A quinolone compound and its preparation method and use

Abstract

The present invention discloses a quinolone compound, its preparation method, and use, belonging to the field of pharmaceutical technology. The present invention provides a novel quinolone compound, including pharmaceutically acceptable salts, hydrates, solvates, polycrystals, or cocrystals thereof, as well as pharmaceutical prodrugs or derivatives thereof. The provided quinolone compound and its derivatives can be used to prepare drugs for treating bacterial infections. The compounds exhibit significant anti-MRSA activity and lack cross-resistance with existing fluoroquinolones.

Description

Technical Field

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

[0002] Methicillin-resistant Staphylococcus aureus (MRSA) is multidrug-resistant, exhibiting resistance to multiple first-line antibiotics and is often referred to as a "superbug." The infections it causes are difficult to control, posing a significant challenge to clinical treatment. Due to the emergence of community-associated MRSA, the morbidity and mortality rates of MRSA infections have skyrocketed globally. Approximately 150,000 people in Europe are infected with MRSA annually, with Asia having one of the highest infection rates globally. Fluoroquinolones are second only to β-lactam antibiotics in the global antimicrobial market. Fluoroquinolones act on the topoisomerase catalytic subunits GyrA and ParC, interacting through the C-3 / C-4 ketoacid moiety in their molecular structure with a magnesium ion-water bridge to form a stable DNA-target enzyme-drug ternary complex, inhibiting bacterial DNA replication and thereby exerting their antimicrobial activity. However, the development of resistance to fluoroquinolones is also related to their mechanism of action. In topoisomerases, serine and acidic amino acids that anchor metal-water bridges are prone to mutation (e.g., Ser83 and Asp87 in Escherichia coli GyrA), which can affect the metal-water bridge interaction, reduce the affinity of the drug for the DNA / target enzyme complex, and lead to drug resistance (Biochemistry 2014, 53, 1565-1574). Because fluoroquinolone antibiotics exhibit mechanism-based resistance, cross-resistance to traditional fluoroquinolone antibiotics is unavoidable. Summary of the Invention

[0003] In response to the above technical problems, the present invention provides a quinolone compound, 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 having a structural formula shown in Formula (I), Formula (II) or Formula (III);

[0006]

[0007] 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.

[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] Negishi coupling of substituted benzyl bromide and 2,4-dichloropyrimidine to produce Int-1 (4-substituted benzyl-2-chloropyrimidine); catalytic oxidation of Int-1 to produce Int-2; amination of Int-2 to produce Int-3; Int-3 reacts with a 7-bromoquinolone core A in the presence of a palladium catalyst, a ligand, and a base in an organic solvent to produce Int-4; Int-4 is hydrolyzed in the presence of a base to produce 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 reagent 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-butylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, 4,5-bisdiphenylphosphino-9,9-dimethylxanthene, 1,1'-bisdiphenylphosphinoferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl Isopropoxy-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl or 2-dicyclohexylphosphino-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] Negishi coupling of substituted benzyl bromide with 2,4-dichloropyrimidine to produce Int-1; catalytic oxidation of Int-1 to produce Int-2; reaction of Int-2 with bis(2-methoxyethyl)aminosulfur trifluoride to produce difluoro-substituted Int-5; amination of Int-5 to produce Int-6; reaction of Int-6 with a 7-bromoquinolone core A in the presence of a palladium catalyst, a ligand, and a base in an organic solvent to produce Int-7; hydrolysis of Int-7 in the presence of a base to produce 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 reagent 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-butylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, 4,5-bisdiphenylphosphino-9,9-dimethylxanthene, 1,1'-bisdiphenylphosphinoferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl Isopropoxy-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl or 2-dicyclohexylphosphino-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 R2 is methylamino, isopropylamino or cyclopropylamino, the preparation steps of the quinolone compound represented by formula (III) include:

[0030] Negishi coupling of substituted benzyl bromide with 2,4-dichloropyrimidine to produce Int-1; catalytic oxidation of Int-1 to produce Int-2; amination of Int-2 to produce Int-3; reaction of Int-3 with a 7-bromoquinolone core A in an organic solvent in the presence of a palladium catalyst, a ligand, and a base to produce Int-4; reductive amination of Int-4 to produce Int-8; and hydrolysis of Int-8 in the presence of a base to produce a quinolone compound represented by formula (III);

[0031] When R2 is amino, isopropylamino or cyclopropylamino, the reaction equation of the quinolone compound represented by formula (III) is as follows:

[0032]

[0033] Said R3 is 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 reagent 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-butylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, 4,5-bisdiphenylphosphino-9,9-dimethylxanthene, 1,1'-bisdiphenylphosphinoferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl Isopropoxy-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl or 2-dicyclohexylphosphino-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 R2 is N,N-dimethylamino, the preparation steps of the quinolone compound represented by formula (III) include:

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

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

[0044]

[0045] The R3 is a methyl group.

[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 reagent 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-butylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, 4,5-bisdiphenylphosphino-9,9-dimethylxanthene, 1,1'-bisdiphenylphosphinoferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl Isopropoxy-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl or 2-dicyclohexylphosphino-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 R2 is a hydroxyl group, the preparation steps of the quinolone compound represented by formula (III) include:

[0055] Negishi coupling of substituted benzyl bromide and 2,4-dichloropyrimidine to produce Int-1; catalytic oxidation of Int-1 to produce Int-2; amination of Int-2 to produce Int-3; Int-3 reacting with a 7-bromoquinolone core A in the presence of a palladium catalyst, a ligand, and a base in an organic solvent to produce Int-4; reducing Int-4 to produce Int-10; and hydrolyzing Int-10 in the presence of a base to produce a quinolone compound represented by formula (III);

[0056] When R2 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 reagent 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-butylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, 4,5-bisdiphenylphosphino-9,9-dimethylxanthene, 1,1'-bisdiphenylphosphinoferrocene, 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl Isopropoxy-1,1'-biphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl or 2-dicyclohexylphosphino-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 a 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: provides the 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 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 cocrystals 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 present invention has inhibitory activity against MRSA and has no cross-resistance with existing fluoroquinolone antibacterial drugs. DETAILED DESCRIPTION

[0071] Various exemplary embodiments of the present invention are now described in detail. 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, features, and embodiments of the present invention. It should be understood that the terms used in the present invention are only for describing specific embodiments and are not intended to limit the present invention.

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

[0073] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein can 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” 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 under a nitrogen atmosphere for 15 min, 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 prepare 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). The mixture was heated and stirred at 60 ° C. under a nitrogen atmosphere for 8 h. The reaction system was cooled to room temperature, and a saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate. The organic phase was washed with water, brine, and dried over anhydrous sodium sulfate. 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 (R1=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 (R1=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 (R1=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 (R1=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 (R1=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 (R1=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] 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). The mixture was stirred and heated at 100°C under an oxygen atmosphere. The reaction was monitored by TLC until completion, and the reaction system was cooled to room temperature. 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. The solvent was removed by distillation under reduced pressure, and the resulting residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1, v:v) to obtain intermediate Int-2.

[0096] Int-2a(R1=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(R1=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(R1=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(R1=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(R1=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 (R1=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] Aqueous ammonia (14 mL) was added to a solution of the intermediate Int-2 (2 mmol) in anhydrous ethanol (3 mL). The mixture was heated at 80°C with stirring and reacted overnight. After the reaction was monitored by TLC, the reaction system was cooled to room temperature and ethanol was removed by distillation under reduced pressure. 10 mL of ethyl acetate was added and the mixture was extracted with 5.0 M hydrochloric acid (6 mL × 5) to obtain an aqueous phase. The pH was adjusted to 10.0 with 5.0 M sodium hydroxide under ice bath and stirring. The solid obtained was filtered, washed with water, and dried to obtain the intermediate Int-3, which was 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), and anhydrous potassium carbonate (1.2 mmol) were added to anhydrous toluene (8.0 mL). The mixture was heated and stirred at 110° C. under a nitrogen atmosphere to react overnight. The reaction was monitored by TLC until completion. The reaction system was cooled to room temperature and the insoluble matter was removed by filtration through celite. The filtrate was concentrated and then subjected to column chromatography. The mixture was eluted with dichloromethane:methanol = 30:1, 25:1, and 20:1, V:V, to obtain 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 (R1=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 (R1=3-Cl): Yield 65%; 1 H NMR(400MHz,DMSO-d6)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(R1=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(R1=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(R1==3,4-diF):Yield 50%; 1H 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 mixture was heated at 50° C. with stirring for 3.0 h. After the reaction was completed, 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 obtained was filtered, washed with water, and dried to obtain the target compound I.

[0131] Ia(R1=2-Cl):Yield 67%; 1 H NMR(400MHz,DMSO-d6)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 (R1 = 3-Cl): Yield 74%; 1 H NMR(400MHz,DMSO-d6)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(R1=4-Cl):Yield 98%; 1 H NMR(400MHz,DMSO-d6)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(R1=2,4-diCl):Yield 82%; 1 H NMR(400MHz,DMSO-d6)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(R1=3,4-diF):Yield 88%; 1 H NMR(400MHz,DMSO-d6)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). 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 temperature was slowly raised to 65°C and the mixture was 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. The solvent was then distilled off 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 (R1=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 (R1=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 (R1=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 (R1=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 (R1=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 mixture was heated at 80°C with stirring and reacted overnight. After the reaction was monitored by TLC, the reaction system was cooled to room temperature, and the ethanol was removed by distillation under reduced pressure. Ethyl acetate was added, and the aqueous phase was extracted several times with 5.0 M hydrochloric acid. The pH was adjusted to 10.0 with 5.0 M sodium hydroxide under ice bath and stirring. 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), and anhydrous potassium carbonate (166 mg, 1.2 mmol) were added to anhydrous toluene (8.0 mL). The mixture was stirred and heated at 110° C. under a nitrogen atmosphere to react overnight. The reaction was monitored by TLC until completion. The reaction system was cooled to room temperature, the insoluble matter was removed by filtration through celite, and the residue obtained by concentration of the filtrate was separated and purified by column chromatography (dichloromethane:methanol=20:1, V:V) to obtain intermediate Int-7.

[0163] Int-7a (R1=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 (R1=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(R1=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(R1=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(R1=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 mixture was heated at 50° C. with stirring 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. The pH was adjusted to 2.0 with 4.0 M hydrochloric acid under ice bath and stirring. The solid obtained was filtered, washed with water, and dried to obtain the target compound II.

[0177] IIa (R1 = 2-Cl): Yield 85%; 1 H NMR(400MHz,DMSO-d6)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 (R1 = 3-Cl): Yield 91%; 1 H NMR(400MHz,DMSO-d6)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(R1=4-Cl):Yield 87%; 1 H NMR(400MHz,DMSO-d6)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(R1=2,4-diCl):Yield 99%; 1 H NMR(400MHz,DMSO-d6)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(R1=3,4-diCl):Yield 87%; 1 H NMR(400MHz,DMSO-d6)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] Intermediate Int-4 (0.5 mmol), anhydrous sodium sulfate (107 mg, 0.75 mmol), an aliphatic amine (methylamine, isopropylamine, or cyclopropylamine, 2.5 mmol), and 1 drop of acetic acid were added to anhydrous ethanol (5.0 mL). The mixture was stirred at 80°C for 3.0 h. The reaction system was then cooled to 60°C and sodium cyanoborohydride (63 mg, 1 mmol) was added. The mixture was stirred at 60°C for 3.0 h. The reaction was monitored by TLC until completion. The reaction system was then cooled to room temperature and saturated aqueous sodium bicarbonate was added. The mixture was extracted with dichloromethane. The organic phase was washed with water, brine, and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to obtain intermediate Int-8. Intermediate Int-8 was directly carried to the next step without purification.

[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 mixture was heated at 50° C. with stirring for 3.0 h. After the reaction was completed, 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 obtained was filtered, washed with water, and dried to obtain the target compound III-1.

[0192] III-1a (R1=3-Cl, R3=Me): Yield 48%; 1 H NMR (400 MHz, DMSO-d6) δ 10.50

[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(R1=3-Cl,R3=iPr):Yield 36%; 1 H NMR(400MHz,DMSO-d6)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(R1=4-Cl,R3=cycloPr):Yield 78%; 1 H NMR(400MHz,DMSO-d6)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),7.39(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(R1=2,4-diF,R3=cycloPr):Yield 78%;1 H NMR (400 MHz, DMSO-d6) 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] Example 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. The reaction was monitored by TLC until completion. Saturated aqueous sodium bicarbonate was added, and the product was extracted with ethyl acetate. The organic phase was washed with water, brine, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, and the resulting residue was separated and purified by column chromatography (dichloromethane:methanol = 20:1, v:v) to give 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 mixture was stirred and heated at 50°C for 3.0 h. After the reaction was completed, the reaction system was monitored by TLC. The 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-2a.

[0207] III-2a: Yield 73%; 1 H NMR (400MHz, DMSO-d6) 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] 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). The reaction was stirred and heated at 60°C for 3.0 h. After completion of the reaction, the reaction system was cooled to room temperature and 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. The solvent was then removed by distillation under reduced pressure to obtain intermediate Int-10. Intermediate Int-10 was directly carried on to the next step without purification.

[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 mixture was stirred and heated at 50°C for 3.0 h. After the reaction was completed, 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 obtained was filtered, washed with water, and dried to obtain the target compound III-3.

[0213] III-3a (R1=3-Cl): Yield 36%; 1 H NMR(400MHz,DMSO-d6)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 against methicillin-resistant Staphylococcus aureus (MRSA) was measured. The test results are shown in Table 1.

[0216] Table 1 Antibacterial biological activity

[0217]

[0218]

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

[0220] As can be seen from Table 1, 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 merely descriptions of preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by persons skilled in the art should fall within the scope of protection defined 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 a monosubstituted or polysubstituted halogen atom; and 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: Negishi coupling of substituted benzyl bromide and 2,4-dichloropyrimidine to produce Int-1; catalytic oxidation of Int-1 to produce Int-2; amination of Int-2 to produce Int-3; Int-3 reacts with a 7-bromoquinolone core A in the presence of a palladium catalyst, a ligand, and a base in an organic solvent to produce Int-4; Int-4 is hydrolyzed in the presence of a base to produce a quinolone compound represented by formula (I); The reaction equation of the quinolone compound represented by 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: Negishi coupling of substituted benzyl bromide with 2,4-dichloropyrimidine to produce Int-1; catalytic oxidation of Int-1 to produce Int-2; reaction of Int-2 with bis(2-methoxyethyl)aminosulfur trifluoride to produce difluoro-substituted Int-5; amination of Int-5 to produce Int-6; reaction of Int-6 with a 7-bromoquinolone core A in the presence of a palladium catalyst, a ligand, and a base in an organic solvent to produce Int-7; hydrolysis of Int-7 in the presence of a base to produce a quinolone compound represented by formula (II); The reaction equation of the quinolone compound represented by 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: Negishi coupling of substituted benzyl bromide with 2,4-dichloropyrimidine to produce Int-1; catalytic oxidation of Int-1 to produce Int-2; amination of Int-2 to produce Int-3; reaction of Int-3 with a 7-bromoquinolone core A in an organic solvent in the presence of a palladium catalyst, a ligand, and a base to produce Int-4; reductive amination of Int-4 to produce Int-8; and hydrolysis of Int-8 in the presence of a base to produce 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: ； Said 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: Negishi coupling of substituted benzyl bromide with 2,4-dichloropyrimidine to produce Int-1; catalytic oxidation of Int-1 to produce Int-2; amination of Int-2 to produce Int-3; reaction of Int-3 with a 7-bromoquinolone core A in an organic solvent in the presence of a palladium catalyst, a ligand, and a base to produce Int-4; reductive amination of Int-4 to produce Int-8; reaction of Int-8 with iodomethane under alkaline conditions to produce Int-9; and hydrolysis of Int-9 in the presence of a base to produce 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 with 2,4-dichloropyrimidine to produce Int-1; catalytic oxidation of Int-1 to produce Int-2; amination of Int-2 to produce Int-3; 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 produce Int-4; Int-4 is reduced to produce Int-10; Int-10 is hydrolyzed in the presence of a base to produce 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 of the quinolone compound according to claim 1.

8. Use of the quinolone compound according to claim 1 and / or the pharmaceutically acceptable salt of the quinolone compound according to claim 7 in the preparation of a drug for treating methicillin-resistant Staphylococcus aureus.

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