Quinolone compound as well as preparation method and application thereof

Abstract

The invention discloses a quinolone compound as well as a preparation method and application thereof, and belongs to the technical field of medicines. The invention provides a novel quinolone compound, which comprises a pharmaceutical salt, a hydrate, a solvate, a polycrystal or a co-crystal of the quinolone compound, and a pharmaceutical prodrug or derivative of the quinolone compound. The quinolone compound and the derivative thereof provided by the invention can be used for preparing related medicines for treating bacterial infection, and the compound has remarkable anti-MRSA activity and has no cross resistance with the existing fluoroquinolone medicines.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to a quinolone compound and a preparation method and use thereof. Background Art

[0002] Methicillin-resistant Staphylococcus aureus (MRSA) is multidrug-resistant and resistant to multiple first-line antibiotics. It is also known as a "superbug". The infection caused by it is difficult to control, which poses a very serious challenge to clinical treatment. Due to the emergence of community-associated MRSA, the incidence and mortality of MRSA infections have risen sharply worldwide. About 150,000 people are infected with MRSA in Europe each year, and Asia is one of the regions with the highest infection rates in the world. In the global antimicrobial drug market, fluoroquinolone antimicrobial drugs are second only to β-lactam antibiotics. Fluoroquinolones act on the topoisomerase catalytic subunits GyrA and ParC, and interact with the metal magnesium ion-water bridge through the C-3 / C-4 ketoacid fragment in the molecular structure to form a stable DNA-target enzyme-drug ternary complex, inhibiting bacterial DNA replication, thereby exerting antibacterial activity. However, the reason for the resistance of fluoroquinolones is also related to their mechanism of action. In topoisomerases, serine and acidic amino acids that fix metal-water bridges are prone to mutation (such as Ser83 and Asp87 in Escherichia coli GyrA), which affects the metal-water bridge interaction, reduces the affinity of the drug to the DNA / target enzyme complex, and produces drug resistance (Biochemistry 2014, 53, 1565-1574). Since fluoroquinolone antibiotics have resistance based on the mechanism of action, traditional fluoroquinolone antibiotics inevitably produce cross-resistance. Summary of the invention

[0003] In view of the above technical problems, the present invention provides a quinolone compound and a preparation method and use thereof. The newly synthesized quinolone compound has inhibitory activity against MRSA and has no cross-resistance with existing fluoroquinolone antibacterial drugs.

[0004] To achieve the above object, the present invention provides the following technical solutions:

[0005] One of the technical solutions of the present invention is to provide a quinolone compound, the structural formula of which is shown in formula (I), formula (II) or formula (III);

[0006]

[0007] In formula (I) to formula (III), R 1are independently selected from mono- or poly-substituted hydrogen, halogen, pyrrolidinyl, C1-6 alkyl, C3-7 cycloalkyl or C1-6 alkoxy; 2 are independently selected from methylamino, isopropylamino, cyclopropylamino, N,N-dimethylamino or hydroxyl.

[0008] The second technical solution of the present invention is to provide a method for preparing the above-mentioned quinolone compounds:

[0009] The preparation steps of the quinolone compound represented by formula (I) include:

[0010] Substituted benzyl bromide and 2,4-dichloropyrimidine are subjected to Negishi coupling to generate Int-1 (4-substituted benzyl-2-chloropyrimidine); Int-1 is catalytically oxidized to generate Int-2; Int-2 is aminated to obtain Int-3; Int-3 reacts with 7-bromoquinolone core A in an organic solvent in the presence of a palladium catalyst, a ligand, and a base to obtain Int-4; Int-4 is hydrolyzed under the action of a base to obtain a quinolone compound represented by formula (I);

[0011] The reaction equation of the quinolone compound shown in formula (I) is as follows:

[0012]

[0013] Preferably, the catalyst used in the Negishi coupling is a mixture of one or more of 1,2-dibromoethane, trimethylchlorosilane and trimethylbromosilane, and the solvent is a mixture of one or more of anhydrous tetrahydrofuran, anhydrous dioxane and anhydrous toluene.

[0014] Preferably, the catalyst used in the catalytic oxidation is ferrous chloride, the oxidant is oxygen or air, and the solvent is a mixture of one or more of dimethyl sulfoxide, DMF, anhydrous tetrahydrofuran and anhydrous dioxane.

[0015] Preferably, the amination agent of the amination is aqueous ammonia, the solvent is anhydrous ethanol or 95% ethanol, and the reaction temperature is 25-80°C.

[0016] Preferably, the palladium catalyst is palladium acetate, tris(dibenzylidene indene acetone) dipalladium or palladium chloride; the ligand is 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl, 2-tert-butylphospho-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphospho-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, 4,5-bis-diphenylphosphino-9,9-dimethylxanthene, 1,1'-bis-diphenylphosphinoferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphospho-2',6'-di isopropoxy-1,1'-biphenyl, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl, 2-di-tert-butylphosphine-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl or 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl; the base is potassium carbonate, potassium phosphate, cesium carbonate, potassium tert-butoxide or lithium hexamethyldisilazide; the organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, 1,4-dioxane, dibutyl ether or tert-butanol.

[0017] Preferably, the base used for the hydrolysis under the action of base is alkaline earth metal hydroxide, the solvent is a mixture of one or more of C1-C4 alcohol, tetrahydrofuran, dioxane, DMF and DMSO, and the reaction temperature is 25-50°C.

[0018] Optionally, the alkaline earth metal hydroxide includes lithium hydroxide, sodium hydroxide or potassium hydroxide.

[0019] The preparation steps of the quinolone compound represented by formula (II) include:

[0020] The substituted benzyl bromide and 2,4-dichloropyrimidine are subjected to Negishi coupling to generate Int-1; the Int-1 is catalytically oxidized to generate Int-2; the Int-2 is reacted with bis(2-methoxyethyl)aminosulfur trifluoride to generate difluoro-substituted Int-5; the Int-5 is aminated to obtain Int-6; Int-6 is reacted with a 7-bromoquinolone mother nucleus A in the presence of a palladium catalyst, a ligand, and a base in an organic solvent to obtain Int-7; the Int-7 is hydrolyzed under the action of a base to obtain a quinolone compound represented by formula (II);

[0021] The reaction equation of the quinolone compound shown in formula (II) is as follows:

[0022]

[0023] Preferably, the catalyst used in the Negishi coupling is a mixture of one or more of 1,2-dibromoethane, trimethylchlorosilane and trimethylbromosilane, and the solvent is a mixture of one or more of anhydrous tetrahydrofuran, anhydrous dioxane and anhydrous toluene.

[0024] Preferably, the catalyst used in the catalytic oxidation is ferrous chloride, the oxidant is oxygen or air, and the solvent is a mixture of one or more of dimethyl sulfoxide, DMF, anhydrous tetrahydrofuran and anhydrous dioxane.

[0025] Preferably, the amination agent of the amination is aqueous ammonia, the solvent is anhydrous ethanol or 95% ethanol, and the reaction temperature is 25-80°C.

[0026] Preferably, the palladium catalyst is palladium acetate, tris(dibenzylidene indene acetone) dipalladium or palladium chloride; the ligand is 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl, 2-tert-butylphospho-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphospho-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, 4,5-bis-diphenylphosphino-9,9-dimethylxanthene, 1,1'-bis-diphenylphosphinoferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphospho-2',6'-di isopropoxy-1,1'-biphenyl, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl, 2-di-tert-butylphosphine-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl or 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl; the base is potassium carbonate, potassium phosphate, cesium carbonate, potassium tert-butoxide or lithium hexamethyldisilazide; the organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, 1,4-dioxane, dibutyl ether or tert-butanol.

[0027] Preferably, the base used for the hydrolysis under the action of base is alkaline earth metal hydroxide, the solvent is a mixture of one or more of C1-C4 alcohol, tetrahydrofuran, dioxane, DMF and DMSO, and the reaction temperature is 25-50°C.

[0028] Optionally, the alkaline earth metal hydroxide includes lithium hydroxide, sodium hydroxide or potassium hydroxide.

[0029] When R 2 When the amino group is methylamino, isopropylamino or cyclopropylamino, the preparation steps of the quinolone compound represented by formula (III) include:

[0030] Substituted benzyl bromide and 2,4-dichloropyrimidine are subjected to Negishi coupling to generate Int-1; Int-1 is catalytically oxidized to generate Int-2; Int-2 is aminated to generate Int-3; Int-3 is reacted with 7-bromoquinolone core A in an organic solvent in the presence of a palladium catalyst, a ligand, and a base to generate Int-4; Int-4 is reductively aminated to generate Int-8; Int-8 is hydrolyzed under the action of a base to generate a quinolone compound represented by formula (III);

[0031] When R 2 When it is amino, isopropylamino or cyclopropylamino, the reaction equation of the quinolone compound represented by formula (III) is as follows:

[0032]

[0033] The R 3 are independently selected from methyl, isopropyl or cyclopropyl.

[0034] Preferably, the catalyst used in the Negishi coupling is a mixture of one or more of 1,2-dibromoethane, trimethylchlorosilane and trimethylbromosilane, and the solvent is a mixture of one or more of anhydrous tetrahydrofuran, anhydrous dioxane and anhydrous toluene.

[0035] Preferably, the catalyst used in the catalytic oxidation is ferrous chloride, the oxidant is oxygen or air, and the solvent is a mixture of one or more of dimethyl sulfoxide, DMF, anhydrous tetrahydrofuran and anhydrous dioxane.

[0036] Preferably, the amination agent of the amination is aqueous ammonia, the solvent is anhydrous ethanol or 95% ethanol, and the reaction temperature is 25-80°C.

[0037] Preferably, the palladium catalyst is palladium acetate, tris(dibenzylidene indene acetone) dipalladium or palladium chloride; the ligand is 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl, 2-tert-butylphospho-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphospho-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, 4,5-bis-diphenylphosphino-9,9-dimethylxanthene, 1,1'-bis-diphenylphosphinoferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphospho-2',6'-di isopropoxy-1,1'-biphenyl, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl, 2-di-tert-butylphosphine-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl or 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl; the base is potassium carbonate, potassium phosphate, cesium carbonate, potassium tert-butoxide or lithium hexamethyldisilazide; the organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, 1,4-dioxane, dibutyl ether or tert-butanol.

[0038] Preferably, in the reductive amination step, the reactants further comprise anhydrous sodium sulfate or anhydrous magnesium sulfate, methylamine, isopropylamine or cyclopropylamine, glacial acetic acid and sodium cyanoborohydride; the solvent is anhydrous ethanol or 95% ethanol, and the reaction temperature is 25-85°C.

[0039] Preferably, the base used for the hydrolysis under the action of base is alkaline earth metal hydroxide, the solvent is a mixture of one or more of C1-C4 alcohol, tetrahydrofuran, dioxane, DMF and DMSO, and the reaction temperature is 25-50°C.

[0040] Optionally, the alkaline earth metal hydroxide includes lithium hydroxide, sodium hydroxide or potassium hydroxide.

[0041] When R 2 When N,N-dimethylamino is used, the preparation steps of the quinolone compound represented by formula (III) include:

[0042] Negishi coupling of substituted benzyl bromide and 2,4-dichloropyrimidine to generate Int-1; catalytic oxidation of the Int-1 to generate Int-2; amination of the Int-2 to obtain Int-3; the Int-3 reacts with a 7-bromoquinolone core A in an organic solvent in the presence of a palladium catalyst, a ligand, and a base to obtain Int-4; reductive amination of the Int-4 to obtain Int-8; the Int-8 reacts with iodomethane under alkaline conditions to obtain Int-9; the Int-9 is hydrolyzed under the action of a base to obtain a quinolone compound represented by formula (III);

[0043] When R2 When it is N,N-dimethylamino, the reaction equation of the quinolone compound represented by formula (III) is as follows:

[0044]

[0045] The R 3 It is methyl.

[0046] Preferably, the catalyst used in the Negishi coupling is a mixture of one or more of 1,2-dibromoethane, trimethylchlorosilane and trimethylbromosilane, and the solvent is a mixture of one or more of anhydrous tetrahydrofuran, anhydrous dioxane and anhydrous toluene.

[0047] Preferably, the catalyst used in the catalytic oxidation is ferrous chloride, the oxidant is oxygen or air, and the solvent is a mixture of one or more of dimethyl sulfoxide, DMF, anhydrous tetrahydrofuran and anhydrous dioxane.

[0048] Preferably, the amination agent of the amination is aqueous ammonia, the solvent is anhydrous ethanol or 95% ethanol, and the reaction temperature is 25-80°C.

[0049] Preferably, the palladium catalyst is palladium acetate, tris(dibenzylidene indene acetone) dipalladium or palladium chloride; the ligand is 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl, 2-tert-butylphospho-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphospho-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, 4,5-bis-diphenylphosphino-9,9-dimethylxanthene, 1,1'-bis-diphenylphosphinoferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphospho-2',6'-di isopropoxy-1,1'-biphenyl, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl, 2-di-tert-butylphosphine-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl or 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl; the base is potassium carbonate, potassium phosphate, cesium carbonate, potassium tert-butoxide or lithium hexamethyldisilazide; the organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, 1,4-dioxane, dibutyl ether or tert-butanol.

[0050] Preferably, in the reductive amination step, the reactants further comprise anhydrous sodium sulfate or anhydrous magnesium sulfate, methylamine, glacial acetic acid and sodium cyanoborohydride, the solvent is anhydrous ethanol or 95% ethanol, and the reaction temperature is 25-85°C.

[0051] Preferably, the alkaline condition is provided by potassium carbonate, sodium hydride, potassium tert-butoxide or sodium amide.

[0052] Preferably, the base used for the hydrolysis under the action of base is alkaline earth metal hydroxide, the solvent is a mixture of one or more of C1-C4 alcohol, tetrahydrofuran, dioxane, DMF and DMSO, and the reaction temperature is 25-50°C.

[0053] Optionally, the alkaline earth metal hydroxide includes lithium hydroxide, sodium hydroxide or potassium hydroxide.

[0054] When R 2 When is hydroxyl, the preparation steps of the quinolone compound represented by formula (III) include:

[0055] Negishi coupling of substituted benzyl bromide and 2,4-dichloropyrimidine to generate Int-1; catalytic oxidation of the Int-1 to generate Int-2; ammoniation of the Int-2 to obtain Int-3; the Int-3 and 7-bromoquinolone core A react in an organic solvent in the presence of a palladium catalyst, a ligand, and a base to obtain Int-4; reduction of the Int-4 to obtain Int-10; hydrolysis of the Int-10 under the action of a base to obtain a quinolone compound represented by formula (III);

[0056] When R 2 When it is a hydroxyl group, the reaction equation of the quinolone compound represented by formula (III) is as follows:

[0057]

[0058] Preferably, the catalyst used in the Negishi coupling is a mixture of one or more of 1,2-dibromoethane, trimethylchlorosilane and trimethylbromosilane, and the solvent is a mixture of one or more of anhydrous tetrahydrofuran, anhydrous dioxane and anhydrous toluene.

[0059] Preferably, the catalyst used in the catalytic oxidation is ferrous chloride, the oxidant is oxygen or air, and the solvent is a mixture of one or more of dimethyl sulfoxide, DMF, anhydrous tetrahydrofuran and anhydrous dioxane.

[0060] Preferably, the amination agent of the amination is aqueous ammonia, the solvent is anhydrous ethanol or 95% ethanol, and the reaction temperature is 25-80°C.

[0061] Preferably, the palladium catalyst is palladium acetate, tris(dibenzylidene indene acetone) dipalladium or palladium chloride; the ligand is 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl, 2-tert-butylphospho-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphospho-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, 4,5-bis-diphenylphosphino-9,9-dimethylxanthene, 1,1'-bis-diphenylphosphinoferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphospho-2',6'-di isopropoxy-1,1'-biphenyl, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl, 2-di-tert-butylphosphine-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl or 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl; the base is potassium carbonate, potassium phosphate, cesium carbonate, potassium tert-butoxide or lithium hexamethyldisilazide; the organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, 1,4-dioxane, dibutyl ether or tert-butanol.

[0062] Preferably, the reducing agent for the reduction is sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride, and the solvent used is anhydrous ethanol, 95% ethanol or anhydrous tetrahydrofuran.

[0063] Preferably, the base used for the hydrolysis under the action of base is alkaline earth metal hydroxide, the solvent is a mixture of one or more of C1-C4 alcohol, tetrahydrofuran, dioxane, DMF and DMSO, and the reaction temperature is 25-50°C.

[0064] Optionally, the alkaline earth metal hydroxide includes lithium hydroxide, sodium hydroxide or potassium hydroxide.

[0065] The third technical solution of the present invention is to provide a pharmaceutically acceptable salt, hydrate, solvate, polycrystal of the above-mentioned quinolone compound or co-crystal containing the quinolone compound.

[0066] The fourth technical solution of the present invention is to provide a pharmaceutical prodrug or derivative of the above-mentioned quinolone compound.

[0067] The fifth technical solution of the present invention is to provide the use of one or more of the above-mentioned quinolone compounds, pharmaceutically acceptable salts, hydrates, solvates, polycrystals of quinolone compounds or co-crystals containing quinolone compounds, and pharmaceutical prodrugs or derivatives of the above-mentioned quinolone compounds in the preparation of drugs for treating bacterial infections.

[0068] Technical solution six of the present invention: Provided is a use of one or more of the above-mentioned quinolone compounds, pharmaceutically acceptable salts, hydrates, solvates, quinolone compound polycrystals or co-crystals containing quinolone compounds, and pharmaceutical prodrugs or derivatives of the above-mentioned quinolone compounds in the preparation of anti-methicillin-resistant Staphylococcus aureus drugs.

[0069] The beneficial technical effects of the present invention are as follows:

[0070] The novel quinolone compound provided by the invention has inhibitory activity against MRSA and has no cross-resistance with existing fluoroquinolone antibacterial drugs. DETAILED DESCRIPTION

[0071] Now, various exemplary embodiments of the present invention are described in detail, and this detailed description should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present invention. It should be understood that the terms described in the present invention are only for describing specific embodiments and are not used to limit the present invention.

[0072] In addition, for the numerical range in the present invention, it is understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. The intermediate value in any stated value or stated range, and each smaller range between any other stated value or intermediate value in the range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0073] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention pertains. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention.

[0074] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0075] Unless otherwise specified, the "room temperature" referred to in the embodiments of the present invention refers to a temperature of 20±5°C.

[0076] Example 1

[0077] Preparation of intermediate Int-1:

[0078]

[0079] Activated zinc powder (2.34 g, 36.0 mmol) was added to 25 mL of anhydrous tetrahydrofuran, and 0.1 mL of 1,2-dibromoethane and 0.1 mL of trimethylsilyl chloride were added dropwise in sequence. After reacting at 60 °C for 15 min under a nitrogen atmosphere, a solution of substituted benzyl bromide (33.0 mmol) in anhydrous tetrahydrofuran (20.0 mL) was slowly added dropwise, and the mixture was heated and stirred for 1 h to obtain the zinc reagent. After cooling to room temperature, the zinc reagent was slowly added dropwise to a solution of 2,4-dichloropyrimidine (4.47 g, 30.0 mmol) and tetrakistriphenylphosphine palladium (191 mg, 0.165 mmol) in anhydrous tetrahydrofuran (30.0 mL), and the mixture was heated and stirred at 60 ° C for 8 h under a nitrogen atmosphere. The reaction system was cooled to room temperature, and a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, brine and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was eluted by column chromatography with petroleum ether: ethyl acetate = 8:1, 6:1, 4:1, V:V, and separated and purified to obtain the intermediate Int-1.

[0080] Int-1a(R 1 =2-Cl): Yield 70%; 1 H NMR(400MHz,Chloroform-d)δ8.46(d,J=

[0081] 5.1Hz,1H),7.43-7.41(m,1H),7.33-7.31(m,1H),7.29-7.26(m,2H),6.96(d,J=5.1Hz,1H),4.26(s,2H).

[0082] Int-1b(R 1 =3-Cl): Yield 67%; 1 H NMR(400MHz,Chloroform-d)δ8.49(d,J=

[0083] 5.1Hz,1H),7.29-7.25(m,3H),7.16-7.13(m,1H),7.02(d,J=5.0Hz,1H),4.08(s,2H).

[0084] Int-1c(R 1 =4-Cl): Yield 46%; 1 H NMR(400MHz,Chloroform-d)δ8.48(d,J=

[0085] 5.1Hz,1H),7.31(d,J=8.4Hz,2H),7.19(d,J=8.2Hz,2H),7.02(d,J=5.1Hz,1H),4.07(s,2H).

[0086] Int-1d(R 1 =2,4-diCl):Yield 59%; 1 H NMR(400MHz,Chloroform-d)δ8.49(d,

[0087] J=5.1Hz,1H),7.44(d,J=2.1Hz,1H),7.28-7.27(m,2H),7.00(d,J=5.0Hz,1H),4.22(s,2H).

[0088] Int-1e(R 1 =3,4-diCl):Yield 71%; 1 H NMR(400MHz,Chloroform-d)δ8.51(d,

[0089] J=5.0Hz,1H),7.24(d,J=8.2Hz,1H),7.36(d,J=2.1Hz,1H),7.11(dd,J=8.2,2.1Hz,1H),7.03(d,J=5.0Hz,1H),4.06(s,2H).

[0090] Int-1f(R 1 =3,4-diF):Yield 71%; 1 H NMR(400MHz,Chloroform-d)δ8.50(d,

[0091] J=5.0Hz,1H),7.15-7.05(m,2H),7.02(d,J=5.1Hz,1H),6.98(ddd,J=8.5,4.1,1.9Hz,1H),4.05(s,2H).

[0092] Example 2

[0093] Preparation of intermediate Int-2:

[0094]

[0095] The intermediate Int-1 (10.0 mmol), ferrous chloride tetrahydrate (1.0 mmol) and acetic acid (10.0 mmol) were dissolved in dimethyl sulfoxide (16 mL), heated and stirred at 100 ° C under an oxygen atmosphere, and the reaction system was cooled to room temperature after TLC monitoring. Saturated sodium bicarbonate aqueous solution was added, extracted with ethyl acetate, and the organic phase was washed with water, brine and dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure distillation. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1, V: V) to obtain the intermediate Int-2.

[0096] Int-2a(R 1 =2-Cl): Yield 78%; 1 H NMR(400MHz,Chloroform-d)δ8.91(d,J=

[0097] 4.9Hz,1H),7.87(d,J=4.9Hz,1H),7.88(dd,J=7.6,1.8Hz,1H),7.51(ddd,J=8.0,7.2,1.8Hz,1H),7.46-7.39(m,2H).

[0098] Int-2b(R 1 =3-Cl): Yield 62%; 1 H NMR(400MHz,Chloroform-d)δ8.97(d,J=

[0099] 4.7Hz,1H),8.11(d,J=2.0Hz,1H),8.03(d,J=7.7Hz,1H),7.85(d,J=4.8Hz,1H),7.63(d,J=7.9Hz,1H),7.50-7.45(m,1H).

[0100] Int-2c(R 1 =4-Cl): Yield 78%; 1 H NMR(400MHz,Chloroform-d)δ8.92(d,J=

[0101] 5.0Hz, 1H), 8.12 (d, J = 8.6Hz, 2H), 7.86 (d, J = 4.9Hz, 1H), 7.51 (d, J = 8.7Hz, 2H).

[0102] Int-2d(R 1 =2,4-diCl):Yield 58%; 1 H NMR(400MHz,Chloroform-d)δ8.93(d,

[0103] J=4.9Hz,1H),7.89(d,J=4.9Hz,1H),7.54(d,J=8.3Hz,1H),7.49(d,J=1.9Hz,1H),7.41(dd,J=8.3,2.0Hz,1H).

[0104] Int-2e(R 1 =3,4-diCl):Yield 66%; 1 H NMR(400MHz,Chloroform-d)δ8.93(d,

[0105] J=4.9Hz,1H),8.29(d,J=2.0Hz,1H),8.04(dd,J=8.4,2.0Hz,1H),7.88(d,J=4.9Hz,1H),7.62(d,J=8.4Hz,1H).

[0106] Int-2f(R 1 =3,4-diF):Yield 56%; 1 H NMR(400MHz,Chloroform-d)δ8.93(d,

[0107] J=4.9Hz,1H),8.09(ddd,J=10.8,7.7,2.1Hz,1H),8.04(dddd,J=8.7,4.4,2.1,1.4Hz,1H),7.88(d,J=4.9Hz,1H),7.32(ddd,J=9.7,8.5,7.5Hz,1H).

[0108] Example 3

[0109] Preparation of intermediate Int-3:

[0110]

[0111] Add ammonia water (14 mL) to a solution of the intermediate Int-2 (2 mmol) in anhydrous ethanol (3 mL), heat and stir at 80°C to react overnight. After the reaction is completed by monitoring by TLC, the reaction system is cooled to room temperature, and ethanol is distilled off under reduced pressure. 10 mL of ethyl acetate is added, and 5.0 M hydrochloric acid is extracted (6 mL×5) to obtain an aqueous phase. Under ice bath and stirring conditions, the pH is adjusted to 10.0 with 5.0 M sodium hydroxide. The solid obtained is filtered, washed with water, and dried to obtain the intermediate Int-3, which is directly used in the next step without purification.

[0112] Example 4

[0113] Preparation of intermediate Int-4:

[0114]

[0115] 7-bromo-4-quinolone mother core intermediate A (0.6 mmol), intermediate Int-3 (0.5 mmol), tris(dibenzylideneacetone)dipalladium (0.02 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.06 mmol), anhydrous potassium carbonate (1.2 mmol) were added to anhydrous toluene (8.0 mL), heated and stirred at 110 ° C under a nitrogen atmosphere to react overnight, and the reaction was monitored by TLC until completion. The reaction system was cooled to room temperature, and the insoluble matter was removed by diatomaceous earth filtration. The filtrate was concentrated and then column chromatography was performed, and the mixture was eluted with dichloromethane:methanol = 30:1, 25:1, 20:1, V:V, respectively, to separate and purify the intermediate Int-4.

[0116] 7-Bromo-4-quinolone core intermediate A was prepared according to Eur. J. Med. Chem. 2024, 271, 116399.

[0117] Int-4a(R 1 =2-Cl): Yield 45%; 1H NMR (400MHz, Chloroform-d) δ8.73 (d, J

[0118] =4.9Hz,1H),8.50(d,J=1.9Hz,1H),8.47(s,1H),8.24(d,J=8.9Hz,2H),7.54(dd,J=7.6,1.6Hz,1H),7.47(dt,J=7.6,1.7Hz,1H),7.42(d ,J=7.9Hz,1H),7.39-7.33(m,3H),4.32(q,J=7.1Hz,2H),3.15-3.08(m,1H),1.35(t,J=7.1Hz,3H),1.21-1.15(m,2H),1.03-0.98(m,2H).

[0119] Int-4b(R 1 =3-Cl): Yield 65%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.60(s,1H),

[0120] 8.93(d,J=4.9Hz,1H),8.74(d,J=1.9Hz,1H),8.39(s,1H),8.07(d,J=8.8Hz,1H),8.05-8.04(m,1H),7.97(dt,J=7.8,1.3Hz,1H),7.82(dd,J=7.5,1.7Hz,1H),7.73(dd,J=8.8,1.9Hz,1H),7.63(t,J=7.9Hz,1H),7.40(d,J=4.9Hz,1H),4.21(q,J=7.1Hz,2H),3.19-3.17(m,1H),1.28(t,J=7.1Hz,3H),1.01-0.98(m,4H).

[0121] Int-4c(R 1 =4-Cl):Yield 25%; 1 H NMR(400MHz,Chloroform-d)δ8.77-8.76

[0122] (m,2H),8.51(s,1H),8.41(d,J=8.7Hz,1H),8.05(d,J=8.5Hz,2H),7.82(s,1H),7.49(d,J=8.5Hz,2H),7.34(d,J=4.8Hz,1H),7.27(dd,J=8.8,2.0Hz,1H),4.38(q,J=7.1Hz,2H),3.06-3.01(m,1H),1.40(t,J=7.1Hz,3H),0.99-0.98(m,4H).

[0123] Int-4d(R 1 =2,4-diCl):Yield 42%; 1 H NMR(400MHz,Chloroform-d)δ8.77(d,

[0124] J=4.9Hz,1H),8.59(d,J=1.9Hz,1H),8.52(s,1H),8.31(d,J=8.8Hz,1H),8.15(s,1H),7.53(d,J=8.2Hz,1H),7.46(d,J=1.9Hz,1H),7.39-7.36(m,3H),4.35(q,J=7.1Hz,2H),3.25-3.21(m,1H),1.38(t,J=7.1Hz,3H),1.28-1.23(m,2H),1.09-1.05(m,2H).

[0125] Int-4e(R 1=3,4-diF):Yield 50%; 1 H NMR(400MHz,Chloroform-d)δ8.78

[0126] (d,J=4.9Hz,1H),8.72(t,J=1.4Hz,1H),8.53(s,1H),8.42(d,J=8.7Hz,1H),8.01(td,J=8.4,4.0Hz,1H),7.95-7.91(m,1H),7.77(s,1H),7.3 6-7.33(m,2H),7.29(d,J=8.6Hz,1H),4.38(q,J=7.1Hz,2H),3.23-3.17(m,1H),1.40(t,J=7.1Hz,3H),1.14-1.09(m,2H),1.07-1.02(m,2H).

[0127]

[0128] Example 5

[0129] Preparation of Compound I:

[0130] The intermediate Int-4 (1.0 mmol) was dissolved in tetrahydrofuran (8.0 mL), and 5.0 M lithium hydroxide (5.0 mL) was added. The reaction was stirred and heated at 50°C for 3.0 h. After the reaction was completed by monitoring by TLC, the reaction system was cooled to room temperature, and tetrahydrofuran was removed by distillation under reduced pressure. The pH was adjusted to 2.0 with 4.0 M hydrochloric acid under ice bath and stirring. The solid was filtered, washed with water and dried to obtain the target compound I.

[0131] Ia(R 1 =2-Cl): Yield 67%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.55(s,1H),8.92

[0132] (d,J=4.8Hz,1H),8.66(s,1H),8.52(s,1H),8.00(d,J=9.0Hz,1H),7.70-7.60(m,4H),7.52(t, J=7.4Hz,1H),7.43(d,J=4.9Hz,1H),3.27-3.20(m,1H),1.20-1.15(m,2H),1.00-0.96(m,2H).

[0133] Ib(R 1 =3-Cl): Yield 74%; 1H NMR(400MHz,DMSO-d 6 )δ10.83(s,1H),

[0134] 8.98-8.97(m,2H),8.65(s,1H),8.23(d,J=8.9Hz,1H),8.05(t,J=1.9Hz,1H),7.98(d,J=7.8Hz,1H),7.90(d,J=9.1Hz,1H),7.83(dd,J=7.8,2.2Hz,1H),7.64(t,J=7.9Hz,1H),7.45(d,J=4.9Hz,1H),3.32-3.30(m,1H),1.11-1.07(m,4H).

[0135] Ic(R 1 =4-Cl):Yield 98%; 1 H NMR(400MHz,DMSO-d 6 )δ10.81(s,1H),9.00

[0136] (s,1H),8.96(d,J=4.9Hz,1H),8.64(s,1H),8.22(d,J=8.9Hz,1H),8.05(d,J=8.6Hz,2H),7.86(d,J=9.1Hz,1H),7.68(d,J=8.6Hz,2H),7.42(d,J=4.8Hz,1H),3.37-3.35(m,1H),1.11-1.08(m,2H),1.04-1.02(m,2H).

[0137] Id(R 1 =2,4-diCl):Yield 82%; 1 H NMR(400MHz,DMSO-d 6 )δ10.71(s,1H),

[0138] 8.97(d,J=4.9Hz,1H),8.70(s,1H),8.64(s,1H),8.08(d,J=8.9Hz,1H),7.85-7.82(m,2H),7.75(d,J=8.2Hz,1H),7.66(d,J=8.4Hz,1H),7.50(d,J=4.9Hz,1H),3.55-3.47(m,1H),1.26-1.24(m,2H),1.15-1.12(m,2H).

[0139] Ie(R 1 =3,4-diF):Yield 88%;1 H NMR (400 MHz, DMSO-d 6 )δ10.75(s,1H),

[0140] 8.92-8.91(m,2H),8.60(s,1H),8.16-8.09(m,2H),7.94-7.91(m,1H),7.85(dd,J=9.0,1.9Hz, 1H),7.64(dt,J=10.3,8.2Hz,1H),7.39(d,J=4.9Hz,1H),3.46-3.42(m,1H),1.14-1.10(m,4H).

[0141] Example 6

[0142] Preparation of intermediate Int-5:

[0143]

[0144] The intermediate Int-2 (2.0 mmol) and anhydrous ethanol (18.4 mg, 0.4 mmol) were dissolved in anhydrous dichloromethane (2 mL) solution, and a solution of bis(2-methoxyethyl)aminosulfur trifluoride (751 mg, 3.4 mmol) in anhydrous dichloromethane (1 mL) was added dropwise under a nitrogen atmosphere. The room temperature was slowly raised to 65 ° C. and the mixture was heated and stirred for 3.0 h. The reaction system was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with dichloromethane. The organic phase was washed with water, brine and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1, V:V) to obtain the intermediate Int-5.

[0145] Int-5a(R 1 =2-Cl):Yield 35%; 1 H NMR(400MHz,Chloroform-d)δ8.82(d,J=

[0146] 5.1Hz,1H),7.92-7.89(m,1H),7.80(d,J=5.0Hz,1H),7.47-7.38(m,3H).

[0147] Int-5b(R 1 =3-Cl): Yield 61%; 1 H NMR(400MHz,Chloroform-d)δ8.81(d,J=

[0148] 5.0Hz,1H),7.65(d,J=5.0Hz,1H),7.60(d,J=2.0Hz,1H),7.51(ddd,J=7.6,1.9,1.0Hz,1H),7.47-7.44(m,1H),7.42-7.38(m,1H).

[0149] Int-5c(R 1 =4-Cl): Yield 64%; 1 H NMR(400MHz,Chloroform-d)δ8.80(d,J=

[0150] 5.0Hz, 1H), 7.64 (d, J = 5.0Hz, 1H), 7.56 (d, J = 8.5Hz, 2H), 7.43 (d, J = 8.3Hz, 2H).

[0151] Int-5d(R 1 =2,4-diCl):Yield 73%; 1 H NMR(400MHz,Chloroform-d)δ8.84(d,

[0152] J=5.0Hz,1H),7.84(d,J=8.3Hz,1H),7.80(d,J=5.0Hz,1H),7.45(d,J=2.1Hz,1H),7.44(dd,J=8.6,1.6Hz,1H).

[0153] Int-5e(R 1 =3,4-diCl):Yield 33%; 1 H NMR(400MHz,Chloroform-d)δ8.83(d,

[0154] J=5.0Hz,1H),7.72(d,J=2.1Hz,1H),7.61(d,J=5.1Hz,1H),7.56(d,J=8.4Hz,1H),7.48(dd,J=8.5,2.1Hz,1H).

[0155] Example 7

[0156] Preparation of intermediate Int-6:

[0157]

[0158] Aqueous ammonia (14 mL) was added to a solution of the intermediate Int-5 (2 mmol) in anhydrous ethanol (3 mL). The reaction was heated and stirred at 80°C overnight. After the reaction was completed by monitoring by TLC, the reaction system was cooled to room temperature, ethanol was removed by distillation under reduced pressure, ethyl acetate was added, and 5.0 M hydrochloric acid was used for multiple extractions to obtain an aqueous phase. Under ice bath and stirring conditions, the pH was adjusted to 10.0 with 5.0 M sodium hydroxide. The solid obtained was filtered, washed with water, and dried to obtain the intermediate Int-6, which was directly used in the next step without further purification.

[0159] Example 8

[0160] Preparation of intermediate Int-7:

[0161]

[0162] 7-bromo-4-quinolone core intermediate A (201 mg, 0.6 mmol), intermediate Int-6 (0.5 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (29 mg, 0.06 mmol), anhydrous potassium carbonate (166 mg, 1.2 mmol) were added to anhydrous toluene (8.0 mL), and the mixture was stirred and heated at 110 °C under a nitrogen atmosphere to react overnight. After the reaction was completed, the reaction system was cooled to room temperature, the insoluble matter was removed by diatomaceous earth filtration, and the residue obtained by concentrating the filtrate was separated and purified by column chromatography (dichloromethane:methanol=20:1, V:V) to obtain intermediate Int-7.

[0163] Int-7a(R 1 =2-Cl): Yield 48%; 1 H NMR(400MHz,Chloroform-d)δ8.63(d,J=

[0164] 5.0Hz,1H),8.50(d,J=2.0Hz,1H),8.48(s,1H),8.24(d,J=8.8Hz,1H),8.12(s,1H),7.80(dd,J=8.0,2.1Hz,1H),7.44-7.36(m,3H),7.28(dd,J =8.8,2.0Hz,1H),7.19(d,J=5.0Hz,1H),4.32(q,J=7.1Hz,2H),3.34-3. 28(m,1H),1.34(t,J=7.1Hz,3H),1.26-1.23(m,2H),1.06-1.02(m,2H).

[0165] Int-7b(R 1 =3-Cl): Yield 64%;1 H NMR(400MHz,Chloroform-d)δ8.68(d,J=

[0166] 2.0Hz,1H),8.61(d,J=4.9Hz,1H),8.50(s,1H),8.47(s,1H),8.33(d,J=8.8Hz,1H),7.56(d,J=1.9Hz,1H),7.43-7.30(m,4H),7.11(d,J=5.0Hz,1H),4.31(q,J=7.1Hz,2H),3.36-3.31(m,1H),1.33(t,J=7.1Hz,3H),1.25-1.20(m,2H),1.05-1.01(m,2H).

[0167] Int-7c(R 1 =4-Cl):Yield 82%; 1 H NMR(400MHz,Chloroform-d)δ8.74(d,J=

[0168] 2.0Hz,1H),8.64(d,J=4.9Hz,1H),8.55(s,1H),8.39(d,J=8.7Hz,1H),7.99(s,1H),7.53(d,J=8.5Hz,2H),7.40(d,J=8.4Hz,2H),7.32(dd,J=8.8,2.0Hz,1H),7.15(d,J=5.0Hz,1H),4.37(q,J=7.1Hz,2H),3.38-3.33(m,1H),1.39(t,J=7.1Hz,3H),1.29-1.24(m,2H),1.10-1.05(m,2H).

[0169] Int-7d(R 1 =2,4-diCl):Yield 47%; 1 H NMR(400MHz,Chloroform-d)δ8.70(d,

[0170] J=5.0Hz,1H),8.60(d,J=2.0Hz,1H),8.58(s,1H),8.38(d,J=8.8Hz,1H),7.80(d,J=8.3Hz,1H),7.64(s,1H),7.47-7.44(m,2H),7.31(dd,J=8 .8,1.8Hz,1H),7.26(d,J=5.1Hz,1H),4.41(q,J=7.1Hz,2H),3.41-3.37(m,1H),1.42(t,J=7.1Hz,3H),1.36-1.31(m,2H),1.15-1.11(m,2H).

[0171] Int-7e(R 1 =3,4-diCl):Yield 49%; 1 H NMR(400MHz,Chloroform-d)δ8.70(d,

[0172] J=2.0Hz,1H),8.65(d,J=4.9Hz,1H),8.55(s,1H),8.38(d,J=8.7Hz,1H),8.25(s,1H),7.69(d,J=2.1Hz,1H),7.49(d,J=8.5Hz,1H),7.41(dd,J= 8.4, 2.3Hz, 2H), 7.15 (d, J=5.0Hz, 1H)), 4.36 (q, J=7.1Hz, 2H), 3.42-3. 37(m,1H),1.37(t,J=7.1Hz,3H),1.31-1.26(m,2H),1.11-1.07(m,2H).

[0173] Example 9

[0174] Preparation of compound II:

[0175]

[0176] The intermediate Int-7 (1.0 mmol) was dissolved in tetrahydrofuran (8.0 mL), and 5.0 M lithium hydroxide (5.0 mL) was added. The reaction was stirred and heated at 50°C for 3.0 h. After the reaction was completed by monitoring by TLC, the reaction system was cooled to room temperature, and tetrahydrofuran was removed by distillation under reduced pressure. The pH was adjusted to 2.0 with 4.0 M hydrochloric acid under ice bath and stirring. The solid was filtered, washed with water and dried to obtain the target compound II.

[0177] IIa(R 1 =2-Cl):Yield 85%; 1 H NMR (400 MHz, DMSO-d 6)δ10.72(s,1H),

[0178] 8.91(d,J=5.0Hz,1H),8.75(s,1H),8.65(s,1H),8.10(d,J=8.9Hz,1H),7.91(dd,J=7.8,2.1Hz,1H),7.80(d,J=9.0Hz,1H),7.65-7.59(m,3H),7.42(d,J=5.0Hz,1H),3.61-3.56(m,1H),1.27-1.24(m,2H),1.17-1.15(m,2H).

[0179] IIb(R 1 =3-Cl):Yield 91%; 1 H NMR(400MHz,DMSO-d 6 )δ10.77(s,1H),

[0180] 8.86(d,J=5.0Hz,1H),8.84(s,1H),8.63(s,1H),8.17(d,J=8.9Hz,1H),7.85(dd,J=8.9,1.9Hz,1H),7.68(d,J=2.3Hz,1H),7.64-7.53(m,3H),7.40(d,J=5.0Hz,1H),3.62-3.56(m,1H),1.26-1.21(m,2H),1.15-1.13(m,2H).

[0181] IIc(R 1 =4-Cl):Yield 87%; 1 H NMR(400MHz,DMSO-d 6 )δ10.70(s,1H),

[0182] 8.84(d,J=5.0Hz,1H),8.80(s,1H),8.65(s,1H),8.16(d,J=8.9Hz,1H),7.77(d,J=8.9Hz,1H),7.62(d,J=8.8Hz,2H),7.57(d,J=8.5Hz,2H),7.34(d,J=5.0Hz,1H),3.57-3.49(m,1H),1.23-1.16(m,2H),1.11-1.03(m,2H).

[0183] IId(R 1 =2,4-diCl):Yield 99%; 1 H NMR(400MHz,DMSO-d 6)δ10.71(s,1H),

[0184] 8.92(d,J=5.0Hz,1H),8.74(s,1H),8.66(s,1H),8.12(d,J=8.9Hz,1H),7.92(d,J=8.4Hz,1H),7.82(s,1H),7.79(d, J=8.9Hz,1H),7.71(d,J=8.5Hz,1H),7.43(d,J=5.0Hz,1H),3.65-3.59(m,1H),1.29-1.26(m,2H),1.18-1.17(m,2H).

[0185] IIe(R 1 =3,4-diCl):Yield 87%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.78(s,1H),

[0186] 8.89(d,J=5.0Hz,1H),8.84(s,1H),8.66(s,1H),8.20(d,J=8.9Hz,1H),7.91(d,J=2.1Hz,1H),7.86(dd,J=8.9,1H),7.82(d ,J=8.4Hz,1H),7.62(dd,J=8.4,2.2Hz,1H),7.42(d,J=5.0Hz,1H),3.66-3.60(m,1H),1.29-1.24(m,2H),1.17-1.15(m,2H).

[0187] Example 10

[0188] Preparation of compound III-1:

[0189]

[0190] The intermediate Int-4 (0.5mmol), anhydrous sodium sulfate (107mg, 0.75mmol), aliphatic amine (one of methylamine, isopropylamine or cyclopropylamine, 2.5mmol) and 1 drop of acetic acid were added to anhydrous ethanol (5.0mL), heated and stirred at 80℃ for 3.0h, and then the reaction system was cooled to 60℃ and sodium cyanoborohydride (63mg, 1mmol) was added. After heating and stirring for 3.0h, the reaction was monitored by TLC until the end, and then the reaction system was cooled to room temperature, saturated sodium bicarbonate aqueous solution was added, and dichloromethane was extracted. After the organic phase was washed with water, brine and dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure to obtain the intermediate Int-8. The intermediate Int-8 did not need to be purified and was directly subjected to the next step.

[0191] The intermediate Int-8 (1.0 mmol) was dissolved in tetrahydrofuran (8.0 mL), and 5.0 M lithium hydroxide (5.0 mL) was added. The reaction was stirred and heated at 50 °C for 3.0 h. After the reaction was completed by monitoring by TLC, the reaction system was cooled to room temperature, and tetrahydrofuran was removed by distillation under reduced pressure. Under ice bath and stirring conditions, the pH was adjusted to 2.0 with 4.0 M hydrochloric acid. The solid was filtered, washed with water, and dried to obtain the target compound III-1.

[0192] III-1a(R 1 =3-Cl,R 3 =Me):Yield 48%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.50

[0193] (s,1H),8.97(s,1H),8.68(s,1H),8.61(d,J=5.1Hz,1H),8.22(d,J=8.9Hz,1H),7.92(d,J=9.1Hz,1H),7.51(s,1H),7.38 -7.30(m,3H),7.18(d,J=5.1Hz,1H),4.70(s,1H),3.76-3.70(m,1H),2.27(s,3H),1.32-1.26(m,2H),1.22-1.18(m,2H).

[0194] III-1b(R 1 =3-Cl,R 3 =iPr):Yield 36%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.48

[0195] (s,1H),8.92(s,1H),8.67(s,1H),8.60(d,J=5.0Hz,1H),8.22(d,J=8.9Hz,1H),7.94(d,J=9.0Hz,1H),7.54(s,1H),7.41-7.30(m,3H), 7.23(d,J=5.1Hz,1H),4.95(s,1H),3.74-3.69(m,1H),2.65-2.62(m,1H),1.32-1.27(m,2H),1.22-1.18(m,2H),1.03(d,J=6.0Hz,6H).

[0196] III-1c(R 1 =4-Cl,R 3 =cycloPr):Yield 78%;1 H NMR (400 MHz, DMSO-d 6 )δ

[0197] 10.5(s,1H),8.98(d,J=2.0Hz,1H),8.68(s,1H),8.61(d,J=5.0Hz,1H),8. 22(d,J=8.9Hz,1H),7.90(dd,J=9.0,1.9Hz,1H),7.44(d,J=8.6Hz,2H),7.3 9(d,J=8.6Hz,2H),7.21(d,J=5.1Hz,1H),4.88(s,1H),3.74-3.71(m,1H),2 .03-1.96(m,1H),1.31-1.27(m,2H),1.23-1.18(m,2H),0.36-0.30(m,4H).

[0198] III-1d(R 1 =2,4-diF,R 3 =cycloPr):Yield 78%; 1 H NMR (400 MHz, DMSO-d 6 )δ

[0199] 10.48(s,1H),8.94(s,1H),8.68(s,1H),8.63(d,J=5.1Hz,1H),8.19(d,J=8.9Hz,1H) ,7.93-7.90(m,1H),7.62(d,J=2.1Hz,1H),7.53(q,J=8.1Hz,1H),7.25-7.19(m,1H), 7.11(dt,J=9.7,4.4Hz,1H),5.14(d,J=6.8Hz,1H),3.73-3.66(m,1H),3.52(d,J=8.9 Hz,1H),2.05-2.00(m,1H),1.34-1.29(m,2H),1.23-1.19(m,2H),0.39-0.28(m,4H).

[0200] Embodiment 11

[0201] Preparation of compound III-2a:

[0202]

[0203] Under nitrogen atmosphere, to a solution of intermediate Int-8b (251 mg, 0.5 mmol) in anhydrous acetonitrile (4.0 mL) was added a solution of potassium carbonate (104 mg, 0.75 mmol) in anhydrous acetonitrile (1.0 mL), and the reaction was stirred at room temperature for 15 min. A solution of iodomethane (71 mg, 0.5 mmol) in anhydrous acetonitrile (1.0 mL) was added, and the reaction was stirred at room temperature overnight. After the reaction was monitored by TLC, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, brine and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane: methanol = 20:1, V:V) to obtain intermediate Int-9a.

[0204] Int-9a: Yield 78%; 1 H NMR(400MHz,Chloroform-d)δ8.74(d,J=2.0Hz,

[0205] 1H),8.57(s,1H),8.45(d,J=5.1Hz,1H),8.40(d,J=8.8Hz,1H),7.86(s,1H),7.50(s,1H),7.41-36(m,2H),7.28-7.25(m,2H),7.07(d,J=5. 1Hz,1H),4.41(q,J=7.1Hz,2H),4.11(s,1H),3.51-3.45(m,1H),2.27(s,6H),1.42(t,J=7.1Hz,3H),1.39-1.33(m,2H),1.16-1.12(m,2H).

[0206] The intermediate Int-9a (532 mg, 1.0 mmol) was dissolved in tetrahydrofuran (8.0 mL), and 5.0 M lithium hydroxide (5.0 mL) was added. The reaction was stirred at 50 ° C for 3.0 h. After the reaction was monitored by TLC, the reaction system was cooled to room temperature, and tetrahydrofuran was removed by distillation under reduced pressure. Under ice bath and stirring conditions, the pH was adjusted to 2.0 with 4.0 M hydrochloric acid. The solid was filtered, washed with water, and dried to obtain the target compound III-2a.

[0207] III-2a: Yield 73%; 1 H NMR (400 MHz, DMSO-d 6)δ10.52(s,1H),9.01(s,1H),8.69(s,1H),8.62(d,J=5.0Hz,1H),8.22(d,J=8.8Hz,1H),7.91(d,J=9.0Hz,1H),7.55(s,1H), 7.46-7.33(m,3H),7.26(d,J=5.2Hz,1H),4.27(s,1H),3.77-3.71(m,1H),2.18(s,6H),1.40-1.31(m,2H),1.24-1.19(m,2H).

[0208] Example 12

[0209] Preparation of compound III-3:

[0210]

[0211] The intermediate Int-4 (0.5 mmol), sodium cyanoborohydride (63 mg, 1 mmol) and 1 drop of acetic acid were added to anhydrous ethanol (5.0 mL), heated and stirred at 60 ° C for 3.0 h, and the reaction was monitored by TLC until completion. The reaction system was cooled to room temperature, saturated sodium bicarbonate aqueous solution was added, and dichloromethane was extracted. The organic phase was washed with water, brine and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the intermediate Int-10. The intermediate Int-10 did not need to be purified and was directly subjected to the next step of reaction.

[0212] The intermediate Int-10 (1.0 mmol) was dissolved in tetrahydrofuran (8.0 mL), and 5.0 M lithium hydroxide (5.0 mL) was added. The reaction was stirred and heated at 50°C for 3.0 h. After the reaction was completed by monitoring by TLC, the reaction system was cooled to room temperature, and tetrahydrofuran was removed by distillation under reduced pressure. The pH was adjusted to 2.0 with 4.0 M hydrochloric acid under ice bath and stirring. The solid was filtered, washed with water and dried to obtain the target compound III-3.

[0213] III-3a(R 1 =3-Cl): Yield 36%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.50(s,1H),

[0214] 8.96(s,1H),8.68(s,1H),8.66(d,J=5.2Hz,1H),8.22(d,J=8.9Hz,1H),7.93(d,J=9.0Hz,1H),7.51(s,1H),7.40-7.33(m,3H) ,7.25(d,J=5.0Hz,1H),6.45(d,J=4.3Hz,1H),5.67(d,J=4.2Hz,1H),3.70-3.67(m,1H),1.32-1.27(m,2H),1.19-1.18(m,2H).

[0215] The inhibitory activity of the target compound synthesized in the embodiment of the present invention on methicillin-resistant Staphylococcus aureus (MRSA) was measured, and the test results are shown in Table 1.

[0216] Table 1 Antimicrobial activity

[0217]

[0218]

[0219] Note: ATCC33591 is the standard strain of MRSA, and Mu50 is the MRSA strain resistant to fluoroquinolones.

[0220] It can be seen from Table 1 that the novel quinolone compounds synthesized in the present invention have inhibitory activity against MRSA and have no cross-resistance with existing fluoroquinolone antibacterial drugs.

[0221] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A quinolone compound, characterized in that: The structural formula is shown in formula (I), formula (II) or formula (III); In formula (I) to formula (III), R1 is independently selected from monosubstituted or polysubstituted hydrogen, halogen atom, pyrrolidinyl, C1-6 alkyl, C3-7 cycloalkyl or C1-6 alkoxy; R2 is independently selected from methylamino, isopropylamino, cyclopropylamino, N,N-dimethylamino or hydroxyl.

2. A method for preparing the quinolone compound according to claim 1, characterized in that: The preparation steps of the quinolone compound represented by formula (I) include: Substituted benzyl bromide and 2,4-dichloropyrimidine are subjected to Negishi coupling to generate Int-1; Int-1 is catalytically oxidized to generate Int-2; Int-2 is aminated to obtain Int-3; Int-3 reacts with 7-bromoquinolone core A in an organic solvent in the presence of a palladium catalyst, a ligand, and a base to obtain Int-4; Int-4 is hydrolyzed under the action of a base to obtain a quinolone compound represented by formula (I); The reaction equation of the quinolone compound shown in formula (I) is as follows:

3. A method for preparing the quinolone compound according to claim 1, characterized in that: The preparation steps of the quinolone compound represented by formula (II) include: The substituted benzyl bromide and 2,4-dichloropyrimidine are subjected to Negishi coupling to generate Int-1; the Int-1 is catalytically oxidized to generate Int-2; the Int-2 is reacted with bis(2-methoxyethyl)aminosulfur trifluoride to generate difluoro-substituted Int-5; the Int-5 is aminated to obtain Int-6; Int-6 is reacted with a 7-bromoquinolone mother nucleus A in the presence of a palladium catalyst, a ligand, and a base in an organic solvent to obtain Int-7; the Int-7 is hydrolyzed under the action of a base to obtain a quinolone compound represented by formula (II); The reaction equation of the quinolone compound shown in formula (II) is as follows:

4. A method for preparing the quinolone compound according to claim 1, characterized in that: When R2 is amino, isopropylamino or cyclopropylamino, the preparation steps of the quinolone compound represented by formula (III) include: Substituted benzyl bromide and 2,4-dichloropyrimidine are subjected to Negishi coupling to generate Int-1; Int-1 is catalytically oxidized to generate Int-2; Int-2 is aminated to generate Int-3; Int-3 is reacted with 7-bromoquinolone core A in an organic solvent in the presence of a palladium catalyst, a ligand, and a base to generate Int-4; Int-4 is reductively aminated to generate Int-8; Int-8 is hydrolyzed under the action of a base to generate a quinolone compound represented by formula (III); When R2 is methylamino, isopropylamino or cyclopropylamino, the reaction equation of the quinolone compound represented by formula (III) is as follows: The R3 is independently selected from methyl, isopropyl or cyclopropyl.

5. A method for preparing the quinolone compound according to claim 1, characterized in that: When R2 is N,N-dimethylamino, the preparation steps of the quinolone compound represented by formula (III) include: Substituted benzyl bromide and 2,4-dichloropyrimidine are subjected to Negishi coupling to generate Int-1; Int-1 is catalytically oxidized to generate Int-2; Int-2 is aminated to generate Int-3; Int-3 is reacted with 7-bromoquinolone core A in an organic solvent in the presence of a palladium catalyst, a ligand, and a base to generate Int-4; Int-4 is reductively aminated to generate Int-8; Int-8 is reacted with methyl iodide under alkaline conditions to generate Int-9; Int-9 is hydrolyzed under the action of a base to generate a quinolone compound represented by formula (III); When R2 is N,N-dimethylamino, the reaction equation of the quinolone compound represented by formula (III) is as follows: The R3 is a methyl group.

6. A method for preparing the quinolone compound according to claim 1, characterized in that: When R2 is a hydroxyl group, the preparation steps of the quinolone compound represented by formula (III) include: Negishi coupling of substituted benzyl bromide and 2,4-dichloropyrimidine to generate Int-1; catalytic oxidation of the Int-1 to generate Int-2; ammoniation of the Int-2 to obtain Int-3; the Int-3 and 7-bromoquinolone core A react in an organic solvent in the presence of a palladium catalyst, a ligand, and a base to obtain Int-4; reduction of the Int-4 to obtain Int-10; hydrolysis of the Int-10 under the action of a base to obtain a quinolone compound represented by formula (III); When R2 is a hydroxyl group, the reaction equation of the quinolone compound represented by formula (III) is as follows:

7. A pharmaceutically acceptable salt, hydrate, solvate, polycrystal of the quinolone compound according to claim 1, or a cocrystal containing the quinolone compound.

8. A pharmaceutical prodrug or derivative of the quinolone compound according to claim 1.

9. Use of one or more of the quinolone compound according to claim 1, the pharmaceutically acceptable salt, hydrate, solvate, polycrystal of the quinolone compound or cocrystal containing the quinolone compound according to claim 7, and the pharmaceutical prodrug or derivative of the quinolone compound according to claim 8 in the preparation of a drug for treating bacterial infection.

10. Use of one or more of the quinolone compound according to claim 1, the pharmaceutically acceptable salt, hydrate, solvate, polycrystal of the quinolone compound or cocrystal containing the quinolone compound according to claim 7, and the pharmaceutical prodrug or derivative of the quinolone compound according to claim 8 in the preparation of an anti-methicillin-resistant Staphylococcus aureus drug.

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