Quinoline sulfur-containing derivative as well as preparation method and application thereof

Abstract

The quinoline sulfur-containing derivative compound with a brand new structure is designed on the basis of an ATM-P53 signal and a TLR2 pathway, 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 has a good application prospect. The precious opportunity is won for subsequent comprehensive treatment, and a new thought and direction are provided for developing efficient and safe radiation protection medicines.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a quinoline sulfur-containing derivative, a preparation method thereof and an application thereof. Background Art

[0002] In recent years, with the development of modern science and technology, the potential risk of people suffering from radiation damage has increased greatly. 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, dizziness, etc. will appear. Radiation mainly directly or indirectly destroys various cellular components such as DNA, proteins and cell membrane structures in organisms, making the functions of biological macromolecules abnormal or even ineffective, thereby triggering huge adverse reactions in the body. If the body cannot well cope with these changes in the body functions caused by radiation, it will increase its own risk of cancer, 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 body 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 US. 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 the arrest of the cell cycle. Existing experimental data show that Ex-RAD has a new type of radiation protection mechanism, and its anti-radiation effect is related to the repair of the DNA damage pathway. In in vivo and in vitro experimental studies, Ex-RAD has shown good anti-radiation activity.

[0005] Toll-Like receptors (TLRs) are important pattern recognition receptors in innate immunity and have been widely studied in recent years. Once activated by specific ligands, TLRs initiate some downstream signaling pathways, thereby participating in the regulation of cell proliferation, apoptosis, and immune responses. In vitro and in vivo studies have shown that the activation of TLRs can reduce radiation damage. More and more evidence indicates that compared with traditional radiation protection drugs, TLRs have lower side effects and higher protection efficiency, making TLRs potential candidate drugs for ionizing radiation protection. Based on the above research status, if anti-radiation molecules that act on both of these two pathways can be found, it will provide more options for anti-radiation drugs. Summary of the Invention

[0006] The object of the present invention is to propose a quinoline sulfur-containing 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. The formula I is as follows,

[0007]

[0008] wherein, 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;

[0009] X is a thioether, sulfone or sulfoxide group;

[0010] 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 a substituent 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.

[0011] 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.

[0012] In another alternative example, the quinoline N atom forms an N + -O - ionic bond.

[0013] In another preferred example, R1 is halogen or hydrogen; R2 is hydrogen, halogen, cyano or carboxyl.

[0014] In another alternative example, the substitution position of R2 is the 4'-position.

[0015] In another alternative example, the halogen is fluorine, chlorine, bromine or iodine.

[0016] The quinoline sulfur-containing derivative of the present invention optionally includes any one of the following:

[0017] 6-bromo-2-((4-bromobenzyl)thio)quinoline

[0018] 6-bromo-2-((4-bromobenzyl)sulfinyl)quinoline

[0019] 6-bromo-2-((4-bromobenzyl)sulfonyl)quinoline

[0020] 6-bromo-2-((4-fluorobenzyl)sulfinyl)quinoline

[0021] 6-bromo-2-((4-fluorobenzyl)sulfonyl)quinoline

[0022] 6-bromo-2-((4-chlorobenzyl)thio)quinoline

[0023] 6-bromo-2-((4-chlorobenzyl)sulfinyl)quinoline

[0024] 6-bromo-2-((4-chlorobenzyl)sulfonyl)quinoline

[0025] 6-fluoro-2-(4-fluorobenzyl)sulfonyl)quinoline

[0026] 6-fluoro-2-((4-carboxybenzyl)sulfinyl)quinoline

[0027] 6-fluoro-2-((4-carboxybenzyl)sulfonyl)quinoline

[0028] 6-fluoro-(2-(benzyl)sulfonyl)quinoline

[0029] 2-(4-fluorobenzyl)thioquinoline

[0030] 2-(4-fluorobenzyl)sulfinylquinoline

[0031] 6-chloro-2-((4-bromobenzyl)sulfinyl)quinoline

[0032] 6-chloro-2-((4-bromobenzyl)sulfonyl)quinoline

[0033] 6-chloro-2-(4-chlorobenzyl)sulfinyl)quinoline

[0034] 6-chloro-2-(4-chlorobenzyl)sulfonyl)quinoline

[0035] 6-chloro-2-(4-fluorobenzyl)sulfinyl)quinoline

[0036] 6-chloro-2-(4-fluorobenzyl)sulfonyl)quinoline

[0037] 6-Chloro-2-((4-sodium carboxybenzyl)thio)quinoline

[0038] 6-Fluoro-2-(benzylthio)quinoline

[0039] 6-Bromo-2-(benzyl)sulfinyl)quinoline

[0040] 6-Bromo-2-(benzyl)sulfonyl)quinoline

[0041] 6-Bromo-2-(cyanobenzyl)thio)quinoline

[0042] 6-Bromo-2-(cyanobenzyl)sulfinyl)quinoline

[0043] 2-(4-Chlorobenzyl)sulfinyl)quinoline

[0044] 2-(4-Chlorobenzyl)sulfonyl)quinoline

[0045] 2-(4-Bromobenzyl)thio)quinoline

[0046] 2-(4-Bromobenzyl)sulfinyl)quinoline

[0047] 2-(4-Bromobenzyl)sulfonyl)quinoline

[0048] The present invention also provides a composition, comprising any of the quinoline sulfur-containing derivatives described above, their isomers, their pharmaceutically acceptable salts, their prodrugs, their hydrates or their solvate compounds, and a pharmaceutical carrier or excipient.

[0049] The present invention also provides a method for preparing any of the quinoline sulfur-containing derivatives described above. 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, it is further oxidized with an oxidizing agent to obtain the compound of formula I;

[0050]

[0051] In another preferred embodiment, the compound of formula II and the compound of formula III are added to a solvent in a molar ratio of 1:1.1, and a basic catalyst is added in a molar ratio of 1:3 based on the compound of formula II, and the reaction is carried out at room temperature for 3 h. After evaporation to dryness, it is recrystallized with ethanol to obtain the compound of formula IV. Optionally, the compound of formula IV and the oxidizing agent are subjected to an oxidation reaction at a molar ratio of 1:2 for 4 h, the reaction temperature is 0-10 °C, and then it is separated and purified by column chromatography to obtain the compound of general formula I.

[0052] In another preferred example, 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, triethylamine, piperidine, dimethylaminopyridine, 2,4,5-trimethylpyridine or pyridine; the oxidant is selected from hydrogen peroxide, m-chloroperbenzoic acid or sodium periodate.

[0053] The present invention also provides a use of a quinoline sulfur-containing derivative, its isomer, its pharmaceutically acceptable salt, its prodrug, its hydrate or its solvate as described in any one of the foregoing, characterized in that it is used for (1) preparing an anti-radiation drug; (2) preparing an activator of TLR agonist and / or an inhibitor of P53 protein phosphorylation; and / or (3) preparing a drug for preventing and / or treating radiation intestinal injury.

[0054] The present invention also provides an active ingredient combination, which includes the following components:

[0055] (1) The quinoline sulfur-containing derivative as described in claim 1, or its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate; and

[0056] (2) An anti-radiation drug. For example, it can be Ex-RAD, melatonin, vitamin C, vitamin E, ginsenoside, taurine, the combination of TPO and GM-CSF, etc.

[0057] The beneficial effects of the present invention include:

[0058] 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 effects or large side effects. Based on the ATM-P53 signal and TLR2 pathway, the present invention designs a compound with a brand-new structure, which has the characteristics of high efficiency and low toxicity, both prevention and treatment, stable quality, convenient administration, and effectiveness by oral or injection. It can directly counteract the multi-system damage caused by radiation, effectively relieve the symptoms of acute radiation sickness, win precious time for subsequent comprehensive treatment, and provide new ideas and directions for the research and development of highly efficient and safe radiation protection drugs. Description of the Drawings

[0059] Figure 1 It is the survival situation of mice 30 days after irradiation;

[0060] Figure 2 It is the body weight change of mice 30 days after irradiation;

[0061] Figure 3 It is the spleen index of different treatment groups;

[0062] Figure 4Are pathological sections of different treatment groups;

[0063] Figure 5 Are detection diagrams of radiation protection factors in the TLR 2 signaling pathway (**P<0.01,***P<0.001, compared with the solvent group);

[0064] Figure 6 Are detection diagrams of γ-H2AX foci of DBS damage in vitro cells. Detailed implementation manners

[0065] 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 said terms include "consisting of" and "consisting essentially of".

[0066] 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 said compounds can be synthesized by techniques known in the art and the methods described below. If substituted by more than one substituent group, it should be understood that these multiple groups can be on the same carbon or on different carbons as long as a stable structure is produced.

[0067] As used herein, the term "substituted" or "substitution" 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, that is, a compound that does not spontaneously undergo transformations such as cyclization and elimination.

[0068] 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.

[0069] In the present invention, the term "halogen" refers to F, Cl, Br, or I.

[0070] In the present invention, the term "halogenated" means substituted by a halogen.

[0071] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system group. When a cycloalkyl is preceded by a carbon atom number limitation (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 carbon atom (called a spiro atom) is shared between monocyclic rings, which may 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, where one or more rings may 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, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system.

[0072] The term "alkoxy" refers to an R-O-group, where R is an alkyl group as defined hereinabove. When an alkoxy is preceded by a carbon atom number limitation, such as C1-C6 alkoxy, it means that the alkyl group in the alkoxy has 1-6 carbon atoms. Representative examples of alkoxy include (but are not limited to): methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or similar groups.

[0073] As used herein, the term "alkylthio" refers to an R-S-group, where R is an alkyl group as defined hereinabove. When an alkylthio is preceded by a carbon atom number limitation, such as C1-C6 alkylthio, it means that the alkyl group in the alkylthio has 1-6 carbon atoms. Representative examples of alkylthio include (but are not limited to): methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, or similar groups.

[0074] 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, and representative examples include but are not limited to, monofluoromethoxy, monofluoroethoxy, difluorobutoxy, or similar groups.

[0075] 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, and representative examples include but are not limited to, monofluoromethylthio, monofluoroethylthio, difluorobutylthio, or similar groups.

[0076] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated or partially unsaturated (including but not limited to, for example, a 4- to 7-membered monocyclic ring, a 7- to 11-membered bicyclic ring, or an 8- to 16-membered tricyclic system), in which at least one heteroatom is present in a ring containing at least one carbon atom. When the heterocycloalkyl is preceded by a limitation on the number of members, 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 atoms, oxygen atoms, or sulfur atoms, where the nitrogen atom 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 a ring or ring system. 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 attached 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.

[0077] 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 aryl is preceded by a limitation on the number of carbon atoms, 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 cannot 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.

[0078] 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 bear one or more (such as 1, 2, 3, 4) heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen. When there is a limitation on the number of atoms in the heteroaryl, 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.

[0079] 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 the ester group include (but are not limited to): CH3COO-, C2H5COO-, C3H8COO-, (CH3)2CHCOO-, -COOCH3, -COOC2H5, -COOC3H8, or similar groups.

[0080] As used herein, the term "amino", when used alone or as part of another substituent, represents -NH2.

[0081] As used herein, the term "nitro", when used alone or as part of another substituent, represents -NO2.

[0082] As used herein, the term "cyano", when used alone or as part of another substituent, represents -CN.

[0083] As used herein, the term "hydroxyl", when used alone or as part of another substituent, represents -OH.

[0084] 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, acrylamides, formates, isobutyrates, heptanoates, decanoates, propiolates, oxalates, malonates, succinates, octanedioates, decanedioates, 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, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, glutamates, argininates, lysinates, etc., preferably hydrochlorides and phosphates.

[0085] In this specification, it should be construed that all substituents are unsubstituted unless explicitly described as "substituted" herein. The term "substituted" means that one or more hydrogen atoms on a particular group are replaced by a particular substituent. The particular substituent is the substituent described correspondingly in the foregoing or the substituent appearing in each embodiment. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a particular group at any substitutable site of the group, and the substituents may be the same or different at each position.

[0086] The present invention provides a method for (1) preparing anti-radiation drugs; (2) preparing TLR agonists and / or P53 protein phosphorylation inhibitors; and / or (3) preparing drugs for preventing and / or treating intestinal injury in irradiated mice.

[0087] In the present invention, the term "prevention" refers to a method of preventing the onset of a disease and / or its attendant symptoms or protecting a subject from acquiring a disease. As used herein, "prevention" also includes delaying the onset of a disease and / or its attendant symptoms and reducing the risk of the subject contracting the disease.

[0088] 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 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 attendant symptoms.

[0089] Typically, the composition is a pharmaceutical composition, which 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.

[0090] In the composition of the present invention, the amount of the compound of Formula I is a therapeutically effective amount, wherein "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 co-administration with other drugs.

[0091] In the present invention, the dosage forms of the quinoline sulfur-containing derivative pharmaceutical composition include (but are not limited to) oral preparations, injections, and topical preparations.

[0092] Representative ones include (but are not limited to): tablets, injections, infusions, ointments, gels, solutions, microspheres, and films.

[0093] 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, the active ingredient of the drug, and their admixtures do not significantly reduce the drug efficacy.

[0094] Some examples of pharmaceutically acceptable carriers are 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), buffering agents, chelating agents, thickening agents, pH regulators, transdermal enhancers, coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, bacteriostatic agents, pyrogen-free water, etc.

[0095] Typically, in addition to the active pharmaceutical ingredient, the liquid dosage form 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, etc. In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers, and suspending agents.

[0096] 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 a 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 - 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 status, which are within the scope of the skills of a skilled physician.

[0097] 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 stated, percentages and parts are calculated by weight.

[0098] Part I: Preparation of quinoline thioether compounds

[0099] Synthesis of 6-bromoquinoline-1-oxide (a1)

[0100] Dissolve 1.5 g of 6-bromoquinoline in 14.4 mL of dichloromethane, add 2.92 g (14.4 mmol, 2 eq) of (85%) m-chloroperbenzoic acid at 0 °C, and react at room temperature for 12 hours. Dilute the reaction mixture with dichloromethane and wash it three times with 15 mL of potassium hydroxide. The organic layer is dried with anhydrous sodium sulfate for 3 hours, and the solvent is removed under reduced pressure to obtain 1.42 g of a light yellow solid, with a yield of 87.93%.

[0101] Synthesis of 6-fluoroquinoline-1-oxide (a2)

[0102] According to the preparation method of a1, 0.85 g of a light yellow solid was obtained from 6-fluoroquinoline and m-chloroperbenzoic acid, with a yield of 72.56%.

[0103] Synthesis of 6-chloroquinoline-1-oxide (a3)

[0104] According to the preparation method of a1, 1.02 g of a light yellow solid was obtained from 6-chloroquinoline and m-chloroperbenzoic acid, with a yield of 79.47%.

[0105] Synthesis of quinoline-1-oxide (a4)

[0106] According to the preparation method of a1, 0.87 g of a light yellow solid was obtained from quinoline and m-chloroperbenzoic acid, with a yield of 83.56%.

[0107] Synthesis of 2-chloro-6-bromoquinoline (b1)

[0108] Dissolve 1.42 g (6.3 mmol) of 6-bromo-1-oxide quinoline in 63 mL of dichloromethane solution. Under the protection of argon at 0 °C, add 1.17 g (7.6 mmol, 1.2 eq) of phosphorus oxychloride to the solution, and then continue to dropwise add 0.244 mL of N,N-dimethylformamide to the reaction solution. Heat the reaction mixture to 25 °C and stir for 12 hours. Slowly add saturated aqueous sodium carbonate solution to the reaction mixture to adjust the pH value to 7 - 8. Wash the organic phase three times with saturated brine, then dry it with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain 0.68 g of a white fluffy solid with a yield of 54.08%. mp 151.4 - 153.1 °C.

[0109] Synthesis of 2-chloro-6-fluoroquinoline (b2)

[0110] According to the preparation method of b1, 0.69 g of a white solid was obtained from a2 and phosphorus oxychloride with a yield of 59.45%.

[0111] Synthesis of 2-chloro-6-chloroquinoline (b3)

[0112] According to the preparation method of b1, 0.62 g of a white solid was obtained from a3 and phosphorus oxychloride with a yield of 50.45%.

[0113] Synthesis of 2-chloroquinoline (b4)

[0114] According to the preparation method of b1, 0.60 g of a white solid was obtained from a4 and phosphorus oxychloride with a yield of 58.77%.

[0115] Example 1: Synthesis of 6-bromoquinoline-2-thiol (c1)

[0116] Put 0.68 g (2.8 mmol) of 2-chloro-6-bromoquinoline and 0.21 g (2.8 mmol) of thiourea into a 150 mL eggplant-shaped flask, add 19.4 mL of ethanol and 18.0 mL of sodium hydroxide solution (0.625 mol / L). After stirring until completely dissolved, react at 100 °C for 2 h until the reaction is complete to obtain a yellow clear solution. Wash it 3 times with 30 mL of dichloromethane, adjust the pH of the aqueous phase to 3 - 4 with 3N hydrochloric acid, and precipitate a yellow solid. Filter it under reduced pressure to obtain 570 mg of a yellow solid with a yield of 85.18%. mp 225.6 - 227.0 °C; 1 H NMR (600 MHz, DMSO-d6) δ 11.86 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.64 (dd, J = 8.7, 2.3 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 6.55 (dd, J = 9.6, 1.5 Hz, 1H).

[0117] Example 2: Synthesis of 6-Fluoroquinoline-2-thiol (c2)

[0118] According to the preparation method of c1, 2-Chloro-6-fluoroquinoline and thiourea were used to prepare 375 mg of yellow solid, with a yield of 74.78%. mp 215.6 - 217.8 °C. 1 H NMR (600 MHz, DMSO-d6) δ 13.77 (s, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.66 (td, J = 9.0, 3.8 Hz, 2H), 7.55 (td, J = 8.9, 2.9 Hz, 1H), 7.30 (dd, J = 9.2, 1.7 Hz, 1H).

[0119] Example 3: Synthesis of 6-Chloroquinoline-2-thiol (c3)

[0120] According to the preparation method of c1, 2,6-Dichloroquinoline and thiourea were used to prepare 443.63 mg of yellow solid, with a yield of 80.00%. mp 218.5 - 219.7 °C. 1H NMR (600 MHz, DMSO-d6) δ 13.78 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.66 (dd, J = 8.8, 2.3 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.31 (dd, J = 9.1, 1.6 Hz, 1H).

[0121] Example 4: Synthesis of Quinoline-2-thiol (c4)

[0122] According to the preparation method of c1, 2-Chloroquinoline and thiourea were used to prepare 309 mg of yellow solid, with a yield of 68.61%. mp 214.5 - 216.7 °C, 1H NMR (600 MHz, DMSO-d6) δ 13.68 (s, 1H, -SH), 7.84 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.66–7.60 (m, 2H), 7.35 (ddd, J = 8.1, 5.6, 2.6 Hz, 1H), 7.26 (dd, J = 9.0, 1.8 Hz, 1H)

[0123] Example 5: Synthesis of 6-Bromo-2-((4-bromobenzyl)thio)quinoline (Comp#1)

[0124] At room temperature, 2 g (8.33 mmol) of c1 was placed in a 250 mL single-necked flask, 100 mL of ethanol and 10 mL of sodium hydroxide solution (3 mol / L) were added. Under stirring, 1.32 g (6.42 mmol) of 4-bromobenzyl chloride was added, and the mixture was heated under reflux for 3 h. It was poured into 500 mL of ice water, and a large amount of light yellow solid was precipitated. It was filtered under reduced pressure and air-dried naturally to obtain 2.52 g of white crystals, with a yield of 74.2%. mp 113 - 115 °C. 1 H NMR (600 MHz, DMSO-d6) δ 8.20 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.90–7.82 (m, 2H), 7.51–7.47 (m, 3H), 7.47–7.42 (m, 1H), 4.54 (s, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 159.45, 146.57, 138.32, 135.79, 133.50, 131.81, 131.68, 130.49, 130.01, 127.61, 122.04, 120.56, 118.60, 32.68. HRMS (ESI) m / z calculated for C 16 H 11 Br2N2[M + H] + : 409.9058, found: 409.9029.

[0125] Example 6: Synthesis of 6-bromo-2-((4-chlorobenzyl)thio)quinoline (Comp#6)

[0126] According to the preparation method of Comp#1, 2.30 g of white flocculent solid was obtained from c1 and 4-chlorobenzyl chloride, with a yield of 75.9%. mp 110 - 112 °C. 1 H NMR (600 MHz, DMSO-d6) δ 8.17–8.13 (m, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.94 (dt, J = 8.9, 0.6 Hz, 1H), 7.74 (dd, J = 9.0, 2.5 Hz, 1H), 7.52–7.46 (m, 4H), 7.44 (d, J = 8.7 Hz, 1H), 4.55 (s, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 159.46, 146.57, 137.88, 135.78, 133.48, 132.06, 131.44, 130.48, 130.00, 128.76, 127.61, 122.04, 118.59, 32.63. HRMS (ESI) m / z calculated for C16 H 11 BrClNS[M+H] + : 365.9543, found: 365.9533.

[0127] Example 7: Synthesis of 2-((4-fluorobenzyl)thio)quinoline (Comp#13)

[0128] According to the preparation method of Comp#1, 1.89 g of white crystals were obtained from c4 and 4-fluorobenzyl chloride, with a yield of 84.5%. mp 112 - 113 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.00–7.95 (m, 1H), 7.89 (dd, J = 8.6, 0.8 Hz, 1H), 7.72 (dd, J = 8.0, 1.5 Hz, 1H), 7.67 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.49–7.41 (m, 3H), 7.18 (d, J = 8.6 Hz, 1H), 7.00–6.93 (m, 2H), 4.59 (s, 2H). 13 C NMR (126 MHz, Chloroform-d) δ 162.94, 160.99, 158.50, 148.26, 135.55, 130.81, 129.79, 128.01, 127.73, 126.16, 125.41, 120.78, 115.40, 33.13. HRMS (ESI) m / z calculated for C 16 H 12 FNS[M+H] + : 270.0753, found: 270.0747.

[0129] Example 8: Synthesis of 6-chloro-2-((4-carboxybenzyl)thio)(Comp#21)quinoline

[0130] According to the preparation method of Comp#1, 2.08 g of white crystals were obtained from c3 and 4-carboxybenzyl chloride, with a yield of 75.7%. mp 122 - 124 °C. 1 H NMR (600 MHz, DMSO-d6) δ 8.18–8.13 (m, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.80–7.76 (m, 2H), 7.74 (dd, J = 8.9, 2.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.40–7.35 (m, 2H), 4.56 (s, 2H). 1313C NMR(151MHz, DMSO-d6) δ 167.51, 159.24, 146.36, 144.00, 135.93, 130.96, 130.20, 129.92, 129.87, 129.84, 129.76, 127.25, 127.07, 122.06, 33.07.

[0131] Example 9: Synthesis of 6-Fluoro-2-(benzyl)thioquinoline (Comp#22)

[0132] According to the preparation method of Comp#1, 1.34 g of white crystals were obtained from c2 and benzyl chloride, with a yield of 60.5%. mp 117 - 119 °C. 1 1H NMR(600MHz, DMSO-d6) δ 8.18–8.14(m, 1H), 8.00(dd, J = 9.2, 5.3Hz, 1H), 7.73(dd, J = 9.3, 2.8Hz, 1H), 7.64(td, J = 8.9, 2.9Hz, 1H), 7.50(d, J = 6.8Hz, 2H), 7.45–7.40(m, 1H), 7.33–7.29(m, 2H), 7.23(t, J = 7.4Hz, 1H), 4.58(s, 2H). 13 13C NMR(126MHz, Chloroform-d) δ 160.73, 158.77, 158.18, 145.33, 138.25, 134.82, 130.29, 129.18, 128.53, 127.16, 121.57, 119.55, 111.06, 33.99. HRMS(ESI) m / z calculated for C 16 H 12 FNS[M + H] + : 270.0753, found: 270.0747.

[0133] Example 10: Synthesis of 6-Bromo-2-((4-cyanobenzyl)thio)quinoline (Comp#25)

[0134] According to the preparation method of Comp#1, 2.37 g of white flaky crystals were obtained from c1 and 4-cyanobenzyl chloride, with a yield of 80.5%. mp 121 - 124 °C. 11H NMR (600 MHz, Chloroform-d) δ 7.88 (d, J = 2.2 Hz, 1H), 7.83 (t, J = 8.4 Hz, 2H), 7.74 (dd, J = 8.9, 2.2 Hz, 1H), 7.65–7.62 (m, 1H), 7.59 (s, 1H), 7.58 (s, 1H), 7.53–7.47 (m, 1H), 7.21 (d, J = 8.6 Hz, 1H), 4.62 (s, 2H). 13 13C NMR (126 MHz, Chloroform-d) δ 158.23, 146.64, 144.27, 134.74, 133.29, 132.61, 132.24, 129.88, 129.79, 129.73, 129.50, 127.30, 121.51, 119.14, 118.82, 110.90, 33.37. HRMS (ESI) m / z calculated for C 17 H 11 BrNS [M+H] + : 356.9885, found: 356.9882.

[0135] Example 11: Synthesis of 2-((4-bromobenzyl)thio)quinoline (Comp#29)

[0136] According to the preparation method of Comp#1, 2.45 g of white crystals were obtained from c4 and 4-bromobenzyl chloride, with a yield of 89.3%. mp 107 - 109 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 7.96 (dd, J = 8.5, 1.1 Hz, 1H), 7.85 (dd, J = 8.6, 0.8 Hz, 1H), 7.69 (dd, J = 8.1, 1.5 Hz, 1H), 7.65 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 7.44–7.33 (m, 5H), 7.16 (d, J = 8.6 Hz, 1H), 4.54 (s, 2H). 13 13C NMR (126 MHz, Chloroform-d) δ 162.92, 160.97, 158.49, 148.25, 135.54, 130.73, 129.77, 128.00, 127.71, 126.15, 125.40, 120.77, 115.38, 33.12. HRMS (ESI) m / z calculated for C 16 H 12 BrNS [M+H] + : 331.9932, found: 331.9926.

[0137] Example 12: Synthesis of 6-Bromo-2-((4-fluorobenzyl)thio)quinoline

[0138] According to the preparation method of Comp#1, 2.09 g of white solid was obtained from c1 and 4-fluorobenzyl chloride, with a yield of 72.3%. mp 110.08 - 111.9 °C; 1 H NMR(600MHz,DMSO-d6)δ8.20(d,J=2.2Hz,1H),8.17–8.13(m,1H),7.88(d,J=8.9Hz,1H),7.85(dd,J=8.9,2.3Hz,1H),7.57–7.51(m,2H),7.44(d,J=8.7Hz,1H),7.16–7.09(m,2H),4.56(s,2H). 13 C NMR(151MHz,DMSO-d6)δ162.50,160.88,159.65,146.59,135.76,134.89,133.48,131.50,130.49,130.02,127.61,122.06,118.56,115.66,115.52,32.59.HRMS(ESI)m / z calculated for C 16 H 11 BrFNS[M+H] + :349.9838,found:349.9832。

[0139] Example 13: Synthesis of 6-Fluoro-2-((4-fluorobenzyl)thio)quinoline

[0140] According to the preparation method of Compd#1, 1.57 g of white crystal was obtained from c2 and 4-fluorobenzyl chloride, with a yield of 65.4%. mp 115 - 117 °C. 1 H NMR(600MHz,Chloroform-d)δ7.86(dd,J=9.2,5.3Hz,1H),7.71(d,J=8.7Hz,1H),7.38–7.29(m,3H),7.23(dd,J=8.8,2.9Hz,1H),7.09(dd,J=8.6,0.9Hz,1H),6.91–6.84(m,2H),4.46(s,2H). 1313C NMR(151MHz,DMSO-d6)δ162.48,160.87,160.32,158.70,158.15,145.14,136.13,134.97,131.50,130.41,126.80,121.90,120.18,115.47,111.75,32.56.HRMS(ESI)m / z calculated for C 16 H 11 F2NS[M+H] + :288.0659,found:288.0653.

[0141] Example 14: Synthesis of 6-chloro-2-((4-bromobenzyl)thio)quinoline

[0142] According to the preparation method of Compd#1, 2.40 g of white crystals were obtained from c3 and 4-bromobenzyl chloride, with a yield of 79.2%. mp 114 - 116 °C. 1 1H NMR(600MHz,DMSO-d6)δ8.20(d,J = 2.2Hz,1H),8.18–8.13(m,1H),7.90–7.82(m,2H),7.56–7.51(m,2H),7.44(d,J = 8.7Hz,1H),7.39–7.33(m,2H),4.56(s,2H). 13 13C NMR(126MHz,Chloroform-d)δ158.81,146.55,137.43,134.55,131.57,130.92,130.90,130.54,129.49,126.69,126.44,121.59,121.04,33.26.HRMS(ESI)m / z calculated forC 16 H 11 ClBrNS[M+H] + :365.9543,found:365.9534.

[0143] Example 15: Synthesis of 6-chloro-2-((4-chlorobenzyl)thio)quinoline

[0144] According to the preparation method of Compd#1, 2.05 g of white crystals were obtained from c3 and p-chlorobenzyl chloride, with a yield of 77.4%. mp 118 - 120 °C. 11H NMR (600 MHz, Chloroform-d) δ 7.90 (d, J = 8.9 Hz, 1H), 7.80 (dd, J = 8.8, 0.8 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 8.9, 2.4 Hz, 1H), 7.44–7.39 (m, 2H), 7.26 (s, 1H), 7.25 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 4.55 (s, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 158.83, 146.53, 136.84, 134.58, 132.90, 130.93, 130.55, 130.49, 129.44, 128.59, 126.69, 126.42, 121.62, 33.19. HRMS (ESI) m / z calculated for C 16 H 11 Cl2NS [M+H] + : 320.0068, found: 320.0062.

[0145] Example 16: Synthesis of 6-Chloro-2-((4-fluorobenzyl)thio)quinoline

[0146] According to the preparation method of Compd#1, 1.81 g of white crystals were obtained from c3 and 4-fluorobenzyl chloride, with a yield of 71.5%. mp 115 - 117 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 7.90 (dt, J = 8.9, 0.6 Hz, 1H), 7.80 (dt, J = 8.6, 0.6 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 8.9, 2.4 Hz, 1H), 7.47–7.41 (m, 2H), 7.20 (d, J = 8.6 Hz, 1H), 7.01–6.94 (m, 2H), 4.56 (s, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 162.50, 160.88, 159.52, 146.40, 135.84, 134.88, 131.55, 130.91, 130.15, 129.88, 127.24, 127.04, 122.09, 115.65, 115.51, 32.59. HRMS (ESI) m / z calculated for C 16 H 11 ClFNS [M+H] +: 304.0337, found: 304.0358.

[0147] Example 17: Synthesis of 6-Bromo-2-(benzylthio)quinoline

[0148] According to the preparation method of Compd#1, 2.11 g of white crystals were obtained from c1 and benzyl chloride, with a yield of 76.7%. mp 112 - 113 °C. 1 H NMR (600 MHz, Chloroform-d) δ 7.89–7.84 (m, 2H), 7.78 (d, J = 8.7 Hz, 1H), 7.72 (dd, J = 8.9, 2.2 Hz, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.25 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 4.60 (s, 2H). 13 C NMR (126 MHz, Chloroform-d) δ 159.57, 146.81, 138.09, 134.34, 133.03, 129.71, 129.19, 128.55, 127.21, 121.60, 118.79, 34.02. HRMS (ESI) m / z calculated for C 16 H 12 BrNS [M + H] + : 331.9932, found: 331.9928.

[0149] Example 18: Synthesis of 2-((4-chlorobenzyl)thio)quinoline

[0150] According to the preparation method of Compd#1, 1.94 g of white crystals were obtained from c4 and 4-chlorobenzyl chloride, with a yield of 81.7%. mp 108 - 110 °C. 1 H NMR (600 MHz, DMSO-d6) δ 8.18 (d, J = 8.6 Hz, 1H), 7.97–7.93 (m, 1H), 7.91 (dd, J = 8.1, 1.5 Hz, 1H), 7.74 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.57–7.49 (m, 3H), 7.43–7.31 (m, 3H), 4.58 (s, 2H). 1313C NMR (126 MHz, Chloroform-d) δ 158.28, 148.23, 137.22, 135.59, 132.82, 130.57, 129.80, 128.59, 127.99, 127.72, 126.16, 125.44, 120.75, 33.16. HRMS (ESI) m / z calculated for C 16 H 12 ClNS [M+H] + : 286.0458, found: 286.0453.

[0151] Part II: Synthesis of Quinoline (Sub) Sulfoxide Compounds

[0152] Example 1: Synthesis of 6-Bromo-2-((4-bromobenzyl)sulfinyl)quinoline (Comp#2)

[0153] A white solid was prepared from 6-bromo-2-((4-bromobenzyl)thio)quinoline and H2O2 according to the method of Comp#5, with a yield of 65.4% and a melting range of 144.0 - 146.2 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 8.58–8.50 (m, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.08–7.99 (m, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.43–7.38 (m, 2H), 6.93–6.88 (m, 2H), 4.53 (d, J = 13.2 Hz, 1H), 4.25 (d, J = 13.2 Hz, 1H). 13 13C NMR (126 MHz, Chloroform-d) δ 164.29, 145.80, 137.04, 134.49, 131.89, 131.51, 130.75, 130.23, 129.17, 128.10, 122.69, 122.16, 117.22, 59.40. HRMS (ESI) m / z calculated for C 16 H 11 Br2NOS [M+H] + : 425.8987, found: 425.8980.

[0154] Example 2: Synthesis of 6-Bromo-2-((4-bromobenzyl)sulfonyl)quinoline (Comp#3)

[0155] A white solid was prepared from 6-bromo-2-((4-bromobenzyl)thio)quinoline and H2O2 according to the method of Comp#6, with a yield of 67.6% and a melting range of 148.0 - 149.7 °C.1 1H NMR (600 MHz, DMSO-d6) δ 8.68 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H), 8.12 (dd, J = 9.0, 2.2 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.52–7.47 (m, 2H), 7.23–7.18 (m, 2H), 5.00 (s, 2H). 13 13C NMR (126 MHz, Chloroform-d) δ 156.39, 145.63, 137.71, 135.10, 132.72, 131.94, 131.60, 130.09, 126.30, 124.00, 123.35, 118.81, 57.50, 1.05. HRMS (ESI) m / z calculated for C 16 H 11 Br2NO2S [M+H] + : 441.8936, found: 441.8930。

[0156] Example 3: Synthesis of 6-Bromo-2-((4-fluorobenzyl)sulfonyl)quinoline (Comp#4)

[0157] Under ice bath conditions, 1.0 g (2.87 mmol) of 6-bromo-2-((4-fluorobenzyl)thio)quinoline was placed in a single-necked flask under argon protection, 100 mL of glacial acetic acid was added, and after stirring for 10 min, 1.44 ml (14.35 mmol) of 30% hydrogen peroxide was added. The reaction was carried out at 50 °C for 2 h until the reaction was complete (monitored by TLC). The liquid in the flask was poured into about 1000 mL of ice-water mixture, and a white solid precipitated. It was filtered by suction, the filter cake was washed with water, and after drying, 556 mg of white powdery solid was obtained, with a yield of 51.45% and a melting range of 147.5 - 148.5 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 8.69–8.65 (m, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.22–8.17 (m, 1H), 8.12 (dd, J = 9.0, 2.2 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.32–7.23 (m, 2H), 7.16–7.09 (m, 2H), 4.99 (s, 2H). 1313C NMR (151 MHz, DMSO-d6) δ 163.47, 161.84, 157.09, 145.40, 139.37, 135.35, 133.86, 131.86, 130.96, 130.47, 124.58, 123.33, 119.12, 115.88, 115.73, 56.86. HRMS (ESI) m / z calculated for C 16 H 11 BrFNO2S [M+H] + : 381.9736, found: 381.9730。

[0158] Example 4: Synthesis of 6-Bromo-2-((4-fluorobenzyl)sulfinyl)quinoline (Comp#5)

[0159] Under ice bath conditions, 1.0 g (2.87 mmol) of 6-bromo-2-((4-fluorobenzyl)thio)quinoline was placed in a single-necked flask protected by argon, 100 mL of glacial acetic acid was added, and after stirring for 10 min, 0.57 mL (5.74 mmol) of 30% hydrogen peroxide was added. The reaction was carried out at room temperature for 4 h, and the reaction was complete (monitored by TLC). The liquid in the flask was poured into about 1000 mL of ice-water mixture, and a white solid precipitated. It was filtered by suction, the filter cake was washed with water, and after drying, 759 mg of white powdery solid was obtained, with a yield of 72.47% and a melting range of 141.5 - 142.5 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 8.54 (d, J = 8.5 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.08–8.00 (m, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.07–7.01 (m, 2H), 7.00 (dd, J = 8.7, 5.7 Hz, 2H), 4.52 (d, J = 13.3 Hz, 1H), 4.25 (d, J = 13.2 Hz, 1H). 13 13C NMR (151 MHz, DMSO-d6) δ 165.28, 163.24, 161.62, 145.68, 138.22, 134.65, 132.81, 131.28, 130.99, 129.57, 126.46, 121.56, 117.50, 115.51, 115.36, 58.65. HRMS (ESI) m / z calculated for C 16 H 11 BrFNOS [M+H] + : 365.9787, found: 365.9784。

[0160] Example 5: Synthesis of 6-Bromo-2-((4-chlorobenzyl)sulfinyl)quinoline (Comp#7)

[0161] A white solid was prepared from 6-bromo-2-((4-chlorobenzyl)thio)quinoline and H2O2 according to the method of Comp#5, with a yield of 51.2% and a melting range of 139.2 - 140.5 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 8.58–8.54 (m, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.13 (dt, J = 9.1, 0.7 Hz, 1H), 7.93 (dd, J = 9.0, 2.4 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.43–7.38 (m, 2H), 6.94–6.89 (m, 2H), 4.53 (d, J = 13.2 Hz, 1H), 4.25 (d, J = 13.2 Hz, 1H). 13 13C NMR (151 MHz, DMSO-d6) δ 165.18, 145.69, 138.27, 134.67, 133.26, 132.57, 131.28, 131.00, 129.58, 129.24, 128.54, 121.59, 117.52, 58.65. HRMS (ESI) m / z calculated for C 16 H 11 BrClNOS [M+H] + : 381.9492, found: 381.9482.

[0162] Example 6: Synthesis of 6-Bromo-2-((4-chlorobenzyl)sulfonyl)quinoline (Comp#8)

[0163] A white solid was prepared from 6-bromo-2-((4-chlorobenzyl)thio)quinoline and H2O2 according to the method of Comp#4, with a yield of 53.8% and a melting range of 152.4 - 153.9 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 8.71–8.66 (m, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.02 (dd, J = 8.9, 2.4 Hz, 2H), 7.52–7.47 (m, 2H), 7.24–7.18 (m, 2H), 5.00 (s, 2H). 1313C NMR (151 MHz, DMSO-d6) δ 157.04, 145.41, 139.46, 135.41, 133.88, 133.53, 131.89, 131.01, 130.51, 128.91, 127.44, 123.37, 119.12, 56.94. HRMS (ESI) m / z calculated for C 16 H 11 BrClNO2S [M+H] + : 397.9441, found: 397.9435.

[0164] Example 7: Synthesis of 6-Fluoro-2-((4-fluorobenzyl)sulfonyl)quinoline (Comp#9)

[0165] A white solid was prepared from 6-fluoro-2-((4-fluorobenzyl)thio)quinoline and H2O2 according to the method of Comp#4, with a yield of 48.6% and a melting range of 158.4 - 160.7 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 8.71–8.66 (m, 1H), 8.34 (dd, J = 9.3, 5.3 Hz, 1H), 8.02 (dd, J = 9.2, 2.9 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.97–7.90 (m, 1H), 7.32–7.26 (m, 2H), 7.16–7.08 (m, 2H), 4.98 (s, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 163.46, 162.57, 161.84, 160.91, 156.24, 144.04, 139.66, 133.85, 133.00, 130.47, 124.67, 122.78, 118.96, 115.87, 112.17, 56.89. HRMS (ESI) m / z calculated for C 16 H 11 F2NO2S [M+H] + : 320.0558, found: 320.0550.

[0166] Example 8: Synthesis of 6-Fluoro-(2-(benzyl)sulfonyl)quinoline (Comp#10)

[0167] A white solid was prepared from 6-fluoro-(2-(benzyl)thio)quinoline and H2O2 according to the method of Comp#4, with a yield of 47.9% and a melting range of 162.4 - 163.7 °C. 11H NMR (600 MHz, DMSO-d6) δ 8.67 (d, J = 8.6 Hz, 1H), 8.35 (dd, J = 9.3, 5.3 Hz, 1H), 8.04–7.96 (m, 2H), 7.93 (td, J = 8.9, 2.9 Hz, 1H), 7.33–7.22 (m, 5H), 4.96 (s, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 162.54, 160.88, 156.34, 144.03, 139.57, 132.99, 131.73, 130.43, 128.89, 128.30, 122.73, 118.93, 111.99, 57.80. HRMS (ESI) m / z calculated for C 16 H 12 FNO2S [M + H] + : 306.0652, found: 302.0646.

[0168] Example 9: Synthesis of 6-Fluoro-2-((4-carboxybenzyl)sulfonyl)quinoline (Comp#11)

[0169] A white solid was prepared from 6-Fluoro-2-((4-carboxybenzyl)thio)quinoline and H2O2 according to the method of Comp#4, with a yield of 61.5% and a melting range of 160.4 - 162.7 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.68 (d, J = 8.5 Hz, 1H), 8.34 (dd, J = 9.3, 5.3 Hz, 1H), 8.02–7.96 (m, 2H), 7.85–7.81 (m, 2H), 7.63–7.54 (m, 1H), 7.41–7.36 (m, 2H), 5.08 (s, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 167.37, 162.59, 160.93, 156.19, 144.02, 139.72, 133.30, 133.01, 131.96, 131.21, 129.68, 128.12, 122.64, 118.91, 112.03, 57.60. HRMS (ESI) m / z calculated for C 17 H 12 FNO4S [M + H] - : 344.0392, found: 344.0398.

[0170] Example 10: Synthesis of 6-Fluoro-2-((4-carboxybenzyl)sulfinyl)quinoline (Comp#12)

[0171] A white solid was prepared from 6-fluoro-2-((4-carboxybenzyl)thio)quinoline and H2O2 according to the method of Comp#5, with a yield of 58.7% and a melting range of 156.4 - 158.7 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 12.95 (s, 1H), 8.56 (d, J = 8.5 Hz, 1H), 8.19 (dd, J = 9.2, 5.3 Hz, 1H), 7.94 (dd, J = 9.3, 2.9 Hz, 1H), 7.84 (td, J = 8.8, 2.9 Hz, 1H), 7.78–7.74 (m, 2H), 7.69 (d, J = 8.6 Hz, 1H), 7.12–7.08 (m, 2H), 4.61 (d, J = 13.1 Hz, 1H), 4.33 (d, J = 13.1 Hz, 1H). 13 13C NMR (151 MHz, DMSO-d6) δ 167.50, 163.95, 161.68, 160.04, 144.30, 138.63, 135.38, 132.08, 130.97, 130.63, 129.44, 129.22, 121.73, 117.25, 112.13, 59.43. HRMS (ESI) m / z calculated for C 17 H 12 FNO3S [M + H] - : 328.0443, found: 328.0449.

[0172] Example 11: Synthesis of 2-(4-Fluorobenzyl)sulfinylquinoline (Comp#14)

[0173] A white solid was prepared from 2-(4-fluorobenzyl)thioquinoline and H2O2 according to the method of Comp#5, with a yield of 57.2% and a melting range of 139.8 - 141.8 °C. 11H NMR (500 MHz, Chloroform-d) δ 8.23 (t, J = 7.5 Hz, 1H), 8.12 (dd, J = 8.6, 4.6 Hz, 1H), 7.86 (t, J = 7.2 Hz, 1H), 7.80 (q, J = 7.1 Hz, 1H), 7.68 (dd, J = 8.5, 4.3 Hz, 1H), 7.62 (q, J = 7.1 Hz, 1H), 6.96 (dp, J = 8.1, 3.3 Hz, 2H), 6.85 (ddt, J = 11.3, 8.5, 3.7 Hz, 2H), 4.39 (dd, J = 13.3, 4.8 Hz, 1H), 4.16 (dd, J = 13.3, 4.7 Hz, 1H). 13 13C NMR (126 MHz, Chloroform-d) δ 163.70, 161.77, 147.26, 138.04, 132.05, 131.98, 130.88, 129.12, 128.18, 128.14, 127.97, 125.15, 116.19, 115.39, 115.21, 59.34. HRMS (ESI) m / z calculated for C 16 H 12 FNOS [M + H] + : 286.0703, found: 286.0696.

[0174] Example 12: Synthesis of 6-chloro-2-((4-bromobenzyl)sulfinyl)quinoline (Comp#15)

[0175] A white solid was prepared from 6-chloro-2-((4-bromobenzyl)thio)quinoline and H2O2 according to the method of Comp#5, with a yield of 65.8% and a melting range of 133.8 - 135.8 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 8.57–8.53 (m, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.08–8.00 (m, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.29–7.24 (m, 2H), 7.01–6.94 (m, 2H), 4.54 (d, J = 13.2 Hz, 1H), 4.26 (d, J = 13.2 Hz, 1H). 13 13C NMR (151 MHz, DMSO-d6) δ 165.10, 145.52, 138.39, 132.90, 132.14, 131.47, 131.24, 129.66, 129.09, 127.69, 121.90, 117.55, 58.77. HRMS (ESI) m / z calculated for C16 H 11 ClBrNOS[M + H] + : 381.9492, found: 381.9481.

[0176] Example 13: Synthesis of 6-chloro-2-((4-bromobenzyl)sulfonyl)quinoline (Comp#16)

[0177] A white solid was obtained from 6-chloro-2-((4-bromobenzyl)thio)quinoline and H2O2 according to Comp#4, with a yield of 69.4% and a melting range of 138.8 - 139.8 °C. 1 H NMR (600 MHz, DMSO-d6) δ 8.70–8.66 (m, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.19 (dt, J = 9.0, 0.7 Hz, 1H), 8.12 (dd, J = 9.0, 2.2 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.39–7.33 (m, 2H), 7.31–7.24 (m, 2H), 5.01 (s, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 157.00, 145.24, 139.58, 134.53, 133.83, 132.89, 131.91, 131.84, 130.09, 127.85, 127.68, 122.56, 119.14, 57.01. HRMS (ESI) m / z calculated for C 16 H 11 ClBrNO2S[M + H] + : 397.9441, found: 397.9434.

[0178] Example 14: Synthesis of 6-chloro-2-(4-chlorobenzyl)sulfinyl)quinoline (Comp#17)

[0179] A white solid was obtained from 6-chloro-2-((4-chlorobenzyl)thio)quinoline and H2O2 according to Comp#5, with a yield of 47.6% and a melting range of 129.5 - 131.4 °C. 11H NMR (600 MHz, DMSO-d6) δ 8.58–8.53 (m, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.13 (dt, J = 9.1, 0.7 Hz, 1H), 7.93 (dd, J = 9.0, 2.4 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.30–7.24 (m, 2H), 7.00–6.95 (m, 2H), 4.55 (d, J = 13.2 Hz, 1H), 4.26 (d, J = 13.2 Hz, 1H). 13 13C NMR (151 MHz, DMSO-d6) δ 165.10, 145.51, 138.37, 133.27, 132.90, 132.56, 132.13, 131.23, 129.25, 129.09, 128.54, 127.68, 117.54, 58.70. HRMS (ESI) m / z calculated for C 16 H 11 Cl2NOS [M+H] + : 336.0017, found: 336.0011.

[0180] Example 15: Synthesis of 6-chloro-2-((4-chlorobenzyl)sulfonyl)quinoline (Comp#18)

[0181] A white solid was prepared from 6-chloro-2-((4-chlorobenzyl)thio)quinoline and H2O2 according to the method of Comp#4, with a yield of 42.8% and a melting range of 135.7 - 136.8 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 8.71–8.66 (m, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.27 (dt, J = 9.1, 0.7 Hz, 1H), 8.04–7.99 (m, 2H), 7.39–7.33 (m, 2H), 7.30–7.25 (m, 2H), 5.01 (s, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 157.00, 145.23, 139.55, 134.53, 133.90, 133.52, 132.86, 131.90, 130.08, 128.90, 127.66, 127.42, 119.13, 56.95. HRMS (ESI) m / z calculated for C 16 H 11 Cl2NO2S [M+H] + : 351.9967, found: 351.9960.

[0182] Example 16: Synthesis of 6-chloro-2-((4-fluorobenzyl)sulfinyl)quinoline (Comp#19)

[0183] A white solid was prepared from 6-chloro-2-((4-fluorobenzyl)thio)quinoline and H2O2 according to the method of Comp#5, with a yield of 66.7% and a melting range of 128.4 - 129.7 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 8.57–8.53 (m, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.13 (dt, J = 9.0, 0.7 Hz, 1H), 7.92 (dd, J = 9.0, 2.4 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.08–6.96 (m, 4H), 4.52 (d, J = 13.2 Hz, 1H), 4.25 (d, J = 13.3 Hz, 1H). 13 13C NMR (151 MHz, DMSO-d6) δ 165.21, 163.23, 161.62, 145.50, 138.32, 132.87, 132.80, 132.10, 131.22, 129.07, 127.66, 126.49, 126.47, 117.51, 115.50, 58.70. HRMS (ESI) m / z calculated for C 16 H 11 ClFNOS [M+H] + : 320.0313, found: 320.0307.

[0184] Example 17: Synthesis of 6-chloro-2-((4-fluorobenzyl)sulfonyl)quinoline (Comp#20)

[0185] A white solid was prepared from 6-chloro-2-((4-fluorobenzyl)thio)quinoline and H2O2 according to the method of Comp#4, with a yield of 61.7% and a melting range of 131.4 - 133.7 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 8.70–8.65 (m, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.28 (dd, J = 9.0, 0.8 Hz, 1H), 8.04–7.98 (m, 2H), 7.33–7.26 (m, 2H), 7.16–7.09 (m, 2H), 4.99 (s, 2H). 1313C NMR (151 MHz, DMSO-d6) δ 163.47, 161.84, 157.06, 145.26, 139.51, 134.51, 133.87, 132.87, 131.92, 130.07, 127.67, 124.62, 124.60, 119.19, 115.89, 56.86. HRMS (ESI) m / z calculated for C 16 H 11 ClFNO2S [M+H] + : 336.0262, found: 336.0256.

[0186] Example 18: Synthesis of 6-Bromo-2-(benzylsulfinyl)quinoline (Comp#23)

[0187] A white solid was prepared from 6-bromo-2-(benzylthio)quinoline and H2O2 according to the method of Comp#5, with a yield of 57.4% and a melting range of 127.1 - 128.9 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 8.56–8.52 (m, 1H), 8.41 (d, J = 2.2 Hz, 1H), 8.08–8.03 (m, 1H), 8.01 (dd, J = 9.0, 2.2 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.29–7.25 (m, 1H), 7.22 (ddt, J = 8.4, 6.7, 1.5 Hz, 2H), 7.05–7.00 (m, 2H), 4.52 (d, J = 13.1 Hz, 1H), 4.24 (d, J = 13.1 Hz, 1H). 13 13C NMR (126 MHz, Chloroform-d) δ 164.72, 145.80, 136.84, 134.28, 130.84, 130.33, 130.17, 129.26, 129.16, 128.40, 128.26, 121.98, 117.18, 60.46. HRMS (ESI) m / z calculated for C 16 H 12 BrNOS [M+H] + : 347.9882, found: 347.9876.

[0188] Example 19: Synthesis of 6-Bromo-2-(benzylsulfonyl)quinoline (Comp#24)

[0189] A white solid was obtained from 6-bromo-2-(benzylthio)quinoline and H2O2 according to Comp#4 method, with a yield of 68.7% and a melting range of 137.5 - 139.4 °C. 1 H NMR (600 MHz, DMSO-d6) δ 8.68–8.64 (m, 1H), 8.51 (d, J = 2.2 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 8.11 (dd, J = 9.0, 2.3 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.33–7.22 (m, 5H), 4.98 (s, 2H). 13 C NMR (126 MHz, Chloroform-d) δ 164.71, 145.84, 136.84, 134.33, 130.85, 130.34, 130.17, 129.24, 129.19, 128.40, 128.27, 122.00, 117.22, 60.47. HRMS (ESI) m / z calculated for C 16 H 12 BrNO2S [M+H] + : 363.9831, found: 363.9828.

[0190] Example 20: Synthesis of 6-bromo-2-(cyanobenzyl)sulfinyl)quinoline (Comp#26)

[0191] A white solid was obtained from 6-bromo-2-(cyanobenzylthio)quinoline and H2O2 according to Comp#5 method, with a yield of 68.7% and a melting range of 141.7 - 142.9 °C. 1 H NMR (600 MHz, DMSO-d6) δ 8.54 (d, J = 8.6 Hz, 1H), 8.45–8.41 (m, 1H), 8.07–8.00 (m, 2H), 7.69–7.62 (m, 3H), 7.15–7.11 (m, 2H), 4.66 (d, J = 13.0 Hz, 1H), 4.38 (d, J = 13.0 Hz, 1H). 13 C NMR (126 MHz, Chloroform-d) δ 163.76, 145.83, 137.16, 134.68, 134.50, 131.93, 130.97, 130.72, 130.27, 129.16, 122.37, 118.43, 117.05, 112.13, 59.36. HRMS (ESI) m / z calculated for C 17 H 11 BrNOS [M+H] +: 372.9834, found: 372.9828.

[0192] Example 21: Synthesis of 2-(4-chlorobenzyl)sulfinyl)quinoline (Comp#27)

[0193] A white solid was obtained from 2-(4-chlorobenzyl)thio)quinoline and H2O2 according to the method of Comp#5, with a yield of 62.4% and a melting range of 134.5 - 137.0 °C. 1 1H NMR (600 MHz, DMSO-d6) δ 8.59 (d, J = 8.5 Hz, 1H), 8.14–8.09 (m, 2H), 7.92 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.75 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.30–7.25 (m, 2H), 7.03–6.98 (m, 2H), 4.59–4.52 (m, 1H), 4.26 (d, J = 13.2 Hz, 1H). 13 13C NMR (126 MHz, Chloroform-d) δ 163.70, 147.28, 138.13, 134.37, 131.63, 131.40, 130.92, 129.15, 128.52, 128.21, 128.19, 128.00, 127.83, 116.25, 59.45. HRMS (ESI) m / z calculated for C 16 H 12 ClNOS [M + H] + : 302.0407, found: 302.0403.

[0194] Example 22: Synthesis of 2-(4-chlorobenzyl)sulfonyl)quinoline (Comp#28)

[0195] A white solid was obtained from 2-(4-chlorobenzyl)thio)quinoline and H2O2 according to the method of Comp#4, with a yield of 65.7% and a melting range of 137.1 - 138.9 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.34 (dd, J = 8.5, 0.8 Hz, 1H), 8.29 (dq, J = 8.5, 0.9 Hz, 1H), 7.95–7.87 (m, 3H), 7.74 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.23–7.17 (m, 4H), 4.78 (s, 2H). 1313C NMR(151MHz,Chloroform-d)δ156.05,147.11,138.69,134.99,132.45,131.38,130.10,129.45,129.17,128.91,127.99,126.00,117.83,57.37.HRMS(ESI)m / z calculated for C 16 H 12 ClNO2S[M+H] + :318.0356,found:318.0352.

[0196] Example 23: Synthesis of 2-((4-bromobenzyl)sulfinyl)quinoline (Comp#30)

[0197] A white solid was prepared from 2-((4-bromobenzyl)thio)quinoline and H2O2 according to the method of Comp#5, with a yield of 49.8% and a melting range of 128.4 - 129.7 °C. 1 1H NMR(600MHz,DMSO-d6)δ8.60(d,J = 8.5Hz,1H),8.12(ddd,J = 7.7,5.4,1.3Hz,2H),7.96–7.88(m,1H),7.75(ddd,J = 8.1,6.9,1.1Hz,1H),7.68(d,J = 8.5Hz,1H),7.55–7.45(m,1H),7.44–7.38(m,2H),6.97–6.91(m,2H),4.57–4.51(m,1H),4.25(d,J = 13.2Hz,1H). 13 13C NMR(126MHz,Chloroform-d)δ163.67,147.32,138.11,131.95,131.47,130.91,129.18,128.35,128.22,128.00,127.71,122.60,116.24,59.50.HRMS(ESI)m / zcalculated for C 16 H 12 BrNOS[M+H] + :347.9882,found:347.9876.

[0198] Example 24: Synthesis of 2-((4-bromobenzyl)sulfonyl)quinoline (Comp#31)

[0199] A white solid was prepared from 2-((4-bromobenzyl)thio)quinoline and H2O2 according to the method of Comp#4, with a yield of 44.7% and a melting range of 131.4 - 132.1 °C.1 1H NMR (600 MHz, DMSO-d6) δ 8.60 (d, J = 8.5 Hz, 1H), 8.12 (ddd, J = 7.7, 5.4, 1.3 Hz, 2H), 7.92 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.75 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.44–7.37 (m, 2H), 6.97–6.92 (m, 2H), 4.53 (d, J = 13.2 Hz, 1H), 4.25 (d, J = 13.2 Hz, 1H). 13 13C NMR (126 MHz, Chloroform-d) δ 163.66, 147.30, 138.12, 131.95, 131.47, 130.92, 129.16, 128.34, 128.21, 128.18, 128.01, 122.59, 116.24, 59.50. HRMS (ESI) m / z calculated for C 16 H 12 BrNO2S [M + H] + : 363.9831, found: 347.9876.

[0200] Example 25: Synthesis of 2-(4-fluorobenzylsulfinyl)-6-bromonaphthalene

[0201] Add 2.87 g (0.020 mol, 1 eq) of 2-naphthol and 8 ml of glacial acetic acid to a 50 ml eggplant-shaped flask, heat to dissolve completely to obtain a brown solution. Cool to room temperature, add a mixture of 2 ml (0.039 mol, 2 eq) of bromine and 2 ml of glacial acetic acid, and white smoke is emitted. Heat under reflux in an oil bath at 120 °C for 7 h and then work up the reaction solution. When the liquid in the flask cools to 50 °C, filter off the precipitate while it is hot, pour the filtrate into about 50 ml of ice water, pink solid precipitates out, filter by suction, wash the filter cake with water, and dry to obtain 4.00 g of 6-bromo-2-naphthol.

[0202] Add 4.00 g (17.9 mmol, 1 eq) of 6-bromo-2-naphthol to a 50 ml reaction flask, dissolve it with 60 ml of N,N-dimethylformamide, slowly add 2.06 g (51.5 mmol, 3 eq) (60%) sodium hydride (with aerosol generation) under ice bath stirring, stir at room temperature for 30 min, and then slowly add 4.25 g (34.38 mmol, 2 eq) of dimethylaminothiocarbonyl chloride; react in an oil bath at 80 °C for 2 h, stir at room temperature for 15 h, then pour the solution in the flask into 300 ml of water, adjust the pH to weakly alkaline (pH = 7 - 8), a large amount of light yellow precipitate precipitates out, filter under reduced pressure to obtain 1 g of 6-O-(2-bromonaphthyl)-dimethylaminothiocarbonate.

[0203] Add 1.00 g (3.225 mmol) of 6-O-(2-bromonaphthyl)-dimethylcarbamothioate to a 50 ml pear-shaped flask, add 10 mL of N-methylpyrrolidone solution, and pass argon for protection. React at 220 °C in an oil bath for 48 hours; after cooling, add three times the amount of water, extract with ethyl acetate 3 times, combine the organic phases, dry the organic phases with anhydrous magnesium sulfate, evaporate to dryness under reduced pressure, and obtain 180 mg of 6-S-(2-bromonaphthyl)-dimethylcarbamate by column chromatography.

[0204] Add 200 mg (0.645 mmol, 1 eq) of 6-S-(2-bromonaphthyl)-dimethylcarbamate and 15 ml of methanol to a 250 ml pear-shaped flask, then slowly add 0.337 g (6 mmol, 10 eq) of potassium hydroxide, and reflux at 80 °C in an oil bath for 2.5 h. After cooling, pour the reaction solution into 15 ml of 1 N hydrochloric acid at 0 °C. White crystals precipitate. Extract with dichloromethane and combine the organic phases. Then wash the organic phases once with saturated brine, dry over anhydrous magnesium sulfate, and evaporate to dryness under reduced pressure to obtain 120 mg of 6-bromo-2-naphthalenethiol.

[0205] Add 120 mg (0.50 mmol, 2 eq) of 6-bromo-2-naphthalenethiol and 3.44 ml of ethanol to a 25 ml pear-shaped flask. While stirring, add 0.34 ml of sodium hydroxide solution. The solution turns yellow. Then add 0.053 g (0.256 mmol, 1 eq) of 4-fluorobenzyl chloride. After heating and refluxing for 3 h, remove the flask from the oil bath. Wait for the liquid in the flask to cool to room temperature, and pour it into about 30 ml of ice water. White solid precipitates. Filter by suction, wash the filter cake with water, and dry to obtain 0.028 g of 2-(4-fluorobenzylthio)-6-bromonaphthalene.

[0206] Add 0.028 g (0.069 mmol) of 2-(4-fluorobenzylsulfinyl)-6-bromonaphthalene and 3 ml of glacial acetic acid to a 25 ml pear-shaped flask. While stirring in an ice bath, add 0.05 ml of 30% (1.632 mmol) hydrogen peroxide. Stir and react at room temperature. After 3 h, the reaction is complete. Pour the liquid in the flask into about 50 ml of ice-water mixture. White solid precipitates. Filter by suction, wash the filter cake with water, and dry to obtain a white powdery solid. The yield is 2.9‰. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 4.17 (d, 1H, J = 12.9 Hz), 4.41 (d, 1H, J = 12.9 Hz), 7.06 - 7.08 (m, 4H), 7.68 - 7.75 (m, 2H), 7.97 - 8.08 (m, 3H), 8.33 (s, 1H).

[0207] Example 26: Synthesis of 3-((p-Fluorobenzylsulfinyl)methylene)-5-bromoisoindolin-2-one

[0208] Thiourea (1.36 g, 17.87 mmol) and 40 mL of ethanol were added to a 100 mL pear-shaped flask, and stirred at 50 °C until dissolved. p-Fluorobenzyl chloride (2.25 g, 16.26 mmol) was added, and the reaction was heated under reflux. The reaction was completed after 10 minutes. The solvent was evaporated under reduced pressure, and then 10 mL of 3 mol / L sodium hydroxide solution was added, and the reaction was heated under reflux. After 1 h, the mixture became clear, and the reaction was stopped. After the mixture in the pear-shaped flask was cooled to room temperature, it was extracted with dichloromethane (100 mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain 1.93 g of G4, a colorless oily liquid.

[0209] G4 (1.70 g, 11.97 mmol) and triethylamine (2.16 g, 21.39 mmol) were added to a 150 mL pear-shaped flask, then 60 mL of dichloromethane and 20 mL of methanol were added. After stirring in an ice bath for 15 minutes, F2 (3.20 g, 11.99 mmol) was added, and the reaction was carried out at room temperature. The progress of the reaction was monitored by TLC (the developing agent was petroleum ether and ethyl acetate, with a ratio of 1:1). After 18 h, the reaction was worked up. After evaporating the solvent under reduced pressure, column chromatography (gradient elution, the eluent was petroleum ether and ethyl acetate, with a ratio changing from 2.5:1 to 1:1) was carried out to obtain 1.30 g of H18, a yellow solid.

[0210] H18 (0.32 g, 0.88 mmol) and 25 mL of glacial acetic acid were added to a 100 mL pear-shaped flask. 30% hydrogen peroxide (0.16 mL, 1.51 mmol) was added under stirring in an ice bath, and the reaction was carried out in a 50 °C water bath. The progress of the reaction was monitored by TLC (the developing agent was petroleum ether and ethyl acetate, with a ratio of 1:1). After 3 h, the reaction was completed. The liquid in the pear-shaped flask was poured into about 300 mL of ice-water mixture, and a large amount of yellow solid precipitated. It was filtered by suction, the filter cake was washed with water, and after drying, 0.19 g of TL035, an orange-yellow solid, was obtained, with a yield of 13.5%, melting point: 213 - 214 °C. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 4.22 (d, 1H, J = 12.6 Hz), 4.33 (d, 1H, J = 12.9 Hz), 6.84 (d, 1H, J = 8.1 Hz), 7.20 - 7.49 (m, 5H), 7.73 (s, 1H), 8.02 (s, 1H), 10.99 (s, 1H, NH).

[0211] The structural formula of the target compound of the example is shown in Table 1.

[0212] Table 1 Structure of the target compound

[0213]

[0214]

[0215]

[0216] Experiment 1: Anti-radiation activity evaluation experiment

[0217] The anti-radiation activities of the target compounds in Table 1 were evaluated. The experimental grouping and data calculation and analysis were all processed according to statistical methods. The X-ray irradiation device of the Institute of Radiation Medicine, Academy of Military Medical Sciences of the Chinese People's Liberation Army was used for cell radiation irradiation, and the Co source irradiation device of the Institute of Radiation Medicine, Academy of Military Medical Sciences of the Chinese People's Liberation Army was used for mouse radiation irradiation.

[0218] ① Anti-radiation cell experiment

[0219] In this experiment, the anti-radiation activity of the compound was determined by detecting the proliferation activity of AHH-1 cells after irradiation by the cck8 method through prophylactic administration.

[0220] (1) Take AHH-1 cells in the logarithmic growth phase, centrifuge, resuspend and count, and adjust the cell density to 1×10 5 cells / mL with complete medium; (2) Inoculate the evenly pipetted single-cell suspension into a 96-well culture plate, 100 μL per well, and fill the periphery of the 96-well plate with 200 μL of sterile water; set up a blank group, a negative irradiation group, a positive drug (Ex-rad) group and a compound group on the 96-well plate, with 3 replicates in each group; the blank group does not contain cell suspension, the negative group is not irradiated, and other operations are the same as the experimental group, and place it in a carbon dioxide cell incubator (37 °C, 5% CO2) for 12 h; (3) Stimulate the cells with drugs. Add 100 μL of fresh complete medium to the blank group, the negative group and the negative irradiation group respectively, and add 100 μL of complete medium with a final concentration of the required drug concentration to the Ex-rad group and 31 compound groups respectively, and place it in a carbon dioxide cell incubator (37 °C, 5% CO2) for 24 h; (4) Irradiate the cells with X-rays (160 kV, 25 mA, 408 s), the irradiation dose is 8 Gy (dose rate is 1.175 Gy / min) / 4 Gy, and after irradiation, put it back into the carbon dioxide incubator and continue to culture for 24 h; (5) Add 10 μL of CCK-8 color reagent to each well, continue to culture for 2 h, measure the OD value at 450 nm with an enzyme-labeled instrument, and substitute it into the formula to calculate the survival rate of the cells after irradiation; Survival rate (%) = (sample OD value - blank OD value) / (negative OD value - blank OD value) × 100%.

[0221] The experimental results are presented as It is shown that one-way ANOVA was performed using SPSS 13.0 software for the comparison between groups of the survival rate data. * P < 0.05, and the activity was higher than that of the negative irradiation group, and the difference was statistically significant; # P, and the activity was higher than that of the Ex-Rad group, and the difference was statistically significant; n = 3, and the experimental results are shown in Table 2.

[0222] Table 2 Survival rates of cells after Coγ irradiation of the target compounds and Ex-Rad at 8 Gy and 4 Gy 60

[0223]

[0224]

[0225] The above test results show that under 8 Gy and / or 4 Gy, the compounds of the present invention as a whole have significant differences compared with the blank group; among them, Compounds 5 and 12 have the most significant activities; the radiation activity is significantly stronger than that of the positive drug Ex-RAD.

[0226] ② Animal experiments

[0227] I. 30-day survival experiment of mice:

[0228] In the cytological screening of radiation protection effects, Compounds 5 and 12 both showed obvious protective effects on the radiation damage of AHH-1 cells; therefore, it is intended to further study the effects of Compounds 5 and 12 on 60 the survival of mice irradiated with Coγ rays.

[0229] Mice were administered (the drug given was Ex-RAD, the administration time was 24 hours and 15 minutes before irradiation, and the administration dose was 250 mg / kg or 500 mg / kg), and the mice were irradiated with Coγ rays at a lethal dose. Ex-RAD could significantly improve the survival rate of mice. The irradiation dose selected for this experiment was 9 Gy, the administration time of the compound was 24 hours and 15 minutes before irradiation, and the administration dose was 300 mg / kg. 60

[0230] The experiment was set up with 4 groups, 10 mice in each group, namely the radiation control group (normal saline containing 20% HPCD), the positive control group (Ex-RAD group at 300 mg / kg), and Compounds 5 and 12 (300 mg / kg). The administration method in this experiment was intraperitoneal injection, and each mouse was administered once at 24 hours and 15 minutes before irradiation, 0.2 mL / mouse each time.

[0231] ​​Observe the survival of mice 30 days after irradiation: Count the day of irradiation as day 0, observe from day 1 to day 30 after irradiation, and record the survival of mice every day. And record the weight changes of mice before irradiation and on days 1, 4, 7, 10, 14, 18, 22, and 30 after irradiation.

[0232] The experimental results are shown in Tables 3-4 and Figure 1-2 :

[0233] Table 3 Survival rate of mice 30 days after irradiation

[0234]

[0235] It can be seen that mice began to die on the 11th day after irradiation and no longer died on the 17th day. All mice in the radiation control group died within 15 days after irradiation, 40% of mice in the Ex-Rad group survived 30 days after irradiation, 80% of mice in the compound 5 group survived 30 days after irradiation, and 50% of mice in the compound 12 group survived 30 days after irradiation. The survival curves of the mice were statistically analyzed, and the differences were statistically significant (p=0.0001, df=3, chi squared value=20.80, log-rank test).

[0236] Table 4 Body weight of mice 30 days after irradiation

[0237]

[0238] From the data in the above chart, it can be seen that the weight of mice has been decreasing within 5-15 days after irradiation, and the radiation control group has the most serious damage. After 15 days, the weight of the Ex-Rad group and the compound group began to recover, slowly increased, and gradually returned to the pre-irradiation level.

[0239] According to the analysis of the survival curve and weight data of mice 30 days after irradiation, the damage caused by radiation to mice was most obvious from the 11th to the 17th day after irradiation. The mice in the radiation control group and the Ex-Rad group began to die one after another, and the weight of the surviving mice was also decreasing; after 17 days, the mice in each group stopped dying and their weight was also on the rise. All the mice in the radiation control group died within 15 days after irradiation, 40% of the mice in the Ex-Rad group survived 30 days after irradiation, 80% of the mice in the compound 5 group survived 30 days after irradiation, and 50% of the mice in the compound 12 group survived 30 days after irradiation, indicating that Ex-Rad and compounds 5 and 12 can effectively reduce the damage caused by radiation to mice, and compound 5 can significantly increase the survival rate of mice after irradiation. Therefore, it is concluded that the target compounds 5 and 12 have good radiation protection effects, among which the protection effects of compounds 5 and 12 are better than those of the positive drug Ex-Rad.

[0240] 2. Protective effect of compounds on intestinal damage in irradiated mice

[0241] The small intestine is a tissue highly sensitive to radiation, and high-dose radiation can cause intestinal injury. When the human body is irradiated globally or abdominally, radiation-induced intestinal injury (RIII) will occur. After high-dose radiation, a large number of intestinal stem cells are depleted, thereby blocking epithelial renewal and destroying the integrity of the epithelium. The disruption of the mucosal barrier further leads to fluid loss, electrolyte disorders, sepsis, and even death in the human body. Currently, there are no approved drugs that can prevent or mitigate RIII. Despite the progress of medical technology today, radiotherapy for the abdomen and pelvis still inevitably causes intestinal injury and leads to acute and chronic gastrointestinal complications, thereby limiting the treatment effect and reducing the quality of life of patients. Therefore, we urgently need radioprotective agents with minor side effects and good treatment effects to alleviate RIII.

[0242] Experimental method: C57BL / 6 mice were randomly divided into 5 groups according to body weight, with 8 mice in each group, namely the blank control group (normal saline containing 20% HPCD), the radiation control group (normal saline containing 20% HPCD), the positive control group (Ex-RAD group at 300 mg / kg), and compound 5 (300 mg / kg). In this experiment, the administration method was intraperitoneal injection, and each mouse was given the drug once at 24 hours and 15 minutes before irradiation, 0.2 mL per mouse each time. Except for the blank group, the other groups received 13 Gy abdominal irradiation. Before irradiation, each mouse in the irradiation group was anesthetized by intraperitoneal injection of 10% chloral hydrate (sodium pentobarbital), and then the anesthetized mouse was placed in the supine position with its limbs extended and fixed in the fixing plate to fully expose its abdomen.

[0243] Detection indicators:

[0244] Determination of immune organ index:

[0245] The spleen was collected on the third day after irradiation, weighed after removing fat and connective tissue, and the spleen index = spleen weight (mg) ÷ mouse body weight (g, on the third day after irradiation)

[0246] Histopathology (HE staining method)

[0247] The small intestine was collected on the 3.5th day after irradiation, fixed with 4% paraformaldehyde for 24 hours before paraffin embedding, and cut into 5-μm-thick sections. The tissue sections were stained with hematoxylin and eosin (HE) and examined under an optical microscope. Villus injury, crypt destruction, and infiltration of lamina propria mononuclear cells were used to evaluate small intestine injury.

[0248] Experimental results:

[0249] Immune organ index:

[0250] The spleen participates in early hematopoiesis during embryogenesis and gradually evolves into the largest lymphoid organ in the body after the bone marrow begins hematopoiesis. Like the thymus, the spleen is an organ that is extremely sensitive to radiation. Therefore, the spleen index is often used as an important parameter to evaluate the intervention effect of radiation protection drugs. The experimental results showed that after the test mice were irradiated with 13 Gy, the spleen indices of the mice in the radiation control group, the positive drug group, and each compound group decreased sharply. At 72 hours after irradiation, the spleen indices of each group decreased to about half of that before irradiation; however, the spleen index of the Compd#5 administration group at 72 hours after irradiation was significantly higher than that of the radiation control group (P < 0.05), indicating that Compd#5 could inhibit radiation-induced spleen atrophy, that is, inhibit the apoptosis of lymphocytes in the spleen.

[0251] As Figure 3 shown, this figure represents the spleen indices of different treatment groups. On the 3.5th day after irradiation, the spleen indices of the simple irradiation group were significantly lower than those of the blank control group (p < 0.01), and compound 5 could significantly increase the spleen index (p < 0.05), indicating that compound 5 had a good protective effect on the spleen organ and could reduce spleen atrophy after irradiation; while Ex-RAD had no protective effect on the spleen organ.

[0252] Pathological section (HE):

[0253] As Figure 4 shown, the crypt-villus cell structure of the blank control group was intact and normal. On the third day after 13 Gy abdominal irradiation, atrophied and distorted villi, crypt abscesses and losses, and lamina propria mononuclear cell infiltration were observed in the simple irradiation group. The mice pretreated with the Ex-RAD group had longer villi and more crypts compared with the simple irradiation group. Compared with the simple irradiation group and the Ex-RAD group, the mice in the compound 5 pretreatment group before irradiation showed longer villi, more crypts, crypt abscesses, and fewer infiltrating mononuclear cells. Therefore, pretreatment with compound 5 before irradiation improved radiation-induced small intestine crypt-villus structure damage and was superior to the positive drug Ex-RAD.

[0254] III. Detection experiment of radiation protection factors in the TLR 2 signaling pathway

[0255] After the TLR2 signaling pathway is activated by lipopeptide compounds, it can further activate downstream signal transduction molecules, including MyD88 and NF-κB, thereby promoting the secretion of various downstream cytokines, such as G-CSF, IL-6, and IL-12. Among them, IL-6 is mainly produced by lymphocytes, fibroblasts, and mononuclear macrophages and plays various biological functions in the body. IL-6 can promote the activation of hematopoietic stem cells in the G0 phase to enter the G1 phase, increase the number of platelets in the blood, and promote the hematopoietic function of the body. At the same time, IL-6 can promote the proliferation and activation of T cells and induce mature B cells to become antibody-producing cells, improving the immune ability of the body. In the research progress of radiation injury treatment, IL-6 can counteract the body infection and hematopoietic function injury after radiation. Therefore, IL-6 is a cytokine that plays an important role in radiation protection and treatment. Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein with various physiological functions. G-CSF mainly acts on the proliferation, differentiation, and activation of hematopoietic cells in the neutrophil lineage and can promote the release of mature hematopoietic cells into the peripheral blood. G-CSF mainly acts on bone marrow hematopoietic stem cells and bone marrow hematopoietic progenitor cells, promoting the differentiation and maturation of bone marrow-related hematopoietic cells and increasing neutrophils in the peripheral blood. Studies on various irradiated animal models have shown that G-CSF has a good preventive and therapeutic effect on animals with acute radiation sickness, significantly reducing the mortality of irradiated animals and promoting the recovery of red blood cells and white blood cells after irradiation.

[0256] Experimental procedures:

[0257] Twenty 20-g male C57BL / 6 experimental mice were randomly divided into 3 groups: the drug-administered irradiation group, the blank control group, and the simple irradiation group. Two hours after the mice received 7.5 Gy of whole-body irradiation, peripheral blood of the mice was collected (1 mL of blood was taken from the heart). The blood samples of the mice were left to clot at room temperature for 30 minutes and then placed in a refrigerator at 4°C overnight. After centrifugation, the serum was taken, and the expression levels of G-CSF, IL-6, and IL-12 in the serum were quantitatively detected by enzyme-linked immunosorbent assay.

[0258] Experimental conclusions: As Figure 5 shown, compared with the blank control group, IL-6 was downregulated to a certain extent in the simple irradiation group, while G-CSF and IL-12 were upregulated to a certain extent. In the drug-administered irradiation group, the expression levels of G-CSF, IL-6, and IL-12 were significantly upregulated. This suggests that the compound may play a role in protecting against radiation injury by upregulating cytokines such as G-CSF, IL-6, and IL-12.

[0259] Detection of γ-H2AX foci in vitro cell DBS injury

[0260] Ionizing radiation acts on biological macromolecules in cells mainly through direct and indirect effects. Among them, DNA is a key target for damage by both direct and indirect effects of ionizing radiation. Its damage can directly lead to the activation of inflammasomes, and then result in processes such as apoptosis and cell death. γ-H2AX is a currently recognized molecular marker for DNA double-strand breaks (DSBs). In this experiment, we evaluated the DSB damage by detecting the formation number of γ-H2AX foci through immunofluorescence.

[0261] Twenty-four hours before irradiation, AHH-1 cells in the logarithmic growth phase were seeded in 6-well plates (2×10^5 cells / well), and were stimulated with compound 5 and Ex-Rad or sterile saline 24 hours before irradiation. Then the cells were irradiated with a dose of 6.0 Gy and a dose rate of 1.175 Gy / min. At 0.5 hour and 2 hours after irradiation, immunohistochemical staining of γ-H2AX foci was performed.

[0262] Experimental procedures:

[0263] a. Centrifuge to collect the cells and wash them once with PBS. After aspirating all the PBS, gently resuspend the cells.

[0264] b. Add the fixing solution, gently suspend the cells, and fix for 5 - 15 minutes.

[0265] c. Centrifuge to remove the fixing solution.

[0266] d. Add the washing solution and wash once.

[0267] e. Take a little washing solution to resuspend the cells, drop them onto a coverslip or a glass slide to make a smear. After drying thoroughly, continue with the subsequent operations. f. Wash twice with the washing solution, 5 minutes each time. Try to aspirate all the residual liquid as much as possible during each washing, and at the same time keep the surface of the sample slightly moist, not dried out. Aspirate all the washing solution after the last washing.

[0268] d. Add the immunostaining blocking solution and block at room temperature for 10 - 20 minutes. The amount of the immunostaining blocking solution should be sufficient to cover the sample. e. Aspirate the immunostaining blocking solution, add rabbit anti-γ-H2AX monoclonal antibody, and incubate at room temperature for 1 hour or overnight at 4°C. The amount of rabbit anti-γ-H2AX monoclonal antibody should be sufficient to cover the sample.

[0269] f. Carefully aspirate the rabbit anti-γ-H2AX monoclonal antibody into a suitable container and store it at 4°C for future use.

[0270] g. Wash three times with the washing solution, 5 - 10 minutes each time. Try to aspirate all the residual liquid as much as possible during each washing, and at the same time keep the surface of the sample slightly moist, not dried out. Aspirate all the washing solution after the last washing.

[0271] h. Add anti-rabbit 488 and incubate at room temperature for 1 hour. The amount of anti-rabbit 488 used should be sufficient to cover the sample.

[0272] i. Carefully aspirate the anti-rabbit 488 into an appropriate container and store it at 4°C for future use.

[0273] j. Wash twice with the washing solution, 5 - 10 minutes each time. Try to aspirate as much of the residual liquid as possible each time while keeping the surface of the sample slightly moist and not allowing it to dry out. Aspirate the washing solution completely after the last wash.

[0274] k. Add the nuclear staining solution (DAPI) and stain at room temperature for about 5 minutes. The amount of the nuclear staining solution used should be sufficient to cover the sample. l. Aspirate the nuclear staining solution and wash 3 times with the washing solution, 3 - 5 minutes each time. Try to aspirate as much of the residual liquid as possible each time while keeping the surface of the sample slightly moist and not allowing it to dry out. Aspirate the washing solution completely after the last wash. Drop an appropriate amount of anti-fluorescence quenching mounting medium, cover with a coverslip, and observe under a fluorescence microscope.

[0275] This experiment was carried out taking Compound 5 as an example, and the results are as Figure 6 shown.

[0276] γ-H2AX foci formation could be detected in AHH-1 at 0.5 hour after irradiation, and the amount of γ-H2AX foci formation increased at 2 hours after irradiation; compared with the simple irradiation group, Ex-Rad and Compound 5 reduced the number of γ-H2AX foci in individual cells at 0.5 hour and 2 hours after irradiation, and Compound 5 had better activity. It was proved that Compound 5 could reduce radiation-induced DNA damage and was superior to the positive drug Ex-Rad.

[0277] 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 quinoline sulfur-containing 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 quinoline sulfur-containing derivative according to claim 1, wherein R1 and R2 are mono-substituted or multi-substituted (2, 3 or 4) on the ring.

3. The quinoline sulfur-containing derivative according to claim 1, wherein The quinoline N atom forms an N + -O - ionic bond.

4. The quinoline sulfur-containing derivative according to claim 1, wherein The halogen is fluorine, chlorine, bromine or iodine.

5. The quinoline sulfur-containing derivative according to claim 1, characterized in that, including any one of the following: 6-bromo-2-((4-bromobenzyl)thio)quinoline 6-bromo-2-((4-bromobenzyl)sulfinyl)quinoline 6-bromo-2-((4-bromobenzyl)sulfonyl)quinoline 6-bromo-2-((4-fluorobenzyl)sulfinyl)quinoline 6-bromo-2-((4-fluorobenzyl)sulfonyl)quinoline 6-bromo-2-((4-chlorobenzyl)thio)quinoline 6-bromo-2-((4-chlorobenzyl)sulfinyl)quinoline 6-bromo-2-((4-chlorobenzyl)sulfonyl)quinoline 6-fluoro-2-(4-fluorobenzyl)sulfonyl)quinoline 6-fluoro-2-((4-carboxybenzyl)sulfinyl)quinoline 6-fluoro-2-((4-carboxybenzyl)sulfonyl)quinoline 6-fluoro-(2-(benzyl)sulfonyl)quinoline 2-(4-fluorobenzyl)thioquinoline 2-(4-fluorobenzyl)sulfinylquinoline 6-chloro-2-((4-bromobenzyl)sulfinyl)quinoline 6-chloro-2-((4-bromobenzyl)sulfonyl)quinoline 6-chloro-2-(4-chlorobenzyl)sulfinyl)quinoline 6-chloro-2-(4-chlorobenzyl)sulfonyl)quinoline 6-chloro-2-(4-fluorobenzyl)sulfinyl)quinoline 6-chloro-2-(4-fluorobenzyl)sulfonyl)quinoline 6-chloro-2-((4-sodium carboxybenzyl)thio)quinoline 6-fluoro-2-(benzylthio)quinoline 6-bromo-2-(benzyl)sulfinyl)quinoline 6-bromo-2-(benzyl)sulfonyl)quinoline 6-bromo-2-(cyanobenzyl)thio)quinoline 6-bromo-2-(cyanobenzyl)sulfinyl)quinoline 2-(4-chlorobenzyl)sulfinyl)quinoline 2-(4-chlorobenzyl)sulfonyl)quinoline 2-(4-bromobenzyl)thio)quinoline 2-(4-bromobenzyl)sulfinyl)quinoline 2-(4-bromobenzyl)sulfonyl)quinoline.

6. A composition comprising the quinoline sulfur-containing derivative according to any one of claims 1-5, its isomers, its prodrugs, its pharmaceutically acceptable salts, its hydrates or its solvate compounds, and a pharmaceutical carrier or excipient.

7. A method for preparing the quinoline sulfur-containing derivative according to any one of claims 1-5, characterized in that, including adding the compound of formula II and the compound of formula III to a solvent, and then adding a basic catalyst and reacting at room temperature 8. The method for the quinoline sulfur-containing 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-chloroperoxybenzoic acid or sodium periodate.

9. Use of the quinoline sulfur-containing derivative, its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate compound according to any one of claims 1-5, characterized in that, For (1) preparing anti-radiation drugs; (2) preparing TLR agonists and / or P53 protein phosphorylation inhibitors; and / or (3) preparing drugs for preventing and / or treating radiation-induced intestinal injury.

10. An active ingredient combination, the active ingredient combination comprising the following components: (1) The quinoline sulfur-containing derivative, its isomer, its prodrug, its pharmaceutically acceptable salt, its hydrate or its solvate as described in claim 1; and (2) An anti-radiation drug.

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