0029] 2-[(4-Bromobenzyl)sulfinyl]quinoxaline

[0030] 6-Chloro-2-[(4-methylbenzyl)sulfinyl]quinoxaline

[0031] The present invention also provides a composition, comprising any one of the above-mentioned quinoxaline derivatives, their isomers, their pharmaceutically acceptable salts, their prodrugs, their hydrates or their solvates, and a pharmaceutical carrier or excipient.

[0032] The present invention also provides a method for preparing any one of the above-mentioned quinoxaline derivatives. The compound of formula II and the compound of formula III are added to a solvent, and then a basic catalyst is added and the reaction is carried out at room temperature. Optionally, the compound of formula I is further prepared by oxidation with an oxidizing agent.

[0033] In another preferred embodiment, the solvent is selected from dichloromethane, N,N-dimethylformamide, or a mixed solvent of dichloromethane and N,N-dimethylformamide; the basic catalyst is selected from sodium hydroxide, potassium hydroxide, ammonia, triethylamine, piperidine, dimethylaminopyridine, 2,4,5-trimethylpyridine or pyridine; the oxidizing agent is selected from hydrogen peroxide, m-chloroperbenzoic acid or sodium periodate.

[0034] Optionally, in the present invention, the preparation method of the compound of general formula I includes: adding the compound of formula II and the compound of formula III into a solvent in a molar ratio of 1:1.1, adding a basic catalyst in a molar ratio of 1:0.9 of the compound of formula II to the basic catalyst, reacting at room temperature for 1.5 h, evaporating to dryness, adding ethanol, heating under reflux, cooling and filtering, slowly adding an appropriate amount of water to the filtrate, a large amount of solid precipitates, ice bath (-10 °C to 0 °C) to obtain the compound of formula IV. The compound of formula IV is subjected to an oxidation reaction with an oxidant in a molar ratio of 1:5 or 1:2 for 1.5 h, the reaction temperature is 55 °C or room temperature, and then purified by column chromatography to obtain the compound of general formula I. The solvent is selected from dichloromethane, N,N-dimethylformamide; the basic catalyst is triethylamine; the oxidant is selected from hydrogen peroxide, m-chloroperoxybenzoic acid.

[0035]

[0036] The present invention also provides a use of a quinoxaline derivative, its isomer, its pharmaceutically acceptable salt, its prodrug, its hydrate or its solvate as described in any one of the preceding paragraphs, which is characterized in that it is used for (1) preparing anti-radiation drugs; (2) preparing P53 protein phosphorylation inhibitors.

[0037] The present invention also provides an active ingredient combination, and the active ingredient combination includes the following components:

[0038] (1) The quinoxaline derivative as described in claim 1, or its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate; and

[0039] (2) Anti-radiation drugs. For example, it can be Ex-RAD, melatonin, vitamin C, vitamin E, ginsenoside, taurine, the combination of TPO and GM-CSF, etc.

[0040] The beneficial effects of the present invention include:

[0041] The research and development of radiation prevention and treatment drugs is a worldwide problem. So far, there are still many deficiencies in the drugs for preventing and treating radiation damage developed at home and abroad in practical applications, such as unclear targets, weak drug efficacy or large side effects, etc. The present invention designs a compound with a completely new structure, which has the characteristics of high efficiency and low toxicity, both prevention and treatment, stable quality, convenient administration, and effective by oral or injection. It can directly counteract the multi-system damage caused by radiation, effectively relieve the symptoms of acute radiation sickness, and win precious time for subsequent comprehensive treatment, providing new ideas and directions for the development of highly efficient and safe radiation protection drugs. Detailed implementation mode

[0042] As used herein, the terms "comprising", "including", and "containing" are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of" and "consisting essentially of".

[0043] It should be understood that those of ordinary skill in the art can select substituents and substitution forms on the compounds of the present invention to produce chemically stable compounds, and the compounds can be synthesized by techniques known in the art and the methods described hereinafter. If substituted by more than one substituent group, it should be understood that these groups can be on the same carbon or on different carbons as long as a stable structure is produced.

[0044] As used herein, the term "substituted" or "substituent" means that a hydrogen atom on a group is replaced by a non-hydrogen atom group, provided that its valence requirements are met and a chemically stable compound is formed by the substitution, i.e., a compound that does not spontaneously undergo transformations such as cyclization, elimination, etc.

[0045] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a group combining straight-chain and branched chains. For example, C1-C4 alkyl refers to an alkyl group containing 1-4 carbon atoms, and representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0046] In the present invention, the term "halogen" refers to F, Cl, Br, or I.

[0047] In the present invention, the term "halogenated" means substituted by a halogen.

[0048] As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic (fused, bridged, or spiro) ring system group having a saturated or partially saturated ring. When a cycloalkyl is preceded by a carbon atom number limit (such as C3-C8), it means that the cycloalkyl has 3-8 ring carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3-8 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which a single ring shares a single carbon atom (called a spiro atom), and these can contain one or more double bonds, but none of the rings has a completely conjugated π electron system. "Fused cycloalkyl" refers to a fully carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, and one or more of the rings can contain one or more double bonds, but none of the rings has a completely conjugated π electron system. "Bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms, and these can contain one or more double bonds, but none of the rings has a completely conjugated π electron system.

[0049] The term "alkoxy" refers to an R-O-group, where R is an alkyl group as defined hereinabove. When a carbon atom number limitation is provided before the alkoxy group, such as C1-C6 alkoxy group, it means that the alkyl group in the said alkoxy group has 1-6 carbon atoms. Representative examples of alkoxy groups include (but are not limited to): methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or similar groups.

[0050] As used herein, the term "alkylthio" refers to an R-S-group, where R is an alkyl group as defined hereinabove. When a carbon atom number limitation is provided before the alkylthio group, such as C1-C6 alkylthio group, it means that the alkyl group in the said alkylthio group has 1-6 carbon atoms. Representative examples of alkylthio groups include (but are not limited to): methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, or similar groups.

[0051] As used herein, the term "haloalkoxy" refers to haloalkyl-O-, where the haloalkyl is as defined above. For example, halo C1-C4 alkoxy refers to a haloalkoxy containing 1-4 carbon atoms. Representative examples include but are not limited to, monofluoromethoxy, monofluoroethoxy, difluorobutoxy, or similar groups.

[0052] As used herein, the term "haloalkylthio" refers to haloalkyl-S-, where the haloalkyl is as defined above. For example, halo C1-C4 alkylthio refers to a haloalkylthio containing 1-4 carbon atoms. Representative examples include but are not limited to, monofluoromethylthio, monofluoroethylthio, difluorobutylthio, or similar groups.

[0053] The term "heterocycloalkyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, for example, 4- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic systems), in which at least one heteroatom is present in a ring containing at least one carbon atom. When the number of members of the heterocycloalkyl is limited, it refers to the number of ring atoms of the heterocycloalkyl. For example, 3- to 12-membered heterocycloalkyl refers to a heterocycloalkyl having 3 to 12 ring atoms, and each heterocyclic ring containing a heteroatom may carry one or more (such as 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, or sulfur atoms, where the nitrogen or sulfur atom may be oxidized and the nitrogen atom may also be quaternized. The heterocycloalkyl may be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule. Typical monocyclic heterocycloalkyls include but are not limited to azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidinonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholine sulfoxide, thiomorpholine sulfone, 1,3-dioxolanyl, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocycloalkyls include spiro, fused, and bridged heterocyclic groups; the spiro, fused, and bridged heterocyclic groups involved are optionally connected to other groups by a single bond, or further fused to other cycloalkyls, heterocycloalkyls, aryls, and heteroaryls through any two or more atoms on the ring.

[0054] The term "aryl" refers to a monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group of all-carbon atoms having a conjugated π-electron system, which is an aromatic cyclic hydrocarbon group. When the number of carbon atoms in the aryl is limited, such as C6-C12 aryl, it means that the aryl has 6 to 12 ring carbon atoms, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated or unsaturated rings), but does not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom of the ring having a conjugated π-electron system.

[0055] The term "heteroaryl" refers to an aromatic heterocyclic group having one or more (preferably 1, 2, 3, or 4) heteroatoms, which can be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic, or polycyclic) fused together or covalently linked, and each heterocyclic ring containing a heteroatom can carry one or more (such as 1, 2, 3, 4) heteroatoms each independently selected from the group consisting of oxygen, sulfur, and nitrogen. When the number of atoms in the heteroaryl is limited, it refers to the number of ring atoms of the heteroaryl. For example, a 5-12 membered heteroaryl refers to a heteroaryl having 5-12 ring atoms. Representative examples include, but are not limited to: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl, etc.

[0056] As used herein, the term "ester group" refers to a group having an R-CO-O- group or a -CO-O-R group, where R is an alkyl group as defined hereinabove. For example, a "C2-C4 ester group" refers to a group having a C1-C3 alkyl-CO-O- structure or a -CO-O-C1-C3 alkyl structure. Representative examples of ester groups include (but are not limited to): CH3COO-, C2H5COO-, C3H8COO-, (CH3)2CHCOO-, -COOCH3, -COOC2H5, -COOC3H8, or similar groups.

[0057] As used herein, when used alone or as part of another substituent, the term "amino" represents -NH2.

[0058] As used herein, when used alone or as part of another substituent, the term "nitro" represents -NO2.

[0059] As used herein, when used alone or as part of another substituent, the term "cyano" represents -CN

[0060] As used herein, when used alone or as part of another substituent, the term "hydroxyl" represents -OH.

[0061] Isomers or hydrates, such as optical isomers or racemic compounds; pharmaceutically acceptable salts, which may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, bromides, iodides, acetates, propionates, octanoates, acrylates, formates, isobutyrates, heptanoates, decanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, 2-butyn-1,4-dioates, 3-cyclohexyn-2,5-dioates, benzoates, chlorobenzoates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, hippurates, β-hydroxybutyrates, glycolates, maleates, tartrates, mesylates, propionates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, glutamates, argininates, lysinates, etc. of the compound of formula I, preferably hydrochlorides and phosphates.

[0062] In this specification, it should be interpreted that all substituents are unsubstituted unless explicitly described as "substituted" herein. The term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent is the substituent described correspondingly in the foregoing text or the substituent appearing in each embodiment. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position.

[0063] The present invention provides a method for (1) preparing anti-radiation drugs; (2) preparing P53 protein phosphorylation inhibitors.

[0064] In the present invention, the term "prevention" refers to a method for preventing the onset of a disease and / or its accompanying symptoms or protecting a subject from acquiring a disease. As used herein, "prevention" also includes delaying the onset of a disease and / or its accompanying symptoms and reducing the risk of the subject getting the disease.

[0065] In the present invention, the term "treatment" refers to any treatment of a disease in a mammal, including (but not limited to): (a) inhibiting the disease, i.e., slowing down or preventing the development of clinical symptoms; and / or (b) alleviating the disease, i.e., causing the regression of clinical symptoms, and / or (c) reducing or eliminating the disease and / or its accompanying symptoms.

[0066] Typically, the composition is a pharmaceutical composition, and the pharmaceutical composition includes a compound of formula I as described in the present invention, or its isomer, or its pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier.

[0067] In the composition of the present invention, the amount of the compound of formula I is a therapeutically effective amount, where "therapeutically effective amount" refers to an amount that produces a function or activity in humans and / or animals and is acceptable to humans and / or animals. Those of ordinary skill in the art should understand that the "therapeutically effective amount" may vary depending on factors such as the form of the pharmaceutical composition, the route of administration, the excipients used in the drug, the severity of the disease, and the combination with other drugs.

[0068] In the present invention, the dosage forms of the quinoxaline derivative pharmaceutical composition include (but are not limited to) oral preparations, injections, and topical preparations.

[0069] Representative ones include (but are not limited to): tablets, injections, infusions, ointments, gels, solutions, microspheres, and films.

[0070] The term "pharmaceutically acceptable carrier" refers to: one or more compatible solid, semi-solid, liquid, or gel fillers that are suitable for human or animal use and must have sufficient purity and sufficiently low toxicity. "Compatibility" means that the components in the pharmaceutical composition and the active ingredient of the drug blend with each other without significantly reducing the drug efficacy.

[0071] Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), buffers, chelating agents, thickening agents, pH regulators, transdermal penetration enhancers, coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, bacteriostatic agents, pyrogen-free water, etc.

[0072] Typically, in addition to the active pharmaceutical ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers. For example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers, and suspending agents.

[0073] The pharmaceutical preparation should match the administration route. The medicament of the present invention can also be used together with other co-therapeutic agents (including before, during or after use). When using the pharmaceutical composition or preparation, a safe and effective amount of the drug is administered to the desired subject (such as a human or non-human mammal), and the safe and effective amount is usually at least about 10 micrograms per kilogram of body weight, and in most cases does not exceed about 8 milligrams per kilogram of body weight. Preferably, the dose is about 10 micrograms per kilogram of body weight to about 1 milligram per kilogram of body weight. Of course, the specific dose should also consider factors such as the administration route and the patient's health condition, which are within the scope of the skills of a skilled physician.

[0074] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0075] Synthesis of the target compound

[0076] Synthesis of 6-bromo-2-[(4-methylbenzyl)thio]quinoxaline (comp.1)

[0077] At room temperature, 1.21 g of 6-bromoquinoxaline-2-thiol (0.005 mol) was placed in a 100 ml eggplant-shaped flask, 20 ml of CH2Cl2 and 3 ml of DMF were added. Under stirring, 0.773 g of p-methylbenzyl chloride (0.0055 mol) was added, and 0.78 ml of Et3N was slowly added dropwise. The reaction was carried out for 1.5 h. After the reaction was completed (monitored by TLC), 2 ml of water was added, and the solvent was evaporated under reduced pressure. A yellow solid was obtained. 100 ml of ethanol was added, and after heating under reflux and then cooling and filtering, an appropriate amount of water was added to the filtrate, and a large amount of solid precipitated. Ice bath (-10 °C to 0 °C) was used to obtain 1.310 g of off-white solid, with a yield of 76%. m.p. 75 - 78 °C. Structure verification: 1 H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.19 (d, J = 1.9 Hz, 1H), 7.90 (d, J = 2.5 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 7.7 Hz, 2H), 4.52 (s, 2H), 2.24 (s, 3H).

[0078] Synthesis of 2-[(4-carboxybenzyl)thio]quinoxaline (comp.2)

[0079] According to the preparation method of comp.1, 0.88 g of yellow solid was obtained from quinoxaline-2-thiol and p-carboxybenzyl chloride, with a yield of 60.5%. m.p. 216 - 220 °C. Structure verification: 11H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.82 (s, 1H), 8.01 (td, J = 7.3, 6.5, 1.5 Hz, 2H), 7.91–7.86 (m, 2H), 7.82 (ddd, J = 8.3, 7.0, 1.6 Hz, 1H), 7.76–7.71 (m, 1H), 7.65 (d, J = 8.0 Hz, 2H), 4.67 (s, 2H).

[0080] Synthesis of 6-chloro-2-[(4-bromobenzyl)sulfonyl]quinoxaline (comp. 3)

[0081] 0.633 g of 6-chloro-2-[(4-bromobenzyl)thio]quinoxaline (0.00173 mol) (the preparation method refers to comp. 1) was placed in a 150 ml eggplant-shaped flask and added to 25 ml of glacial acetic acid. Under stirring in an ice bath, 0.88 ml of 30% hydrogen peroxide (5 eq) was added. The reaction was carried out at 55 °C for 3.5 h. After the reaction was completed (monitored by TLC), it was cooled to room temperature. The solution was poured into 50 ml of ice water to obtain a large amount of solid. The solid was filtered by suction and washed with water. It was dried under vacuum to obtain 0.575 g of an off-white solid with a yield of 84%. m.p. 199 - 201 °C. Structure verification: 1 1H NMR (500 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 9.1 Hz, 1H), 8.13 (dd, J = 9.1, 2.4 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 5.03 (s, 2H).

[0082] Synthesis of 6-chloro-2-[(4-carboxybenzyl)sulfonyl]quinoxaline (comp. 4)

[0083] According to the preparation method of comp. 3, the product was prepared from 6-chloro-2-[(4-carboxybenzyl)thio]quinoxaline and 5 eq of 30% hydrogen peroxide. The product was obtained as a white solid by column chromatography, rotary evaporation under reduced pressure and drying. 0.3 g of the product was obtained with a yield of 78%. m.p. 178 - 180 °C. Structure verification: 1H NMR (500 MHz, DMSO-d6) δ 11.98 (d, J = 10.1 Hz, 1H), 9.33 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 9.1 Hz, 1H), 8.13 (dd, J = 9.0, 2.3 Hz, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 5.13 (s, 2H).

[0084] Synthesis of 2-[(4-Fluorobenzyl)sulfonyl]quinoxaline (comp.5)

[0085] According to the preparation method of comp.3, 2-[(4-Fluorobenzyl)thio]quinoxaline and 5 eq of 30% hydrogen peroxide were used to obtain 0.359 g of a white solid with a yield of 78%. m.p. 171 - 174 °C. Structure verification: 1 H NMR(500MHz,DMSO-d6)δ9.31(s,1H),8.31(ddd,J=16.3,8.0,1.9Hz,2H),8.13(dtd,J=13.1,7.0,3.5Hz,2H),7.43–7.38(m,2H),7.32(d,J=8.5Hz,2H),5.05(s,2H).

[0086] Synthesis of 2-[(4-Bromobenzyl)sulfonyl]quinoxaline (comp.6)

[0087] According to the preparation method of comp.3, 2-[(4-Chlorobenzyl)thio]quinoxaline and 5 eq of 30% hydrogen peroxide were used to obtain 0.854 g of a white solid with a yield of 82%. m.p. 180 - 183 °C. Structure verification: 1 H NMR(500MHz,DMSO-d6)δ9.32(s,1H),8.30(ddd,J=16.4,8.0,1.9Hz,2H),8.13(dtt,J=13.2,7.0,3.5Hz,2H),7.57–7.51(m,2H),7.28–7.23(m,2H),5.04(s,2H).

[0088] Synthesis of 2-[(4-Cyanobenzyl)sulfonyl]quinoxaline (comp.7)

[0089] According to the preparation method of comp.3, 2-[(4-Cyanobenzyl)thio]quinoxaline and 5 eq of 30% hydrogen peroxide were used. After drying, 0.3 g of a white solid was obtained with a yield of 82%. m.p. 229 - 232 °C. Structure verification: 1 H NMR(500MHz,DMSO-d6)δ9.35(s,1H),8.30(ddd,J=7.3,5.1,1.7Hz,2H),8.14(dtt,J=13.3,6.8,3.5Hz,2H),7.85–7.80(m,2H),7.53(d,J=8.1Hz,2H),5.19(s,2H).

[0090] Synthesis of 6-Bromo-2-[(4-chlorobenzyl)sulfonyl]quinoxaline (comp.8)

[0091] According to the preparation method of comp.3, 6-bromo-2-[(4-chlorobenzyl)thio]quinoxaline reacts with 5 eq of 30% hydrogen peroxide to obtain 0.572 g of white solid, with a yield of 67%. m.p. 200 - 202 °C, structure verification: 1 H NMR(600MHz,DMSO-d6)δ9.31(s,1H),8.60–8.56(m,1H),8.28–8.21(m,2H),7.45–7.38(m,2H),7.33–7.28(m,2H),5.04(s,2H).

[0092] Synthesis of 6-bromo-2-[(4-bromobenzyl)sulfonyl]quinoxaline (comp.9)

[0093] According to the preparation method of comp.3, it is prepared from 6-bromo-2-[(4-bromobenzyl)thio]quinoxaline and 5 eq of 30% hydrogen peroxide, dried to obtain 0.366 g of white solid, with a yield of 75%. m.p. 212 - 215 °C. Structure verification: 1 H NMR(600

[0094] MHz,DMSO-d6)δ9.32(s,1H),8.58(dd,J=1.8,0.9Hz,1H),8.25(t,J=1.3Hz,2H),7.57–

[0095] 7.51(m,2H),7.26–7.21(m,2H),5.02(s,2H).

[0096] Synthesis of 6-bromo-2-[(4-methylbenzyl)sulfonyl]quinoxaline (comp.10)

[0097] According to the preparation method of comp.3, 6-bromo-2-[(4-methylbenzyl)thio]quinoxaline and 5 eq of 30% hydrogen peroxide are used, and column chromatography gives 0.223 g of off-white solid, with a yield of 70%. m.p. 200 - 202 °C. Structure verification: 1 H NMR(600MHz,DMSO-d6)δ9.26(s,1H),8.57(d,J=2.1Hz,1H),8.27–8.21(m,2H),7.13(q,J=8.1Hz,4H),4.94(s,2H),2.26(s,3H).

[0098] Synthesis of 2-[(4-methylbenzyl)sulfonyl]quinoxaline (comp.11)

[0099] According to the preparation method of comp.3, it was prepared from 2-[(4-methylbenzyl)thio]quinoxaline and 5 eq of 30% hydrogen peroxide, followed by column chromatography, rotary evaporation under reduced pressure, and drying to obtain 0.33 g of a white solid with a yield of 84%. m.p. 172 - 175 °C. Structure verification 1 H NMR(500MHz,DMSO-d6)δ9.26(s,1H),8.38–8.18(m,2H),8.10(ddd,J=13.3,7.0,5.2Hz,2H),7.24–7.03(m,4H),4.96(s,2H),2.23(s,3H).

[0100] Synthesis of 6-chloro-2-[(4-bromobenzyl)sulfinyl]quinoxaline (comp.12)

[0101] Place 0.382 g of 6-chloro-2-[(4-bromobenzyl)thio]quinoxaline (0.001 mol) in a 250 ml eggplant-shaped flask, and add 100 ml of glacial acetic acid. Under stirring in an ice bath, slowly add 0.2 ml of 30% hydrogen peroxide (3 eq). React at room temperature for 4 h (monitored by TLC). After the reaction is completed, pour the solution into 300 ml of ice water, stir for 0.5 h, filter by suction, and wash the solid with water. Perform column chromatography, rotary evaporation under reduced pressure, and drying to obtain 0.286 g of a white solid. m.p. 167 - 169 °C, yield 75%. Structure verification: 1 H NMR(500MHz,DMSO-d6)δ8.97(s,1H),8.32(d,J=2.3Hz,1H),8.21(d,J=9.0Hz,1H),8.04(dd,J=9.0,2.4Hz,1H),7.44(d,J=8.2Hz,2H),6.99(d,J=8.2Hz,2H),4.63(d,J=13.2Hz,1H),4.39(d,J=13.2Hz,1H).

[0102] Synthesis of 6-chloro-2-[(4-carboxybenzyl)sulfinyl]quinoxaline (comp.13)

[0103] According to the preparation method of comp.12, it was prepared from 6-chloro-2-[(4-carboxybenzyl)thio]quinoxaline and 2 eq of 30% hydrogen peroxide to obtain a gray solid. After column chromatography, rotary evaporation under reduced pressure, and vacuum drying, 0.256 g of a white solid was obtained with a yield of 70%.

[0104] Synthesis of 2-[(4-bromobenzyl)sulfinyl]quinoxaline (comp.14)

[0105] Prepared according to the method of comp.12, from 2-[(4-bromobenzyl)thio]quinoxaline and 3 eq of 30% hydrogen peroxide, 0.273 g of white solid was obtained. The yield was 76%. m.p. 143-146 °C Structure verification: 1 H NMR(500MHz,DMSO-d6)δ8.97(s,1H),8.24–8.16(m,2H),8.05–7.98(m,2H),7.47–7.41(m,2H),7.01(d,J=8.3Hz,2H),4.63(d,J=13.1Hz,1H),4.40(d,J=13.1Hz,1H).

[0106] Synthesis of 6-chloro-2-[(4-methylbenzyl)sulfinyl]quinoxaline (comp.15)

[0107] Prepared according to the method of comp.12, from 6-chloro-2-[(4-methylbenzyl)thio]quinoxaline and 2 eq of 30% hydrogen peroxide, 0.223 g of white solid was obtained. The yield was 79%. m.p. 153-156 °C. Structure verification: 1 H NMR(500MHz,DMSO-d6)δ8.97(s,1H),8.32(d,J=2.3Hz,1H),8.22(d,J=9.0Hz,1H),8.04(dd,J=9.0,2.4Hz,1H),7.04(d,J=7.7Hz,2H),6.96–6.90(m,2H),4.57(d,J=13.2Hz,1H),4.34(d,J=13.2Hz,1H),2.24(s,3H).

[0108] Synthesis of 2-(3-bromobenzylthio)naphthalene

[0109] 0.97 g of 2-naphthalenethiol (6.05 mmol) and 30 mL of ethanol were added to a 100 mL pear-shaped flask. 3 mL of 3 mol / L sodium hydroxide solution was added with stirring. After the solid dissolved, 1.82 g of m-bromobenzyl bromide (7.28 mmol) was added. The reaction was heated under reflux for 3 h (monitored by TLC). After the reaction was completed, the liquid in the flask was cooled to room temperature and poured into about 200 mL of ice water. A white solid precipitated. It was filtered by suction, the filter cake was washed with water, and after drying, 1.4 g of white solid was obtained. The yield was 70%, m.p. 69-71 °C.

[0110] Synthesis of 2-(3-bromobenzylsulfonyl)naphthalene (comp.16)

[0111] 0.37 g of 2-(3-bromobenzylthio)naphthalene (1.12 mmol) and 25 mL of glacial acetic acid were added to a 100 mL pear-shaped flask. Under ice bath conditions, 1.00 mL of 30% hydrogen peroxide (8.5 eq) was added. The reaction was carried out in a water bath at 50 °C for 4 h (monitored by TLC). After the reaction was completed, the liquid in the flask was poured into about 300 mL of ice-water mixture. White solid precipitated out. It was filtered by suction, the filter cake was washed with water, and after drying, 0.25 g of white solid was obtained with a yield of 54% and m.p. 158 - 160 °C.

[0112] Synthesis of methyl 2-(4-carboxybenzylsulfinyl)acetate (3)

[0113] Under ice bath conditions and under argon protection, 1.84 g of methyl 2-(4-carboxybenzylthio)acetate (7.66 mmol) was dissolved in a mixed solvent of 80 ml of dichloromethane and 10 ml of methanol. After stirring and cooling for 10 min, 1.79 g of 85% m-CPBA (8.81 mmol) was added. The reaction was carried out under this ice bath condition for 2 h (monitored by TLC). After the reaction was completed, a large amount of white solid precipitated out. 30 ml of petroleum ether and 30 ml of ethyl acetate at 0 °C were added to the reaction solution, and more white solid precipitated out. It was filtered by suction under reduced pressure and dried to obtain 1.57 g of white solid product with a yield of 80% and m.p. 153.5 - 155 °C.

[0114] Synthesis of 4-(((7-fluoro-2-oxo-2H-chromen-3-yl)sulfinyl)methyl)benzoic acid (comp.17)

[0115] 0.1 g of methyl 2-(4-carboxybenzylsulfinyl)acetate (0.39 mmol) was dissolved in 4 ml of absolute ethanol. 0.065 g of 3-fluoro-2-hydroxybenzaldehyde (0.43 mmol) was added and stirred. The oil bath was heated to 50 °C, and the reaction solution became clear. 0.08 ml of piperidine (0.81 mmol) was added, and the oil bath was heated to 80 °C for reflux. Solid precipitated out after 50 min of reaction. The reaction was detected to be complete by TLC (dichloromethane∶methanol = 15∶1). It was naturally cooled to room temperature, and a large amount of white crystals precipitated out. It was filtered by suction under reduced pressure, washed with a small amount of absolute ethanol, and naturally dried to obtain 0.065 g of white crystals with a yield of 46%. m.p. 260 - 262 °C

[0116]

[0117] Experiment 1: Anti-radiation activity evaluation experiment

[0118] The anti-radiation activities of the target compounds in Tables 1 - 4 were evaluated. The anti-radiation activity evaluation methods were as follows: ① anti-radiation cell experiment; ② single cell gel electrophoresis (comet electrophoresis) experiment; ③ Western Blot experiment; ④ animal experiment. The experimental grouping and data calculation and analysis were all processed according to statistical methods. For the cell radiation irradiation experiment, a 4Gy X-ray (160 kV, 25 mA) irradiation device of the Institute of Radiation Medicine, Academy of Military Medical Sciences, Chinese People's Liberation Army was used; for the animal radiation irradiation experiment, an 8.5Gy 60 Coy irradiation device of the Institute of Radiation Medicine, Academy of Military Medical Sciences, Chinese People's Liberation Army was used.

[0119] ① Anti-radiation cell experiment

[0120] In this experiment, the anti-radiation activity of the compound was determined by detecting the cell viability after drug administration using the CCK-8 method through preventive drug administration.

[0121] AHH-1 cells in the logarithmic growth phase were taken, centrifuged, resuspended and counted, and the cell density was adjusted to 1×10 5 cells / mL with complete medium, and inoculated into a 96-well culture plate at 100 μL per well (10,000 cells per well). A negative group, a negative irradiation group, a positive drug (Ex-rad) group and a compound group were set on the 96-well plate, with 3 replicates in each group; other operations were the same as those in the experimental group, and they were placed in a carbon dioxide cell incubator (37 °C, 5% CO2) and cultured for 12 h.

[0122] After 12 h, the cells were stimulated with drugs. 100 μL of fresh complete medium was added to the blank group, the negative group and the negative irradiation group respectively. 100 μL of complete medium with the final concentration of the required drug concentration was added to the Ex-rad group and the compound group respectively, and they were placed in a carbon dioxide cell incubator (37 °C, 5% CO2) and cultured for 18 h;

[0123] After 18 h, the cells were irradiated with X-rays (160 kV, 25 mA), the irradiation dose was 4 Gy, and after irradiation, they were put back into the carbon dioxide incubator and cultured for another 24 h;

[0124] After 24 h, 10 μL of CCK-8 color reagent was added to each well and cultured for another 2 h. The OD value was measured at 450 nm using an enzyme-labeled instrument, and the survival rate of the cells after irradiation was calculated by substituting into the formula;

[0125] Survival rate (%) = (OD value of sample - OD value of blank) / (OD value of negative control - OD value of blank) × 100%

[0126] Since DMSO was used as the solvent when preparing the Ex-rad and test peptide stock solutions, when calculating their survival rates, the OD value of the negative control in the formula needs to be changed to the solvent control OD value to exclude the influence of DMSO on cell proliferation.

[0127] The experimental results were expressed as One-way ANOVA was performed using SPSS 13.0 software for the comparison between groups of survival rate data. P < 0.05 indicated a significant statistical difference.

[0128] Primary screening of the radioprotective activity of the target compounds

[0129] The primary screening of the target compounds at various concentrations was carried out under 4 Gy X-ray irradiation. The cell survival rates at each concentration are shown in the table.

[0130] Table 1 Cell survival after 4 Gy X-ray irradiation for the target compounds and Ex-Rad at a concentration of 5 μmol / L

[0131] Negative control group <![CDATA[39.78±1.75 # > Ex-Rad <![CDATA[53.98±5.02 * > comp.1 <![CDATA[58.80±3.66 * > comp.10 <![CDATA[54.46±5.28 * > comp.2 <![CDATA[53.98±5.02 * > comp.11 <![CDATA[68.45±2.64 *# > comp.3 <![CDATA[58.70±1.60 * > comp.12 <![CDATA[60.79±1.37 * > comp.4 <![CDATA[70.67±8.37 *# > comp.13 <![CDATA[74.39±3.43 *# > comp.5 <![CDATA[67.80±3.28 *# > comp.14 <![CDATA[62.62±3.17 * > comp.6 <![CDATA[63.43±5.37 * > comp.15 <![CDATA[74.05±3.44 *# > comp.7 <![CDATA[81.32±2.91 *# > comp.16 22.49±0.85 comp.8 <![CDATA[58.96±4.31 * > comp.17 30.27±2.59 comp.9 <![CDATA[67.89±2.33 *# >

[0132] Table 2 Cell survival after 4 Gy X-ray irradiation for some compounds and Ex-Rad at a concentration of 20 μmol / L

[0133] Negative irradiation 29.28±0.73 Ex-Rad 31.45±1.05 comp.1 30.07±0.69 comp.7 <![CDATA[48.47±2.48 *# > comp.2 31.25±1.12 comp.10 <![CDATA[48.57±0.46 *# > comp.3 <![CDATA[47.78±1.07 # > comp.13 <![CDATA[69.55±1.58 *# > comp.4 33.57±0.96 comp.17 02.89±00.28

[0134] Table 3 Cell survival after 4 Gy X-ray irradiation for some compounds and Ex-Rad at a concentration of 10 μmol / L

[0135] Group Survival rate % Group Survival rate % Negative irradiation 24.35±2.99 Ex-Rad 30.21±1.22 comp.1 25.57±3.95 comp.9 <![CDATA[44.77±5.59 *# > comp.2 30.40±1.12 comp.10 28.52±3.10 comp.3 <![CDATA[49.41±5.40 *# > comp.11 28.31±5.72 comp.4 <![CDATA[69.51±8.04 *# > comp.13 <![CDATA[77.87±18.07 *# > comp.7 <![CDATA[48.93±6.10 *# > comp.17 19.36±3.38 comp.8 32.58±4.75

[0136] Note: * P < 0.05, compared with the negative irradiation group; # P < 0.05, compared with the Ex-Rad group; n = 3; n = 3

[0137] The above test results showed that the compounds of the present invention as a whole had a significant difference compared with the negative control group. Among them, compounds 7 and 13 had the most significant activity, and their radioprotective activity was significantly stronger than that of the positive drug Ex-RAD.

[0138] 30-day survival experiment of mice: Three compounds, namely comp.4, comp.7, and comp.13, were selected for the mouse animal experiment. The irradiation model for mice was 60 Coγ rays, and the administration method was intraperitoneal injection. The effect of the compounds of the present invention on the survival of irradiated mice was investigated.

[0139] 1. Test samples

[0140] Three compounds: comp.4, comp.7, and comp.13; Positive control: Ex-Rad.

[0141] 2. Experimental animals

[0142] Adult male C57 mice, bred by SPF Biotechnology Co., Ltd. (Beijing). The body weight of the mice was 18.0 - 22.0 g. Five mice were housed in each cage, fed with mouse feed, and given free access to water. The temperature in the animal laboratory was maintained at about 25°C, the relative humidity was maintained at 40 - 70%, and the daily light exposure was 12 h.

[0143] Experimental methods

[0144] 1. Irradiation conditions: 60 Coγ rays, irradiation rate 66.71 R / min. The absorbed dose of the irradiated mice was 8.5 Gy, with a single whole-body irradiation.

[0145] 2. Grouping and dosing methods

[0146] The experiment was set up with 6 groups, 10 mice in each group, namely the radiation control group (saline containing 20% HPCD), the positive control group (Ex-Rad 250 mg / kg), compound 4 (100 mg / kg), compound 7 (250 mg / kg), and compound 13 (100 mg / kg). By intraperitoneal injection (ip), the drugs were administered once each at 24 h and 15 min before irradiation, 0.2 mL per mouse each time.

[0147] 3. Observation indicators

[0148] Survival: Calculated with the irradiation day as day 0, the survival status was recorded from day 1 to day 30 after irradiation, and the body weights of the mice were weighed before irradiation and on days 1, 4, 7, 10, 14, 18, 22, and 30 after irradiation.

[0149] The body weight data of the mice were statistically analyzed using GraphPad Prism 5 software, and the experimental results were all expressed as . One-way ANOVA was used for the comparison of differences between groups, and P < 0.05 indicated a significant statistical difference. The results are shown in the following table.

[0150] Table 4 Trends in body weight changes of mice

[0151]

[0152]

[0153] Note: *P < 0.05, compared with the radiation control group; #P < 0.05, compared with the Ex-Rad group; n = 10

[0154] Table 5 Survival rate of mice at 30 days

[0155]

[0156] The results in Table 5 show that the survival rate of the radiation control group is 0%, the survival rate of the Ex-Rad group is 20%, the survival rate of the compound 13 group is 80%, the survival rate of the compound 4 group is 50%, and the survival rate of the compound 7 group is 100%. Compared with the Ex-Rad group, each compound can significantly improve the survival rate of irradiated mice.

[0157] As can be seen from Table 4, the body weights of mice in the three compound groups were significantly higher (P < 0.05) than those of the radiation control group and the Ex-Rad group 10 days after irradiation.

[0158] Based on the data of mouse survival and body weight, it can be concluded that the four compounds have good anti-radiation activity, which is significantly better than that of Ex-Rad. Among them, the anti-radiation activity of compound comp.7 is the most prominent.

[0159] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A quinoxaline derivative, its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate, characterized in that, The formula I is as follows, wherein R1 and R2 are each independently hydrogen, halogen, cyano, -COR3, carboxyl, sulfonic acid group, nitro, halomethyl; X is a thioether, sulfone or sulfoxide group; R3 is hydrogen, substituted or unsubstituted C1-C6 alkyl, and the substitution means that one or more (preferably 1, 2, 3 or 4) hydrogen atoms on the group are each independently substituted by substituents selected from the following group: halogen, -CN, hydroxyl, nitro, amino, C1-C6 alkyl, halogenated C1-C4 alkyl (such as -CF3), C3-C8 cycloalkyl or heterocycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester group.

2. The quinoxaline derivative according to claim 1, wherein R1 and R2 are mono-substituted or multi-substituted (2, 3 or 4) on the ring.

3. The quinoxaline derivative according to claim 1, characterized in that, The N atom of quinoline forms N + -O - ionic bond.

4. The quinoxaline derivative according to claim 1, characterized in that, The halogen is fluorine, chlorine, bromine or iodine.

5. The quinoxaline derivative according to claim 1, characterized in that, including any one of the following: 6-bromo-2-[(4-methylbenzyl)thio]quinoxaline 6-bromo-2-[(4-chlorobenzyl)sulfonyl]quinoxaline 6-bromo-2-[(4-bromobenzyl)sulfonyl]quinoxaline 6-bromo-2-[(4-methylbenzyl)sulfonyl]quinoxaline 6-chloro-2-[(4-bromobenzyl)sulfonyl]quinoxaline 6-chloro-2-[(4-carboxybenzyl)sulfonyl]quinoxaline 6-chloro-2-[(4-bromobenzyl)sulfinyl]quinoxaline 6-chloro-2-[(4-carboxybenzyl)sulfinyl]quinoxaline 6-chloro-2-[(4-methylbenzyl)sulfinyl]quinoxaline 2-[(4-carboxybenzyl)thio]quinoxaline 2-[(4-fluorobenzyl)sulfonyl]quinoxaline 2-[(4-bromobenzyl)sulfonyl]quinoxaline 2-[(4-cyanobenzyl)sulfonyl]quinoxaline 2-[(4-methylbenzyl)sulfonyl]quinoxaline 2-[(4-bromobenzyl)sulfinyl]quinoxaline.

6. A composition, comprising the quinoxaline derivative according to any one of claims 1-5, its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate, and a pharmaceutical carrier or excipient.

7. A method for preparing any one of the quinoxaline derivatives according to claims 1-5, characterized in that, including adding the compound of formula II and the compound of formula III into a solvent, and then adding a basic catalyst and reacting at room temperature.

8. The method for the quinoxaline derivative according to claim 7, characterized in that the solvent is selected from dichloromethane, N,N-dimethylformamide, or a mixed solvent of dichloromethane and N,N-dimethylformamide; the basic catalyst is selected from sodium hydroxide, potassium hydroxide, ammonia water, calcium oxide, triethylamine, piperidine, dimethylaminopyridine, 2,4,5-trimethylpyridine or pyridine; the oxidant is selected from hydrogen peroxide, m-chloroperbenzoic acid or sodium periodate.

9. Use of the quinoxaline derivative, its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate according to any one of claims 1-5, characterized in that, for (1) preparing anti-radiation drugs; (2) preparing P53 protein phosphorylation inhibitors.

10. An active ingredient combination, the active ingredient combination comprising the following components: (1) the quinoxaline derivative according to claim 1, its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate; and (2) an anti-radiation drug.

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