4-quinolinone derivative, and preparation method and application thereof

Abstract

The application discloses a 4-quinolinone derivative, a preparation method and application thereof. The compound has a structure shown in general formula I. The application further relates to a pharmaceutical composition containing the compound with the structure of formula I. Activity screening experiments show that the compound has good anti-positive poxvirus activity, and therefore the application further provides application of the compound in preparation of an anti-positive poxvirus drug.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis and pharmaceutical application technology, specifically relating to a 4-quinolinone derivative, its preparation method, and its application as a broad-spectrum orthopoxvirus inhibitor. Background Technology

[0002] The genus *Orthopoxvirus* belongs to the family Poxviridae and includes species such as monkeypoxvirus, smallpox virus, vaccinia virus, camelpoxvirus, and cowpoxvirus. Poxviruses are large, double-stranded DNA viruses with an enveloped structure, a genome size ranging from 130 to 360 kbp, and their life cycle occurs in the cytoplasm of the host. Among them, monkeypoxvirus is the pathogen of the recent monkeypox outbreak, which the World Health Organization declared a Public Health Emergency of International Concern on August 14, 2024. Smallpox is an acute infectious disease caused by the smallpox virus, with a high mortality rate and considered one of the most devastating diseases in human history. Vaccinia virus is a widely used viral model in laboratories and was once used to prepare smallpox vaccines. Camelpox virus is a highly contagious pathogen to camels; this virus was first discovered in India in 1909. Cowpox virus is named for its association with pustular lesions on the teats of cows and the hands of milkmen.

[0003] Orthopoxviruses are closely related antigenically, immunologically, and serologically, and possess cross-protective immune effects. However, since the eradication of smallpox in the 1980s, routine vaccination has ceased, leading to a gradual increase in the global population susceptible to orthopoxviruses. Currently, the U.S. Food and Drug Administration (FDA) has approved tecovir and brincidofovir for the treatment of smallpox; the European Medicines Agency (EMA) has approved tecovir for the treatment of monkeypox. However, these drugs have many limitations, such as the limited mechanism of action of tecovir and the weak antiviral activity and severe hepatotoxicity and nephrotoxicity of brincidofovir. Therefore, there is an urgent need to develop new and effective drugs against monkeypoxvirus and other orthopoxviruses. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a 4-quinolinone derivative and its preparation method; this invention also provides the application of 4-quinolinone derivatives as broad-spectrum orthopoxvirus (monkeypoxvirus, camelpoxvirus, vaccinia virus, and cowpoxvirus) inhibitors in the preparation of broad-spectrum anti-orthopoxvirus (monkeypoxvirus, camelpoxvirus, vaccinia virus, and cowpoxvirus) drugs.

[0005] The technical solution of the present invention is as follows:

[0006] 1,4-Quinolinone derivatives

[0007] A 4-quinolinone derivative and its tautomer, a deuterated derivative of the derivative or the tautomer, or a pharmaceutically acceptable salt thereof, of the present invention have the structure shown in general formula I:

[0008]

[0009] in,

[0010] A is: (CH2) n NH(CH2) n Or CO(CH2) n ;

[0011] n = 0, 1, 2 or 3;

[0012] X is either N or C(U);

[0013] Y is either N or C(V);

[0014] Z is either N or C(W);

[0015] Furthermore, there is exactly one N among X, Y, and Z;

[0016] U, V, and W are each independently selected from: hydrogen, halogen, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl, benzyl, trifluoromethyl, C(=O)NR p R q -NR p R q -NR p C(=O)R s -NR p C(=O)OR s -OC(=O)R s -OR s -NR p C(=O)NR q R r or -OC(=O)OR s Among them, U can be related to R. 1 Connect them into a ring;

[0017] R 1 The following are examples of compounds: hydrogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl containing heteroatoms, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, OC3-C6 cycloalkyl, -C(=O)(C1-C6 alkyl), -C(=O)NR p R qThe substituents are trifluoromethyl, substituted cycloalkyl, substituted benzyl, substituted benzyl, substituted naphthyl, various substituted six-membered heterocycles, various substituted five-membered heterocycles, or various substituted four-membered heterocycles, wherein the substituents are one or more and are independently selected from halogens, hydroxyl, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6 alkyl or C3-C6 cycloalkyl;

[0018] R 2 The substituent is: O-R4, NH-R4, HON-R4 or CH=C(OH)COOR4, wherein R4 is hydrogen, C1-C6 alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl, and the substituent is one or more, independently selected from halogen, hydroxyl, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6 alkyl or C3-C6 cycloalkyl;

[0019] R 3 The substituents are: hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl containing heteroatoms, C1-C6 alkoxy, C2-C6 alkenyl, C3-C6 cycloalkyl or substituted cycloalkyl, OC3-C6 cycloalkyl, trifluoromethyl, substituted benzyl ring, substituted benzyl, substituted naphthyl ring, various substituted six-membered heterocycles, various substituted five-membered heterocycles or various substituted four-membered heterocycles, wherein the substituents are one or more, independently selected from halogen, hydroxyl, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6 alkyl or C3-C6 cycloalkyl;

[0020] T is: C5-C6 cycloalkyl, C4-C5 azacycloalkyl, -CO(C1-C6 alkyl)NH-, -(C1-C6 alkyl)CONH- or -CO(C1-C6 alkyl)CONH-, various substituted six-membered heterocycles, various substituted five-membered heterocycles, various substituted six-membered fused five-membered heterocycles, various substituted six-membered fused six-membered heterocycles, various substituted five-membered fused five-membered heterocycles, wherein the substituent is one or more, independently selected from halogen, hydroxyl, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6 alkyl or C3-C6 cycloalkyl;

[0021] R is: C1-C6 alkyl, OC1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, OC3-C6 cycloalkyl, substituted benzene ring, substituted naphthyl ring, various substituted six-membered heterocycles, various substituted five-membered heterocycles, various substituted six-membered fused five-membered heterocycles, various substituted five-membered fused five-membered heterocycles, various substituted benzo[5] fused five-membered heterocycles, or various substituted benzo[6] fused six-membered heterocycles, wherein the substituent is one or more, independently selected from halogen, hydroxyl, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6 alkyl or C3-C6 cycloalkyl;

[0022] R p R q R s and R r Each of these components is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl groups in each occurrence;

[0023] Where: R p R q R s and R r The C1-C4 alkyl group of any one of them is optionally replaced by 1 to 3 groups selected from halogen, cyano or hydroxyl.

[0024] According to a preferred embodiment of the present invention, in general formula I,

[0025] R 1 The compounds are methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl,

[0026] R 2 It can be hydroxyl, hydroxylamine, or ethoxy;

[0027] R 3 It is hydrogen;

[0028] A is -CH2-, -NH-, or -CO-;

[0029] X, Y, and Z are all C;

[0030] T is triazole, piperidine, piperazine, piperazine ketone, or tetrahydropyrrole;

[0031] R is a substituted benzene ring with the general formula a;

[0032]

[0033] Among them, R 4It is F, Cl, Br, CH3, OCH3, CN, NO2, NH2, 2,6-diF, 2,5-diF, 3,4-diF, 2,4-diF, 2-F-4-CF3-Ph, 3-F-4-CF3-Ph, CONH2, SO2NH2, SO2CH3, NHCH3, NHCOCH3, NHSO2CH3 or NHSO2CF3.

[0034] According to a further preferred embodiment of the present invention, the present invention provides compounds of formula Ia and their tautomers, said derivatives or deuterated derivatives of said tautomers, or pharmaceutically acceptable salts or prodrug derivatives thereof.

[0035]

[0036] in,

[0037] R 1 The compounds are methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl,

[0038] R 2 It can be hydroxyl, hydroxylamine, or ethoxy;

[0039] R 3 It is hydrogen;

[0040] A is -CH2-, -NH-, or -CO-;

[0041] X, Y, and Z are all C;

[0042] R is a substituted benzene ring with the general formula a;

[0043]

[0044] Among them, R 4 It is F, Cl, Br, CH3, OCH3, CN, NO2, NH2, 2,6-diF, 2,5-diF, 3,4-diF, 2,4-diF, 2-F-4-CF3-Ph, 3-F-4-CF3-Ph, CONH2, SO2NH2, SO2CH3, NHCH3, NHCOCH3, NHSO2CH3 or NHSO2CF3.

[0045] According to a further preferred embodiment of the present invention, the present invention provides compounds of formula Ib and their tautomers, said derivatives or deuterated derivatives of said tautomers, or pharmaceutically acceptable salts or prodrug derivatives thereof.

[0046]

[0047] in,

[0048] R 1 The compounds are methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl,

[0049] R 2 It can be hydroxyl, hydroxylamine, or ethoxy;

[0050] R 3 It is hydrogen;

[0051] A is -CH2-, -NH-, or -CO-;

[0052] X, Y, and Z are all C;

[0053] It is piperidine, piperazine, piperazine ketone, or tetrahydropyrrole;

[0054] R is a substituted benzene ring with the general formula a;

[0055]

[0056] Among them, R 4 It is F, Cl, Br, CH3, OCH3, CN, NO2, NH2, 2,6-diF, 2,5-diF, 3,4-diF, 2,4-diF, 2-F-4-CF3-Ph, 3-F-4-CF3-Ph, CONH2, SO2NH2, SO2CH3, NHCH3, NHCOCH3, NHSO2CH3 or NHSO2CF3.

[0057] According to a preferred embodiment of the invention, the pharmaceutically acceptable salt of the compound is a sodium salt, hydrochloride salt, sulfate salt, tartrate salt, or citrate salt.

[0058] According to a further preferred embodiment of the present invention, one of the 4-quinolinone derivatives represented by general formula I is one of the following compounds:

[0059]

[0060] Preparation methods of 2,4-quinolinone derivatives

[0061] The present invention discloses a method for preparing a 4-quinolinone derivative, which can be carried out according to standard chemical practice or as described herein, including the following synthetic scheme and description of the compound for preparing formulas Ia and Ib, their tautomers, the deuterated derivatives of the compound or the tautomers, or the aforementioned pharmaceutically acceptable salts.

[0062] The following non-limiting reaction schemes A and B are preferred embodiments for preparing the compounds of this invention. Other methods and modifications will be apparent to those skilled in the art based on the reaction schemes described below and the structures of the compounds of this invention. These methods are all included within the scope of this invention.

[0063] The general synthesis steps of scheme A are as follows: Starting with compounds A and B, they are first reacted in toluene solvent to generate intermediate compound C. Then, compound C is cyclized in diphenyl ether solvent to generate intermediate compound D. Intermediate compound D undergoes an N-1 alkylation reaction under basic conditions of potassium carbonate to generate intermediate compound E. Intermediate compound E undergoes a stalk coupling reaction with cuprous iodide and bis(triphenylphosphine)palladium dichloride as catalysts and triethylamine as a base to obtain intermediate compound F. Then, intermediate compound F is detrimethylsilane-removed in methanol solvent under the action of potassium carbonate to generate key intermediate G. Then, key intermediate compound G undergoes an azide-alkynyl Husigen-Click cycloaddition reaction in Cu(I) generated by the reaction of sodium ascorbate and copper sulfate pentahydrate to generate intermediate compound H. Finally, intermediate compound H undergoes ester hydrolysis in methanol solvent under the action of lithium hydroxide monohydrate to generate target product Ia.

[0064] The general synthetic route for scheme A is as follows:

[0065]

[0066] Reagents and conditions: (i) Toluene, 90-110℃; (ii) Diphenyl ether, 200-250℃; (iii) Dimethylformamide, iodoalkanes or iodoaromatics or bromoalkanes or bromoaromatics, 60-80℃; (iv) Tetrahydrofuran, cuprous iodide, bis(triphenylphosphine)palladium dichloride, triethylamine, trimethylsilylacetylene, N2, room temperature; (v) Methanol, potassium carbonate, room temperature; (vi) Sodium ascorbate, copper sulfate pentahydrate, tetrahydrofuran, water, azide, 30-65℃; (vii) a) Lithium hydroxide monohydrate, methanol, water, 60℃; b) Potassium hydroxylamine solution, room temperature.

[0067] The general synthetic steps of scheme B are as follows: Starting with compound J, it first reacts with diethyl ethoxymethylene malonate in toluene solvent to generate intermediate compound L. Then, compound L is cyclized in diphenyl ether solvent to generate intermediate compound M. Intermediate compound M undergoes an N-1 alkylation reaction under basic conditions of potassium carbonate to generate intermediate compound N. Intermediate compound N undergoes a Buchwald-Hartwig coupling reaction with palladium acetate and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) as catalysts and cesium carbonate as a base to obtain intermediate compound. Intermediate compound O is then subjected to a reaction in dichloromethane with trifluoroacetic acid to remove the tert-butyloxycarbonyl group, yielding intermediate P. The key intermediate P then undergoes a nucleophilic substitution reaction in the presence of potassium carbonate, or an amide condensation reaction in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIEA), to generate intermediate Q. Finally, intermediate Q undergoes an ester hydrolysis reaction in methanol with lithium hydroxide monohydrate to generate the target product Ib.

[0068] The general synthetic route for scheme B is as follows:

[0069]

[0070] Reagents and conditions: (i) Toluene, 90-110℃; (ii) Diphenyl ether, 200-250℃; (iii) Iodoalkane, iodoaromatic hydrocarbon, bromoalkane or bromoaromatic hydrocarbon, dimethylformamide, 60-80℃; (iv) Palladium acetate, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene, cesium carbonate, 1,4-dioxane, N2, 70-100℃; (v) Trifluoroacetic acid, dichloromethane, room temperature; (vi) a) Substituted benzyl bromo, potassium carbonate, dimethylformamide, room temperature; b) Substituted benzoic acid, HATU, DIEA, dichloromethane, room temperature; c) Substituted bromobenzene, palladium acetate, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene, cesium carbonate, 1,4-dioxane, N2, 70-100℃; (vii) Lithium hydroxide monohydrate, methanol, water, 60℃.

[0071] R, R 1 R 2 R 3 A, X, Y, Z are the same as those in the general formula I above.

[0072] The azide is a substituted benzene ring azide, a substituted naphthyl ring azide, various substituted six-membered heterocyclic azide, various substituted five-membered heterocyclic azide, various substituted six-membered pentane-heterocyclic azide, various substituted six-membered pentane-heterocyclic azide, various substituted five-membered pentane-heterocyclic azide, various substituted benzo[a]-pentane-heterocyclic azide, or various substituted benzo[a]-six-membered heterocyclic azide. The substituent is one or more, independently selected from halogen, hydroxyl, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6 alkyl, or C3-C6 cycloalkyl.

[0073] The room temperature mentioned in this invention refers to 20-30℃.

[0074] 3. Application of a 4-quinolinone derivative as a broad-spectrum orthopoxvirus inhibitor

[0075] This invention discloses the screening results of 4-quinolinone derivatives against broad-spectrum orthopoxviruses (monkeypoxvirus, camelpoxvirus, vaccinia virus, and cowpoxvirus) and their first application as broad-spectrum orthopoxvirus inhibitors. Experiments demonstrate that the 4-quinolinone derivatives of this invention can be used as broad-spectrum orthopoxvirus inhibitors in the preparation of anti-orthopoxvirus drugs. This invention also provides the application of the above compounds in the preparation of broad-spectrum orthopoxvirus drugs.

[0076] Broad-spectrum anti-poxvirus (monkeypoxvirus, camelpoxvirus, vaccinia virus, and cowpoxvirus) activity and toxicity assays of the target compound

[0077] The 4-quinolinone derivatives synthesized according to the above method were screened for broad-spectrum anti-poxvirus (monkeypoxvirus, camelpoxvirus, vaccinia virus, and cowpoxvirus). Their antiviral activity and toxicity data are listed in Table 1, with cidofovir, brincidofovir, and tecovirimat as positive controls.

[0078] As shown in Table 1, the 4-quinolinone derivatives of this invention are a series of novel broad-spectrum orthopoxvirus inhibitors, exhibiting significant broad-spectrum anti-orthopoxvirus activity. Among them, compounds QY6259, QY6268, and QY6281 show particularly outstanding anti-orthopoxvirus activity, with most activities less than 100 nM and very low cytotoxicity, making them worthy of further research and development.

[0079] The 4-quinolinone derivatives of this invention are a series of novel broad-spectrum anti-orchid virus inhibitors and can be used as broad-spectrum anti-orchid virus lead compounds.

[0080] The 4-quinolinone derivatives of this invention can be used as broad-spectrum orthopoxvirus inhibitors. Specifically, they can be used as broad-spectrum orthopoxvirus inhibitors in the preparation of broad-spectrum anti-orthopoxvirus drugs.

[0081] A broad-spectrum anti-vaccinia virus pharmaceutical composition comprising the 4-quinolinone derivative of the present invention and one or more pharmaceutically acceptable carriers or excipients. Detailed Implementation

[0082] The following examples are helpful in understanding the present invention, but should not limit the scope of the invention. In the following examples, all target compounds are numbered the same as in Table 1.

[0083] Synthesis Route 1:

[0084]

[0085] Synthesis Route 2:

[0086]

[0087] Synthesis Route 3:

[0088]

[0089] Example 1. Synthesis of the key intermediate ethyl 1-(cyclobutylmethyl)-6-ethynyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (6)

[0090] The starting material p-iodoaniline (1) (22.83 mmol, 5.0 g) was added to 50 mL of toluene solution, and then diethyl ethoxymethylene malonate (25.11 mmol, 5.43 g) was added to this solution. The mixture was heated under reflux and stirred. After the reaction was completed, the solvent was removed by vacuum distillation, and then diethyl ether was added to the residue in the flask. The mixture was filtered and the filter cake was washed with diethyl ether to obtain 8.10 g of crude 2-(((4-iodophenyl)amino)methylene)malonate (2), with a yield of 91.2% and a melting point of 137-139 °C. 1 HNMR(400MHz,DMSO-d6)δ8.36(d,J=13.8Hz,1H),7.72–7.68(m,2H),7.25–7.20(m,2 H),4.20(q,J=7.1Hz,2H),4.12(q,J=7.1Hz,2H),1.25(q,J=7.2Hz,6H).ESI-MS:m / z 390.36(M+H) + 800.55(2M+Na) + .C 14 H 16 INO4(389.01).

[0091] The crude product 2-(((4-iodophenyl)amino)methylene)malonate diethyl ester (2) (12.85 mmol, 5.0 g) obtained in the previous step was added to 50 mL of diphenyl ether solvent and stirred under reflux at 250 °C. After the reaction was completed, it was cooled to room temperature, and a large amount of brown precipitate was precipitated. The precipitate was filtered and washed with ethyl acetate to obtain 3.95 g of crude 6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (3), with a yield of 89.5% and a melting point of >300 °C. 1 H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 8.42 (d, J = 2.1Hz, 1H), 7.98 (dd, J = 8.6, 2.1Hz, 1H),7.44(d,J=8.6Hz,1H),4.21(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H).ESI-MS:m / z 344.10(M+H) + 366.07 (M+Na) + 708.52 (2M+Na) + .C 12 H 10 INO3 (342.97).

[0092] Ethyl 6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (3) (11.66 mmol, 4.0 g) was added to 40 mL of dimethylformamide, followed by the addition of potassium carbonate (23.32 mmol, 3.22 g) and stirring at room temperature for 15 min. Then, (iodomethyl)cyclobutane (17.49 mmol, 3.43 g) was added, and stirring continued at 80 °C for 2 h. Finally, 100 mL of ice water was added to the mixture, producing a large amount of pale yellow precipitate. This precipitate was filtered, washed with water, and crude ethyl 1-(cyclobutylmethyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (4) was obtained. Recrystallization from methanol yielded 4.33 g of pure product, yield: 90.4%, melting point: 110-112 °C. 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),8.50(d,J=2.2Hz,1H),8.06(dd,J=8.9,2.2Hz,1H),7.69(d,J=9.0Hz,1H),4.42(d,J=7. 5Hz,2H),4.24(q,J=7.1Hz,2H),2.80–2.74(m,1H),1.94–1.89(m,2H),1.86–1.78(m,4H),1.28(t,J=7.1Hz,3H).ESI-MS:m / z 412.83(M+H) + 435.12(M+Na) +844.98 (2M+Na) + .C 17 H 18 INO3 (411.03).

[0093] To a 10 mL tetrahydrofuran solution containing ethyl 1-(cyclobutylmethyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (4) (2.43 mmol, 1.0 g), bis(triphenylphosphine)palladium dichloride (48.63 μmol, 34.14 mg), cuprous iodide (486.34 μmol, 92.62 mg), and triethylamine (9.73 mmol, 1.35 mL) were added sequentially, followed by nitrogen protection. Then, trimethylsilylacetylene (5.35 mmol, 525.45 mg) was added to this mixture, and the mixture was stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and column chromatography was used to obtain intermediate 1-(cyclobutylmethyl)-4-oxo-6-((trimethylsilyl)ethynyl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (5) 707.9 mg, yield: 76.3%. ESI-MS: m / z 383.06 (M+H) + 763.48 (2M+H) + 785.56(2M+Na) + .C 22 H 27 NO3Si(381.18).

[0094] The intermediate 1-(cyclobutylmethyl)-4-oxo-6-((trimethylsilyl)ethynyl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (5) was dissolved in 10 mL of methanol solution, and potassium carbonate (1.86 mmol, 256.42 mg) was added. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the solvent was removed by vacuum distillation, and then 60 mL of dichloromethane was added to the residue in the flask to dissolve it. The residue was washed three times with saturated brine (3 × 30 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain pure 1-(cyclobutylmethyl)-6-ethynyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (6), a light brown solid with a yield of 88.2% and a melting point of 168-170 °C. 1HNMR (400MHz, DMSO-d6) δ8.75(s,1H),8.25(d,J=1.9Hz,1H),7.84(s,1H),7.83(d,J=1.8Hz,1H),4.43(d,J=7.5Hz,2H),4.3 5(s,1H),4.24(q,J=7.1Hz,2H),2.81–2.75(m,1H),1.95–1.92(m,2H),1.84–1.80(m,4H),1.29(t,J=7.1Hz,3H).ESI-MS:m / z 641.15(2M+Na) + .C 19 H 19 NO3 (309.14).

[0095] Example 2. Synthesis of target products QY6251, QY6259, QY6261, QY6268, QY6281 and QY6285

[0096] The key intermediate ethyl 1-(cyclobutylmethyl)-6-ethynyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (6) (1.62 mmol, 500.0 mg) and the azide prepared from substituted benzyl halides (4.04 mmol, 885.45 mg) were added to 10 mL of tetrahydrofuran. Then, a freshly prepared aqueous solution of sodium ascorbate (808.11 μmol, 160.09 mg) and copper sulfate pentahydrate (161.62 μmol, 40.35 mg) was added to this solution. The mixture was heated to 65 °C and stirred vigorously for 4–12 h (TLC detection). After the reaction was complete, the solvent was removed by vacuum distillation. Then, 60 mL of dichloromethane was added to the residue in the flask to dissolve it. The residue was washed three times with saturated saline solution (3 × 30 mL). The organic phase was separated into layers and dried with anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and subjected to column chromatography. The resulting product was then recrystallized in methanol to obtain the target products QY6251 and QY6261.

[0097] Then, different synthesis methods were used for different target products. Target products QY6259 and QY6268 were synthesized using method one, while target products QY6281 and QY6285 were synthesized using method two.

[0098] Method 1: The compounds QY6251 and QY6261 (283.82 μmol, 150 mg) prepared in the previous step were added to a mixed solvent of methanol and water (v / v = 4:1, 5 mL), and lithium hydroxide monohydrate (1.14 mmol, 47.64 mg) was added. The mixture was heated at 60 °C for 2-3 h until the reaction was complete. The pH was adjusted to 10-11 by adding 1 M hydrochloric acid solution, and a large amount of white precipitate was formed. The precipitate was filtered, washed with water, and recrystallized in methanol to obtain the target products QY6259 and QY6268.

[0099] Method 2: Dissolve 14.18 g of KOH in 35 mL of methanol under ice bath conditions to prepare a saturated solution; dissolve 11.68 g of NH₂OH-HCl in 60 mL of methanol to prepare a saturated solution, then add the prepared saturated KOH methanol solution dropwise. After stirring for about 1 hour, filter out the precipitate and collect the filtrate as the NH₂OK solution. Dissolve the compounds QY6251 and QY6261 (0.1 g, 0.19 mmol) prepared in the previous step in NH₂OK (5 mL) solution and stir at room temperature for about 0.5 hours. Monitor the reaction with a TCL. After the reaction is complete, add an appropriate amount of water and adjust the pH to acidic with 1 M hydrochloric acid solution. A white precipitate will form. Filter out the precipitate, dry it, and then recrystallize it in methanol to obtain the target products QY6281 and QY6285.

[0100] Example 3. Synthesis of target products QY6265, QY6270, QY6271, QY6272, QY6299 and QY62100

[0101] The starting material p-bromoaniline (7) (29.07 mmol, 5.0 g) was added to 50 mL of toluene solution, and then diethyl ethoxymethylene malonate (31.97 mmol, 6.91 g) was added to this solution. The mixture was heated to reflux and stirred. After the reaction was completed, the solvent was removed by vacuum distillation, and then diethyl ether was added to the residue in the flask. The mixture was filtered, and the filter cake was washed with diethyl ether to obtain 9.34 g of crude diethyl 2-(((4-bromophenyl)amino)methylene)malonate (8), with a yield of 93.9%.

[0102] The crude product 2-(((4-bromophenyl)amino)methylene)malonate diethyl ester (8) (14.61 mmol, 5.0 g) obtained in the previous step was added to 50 mL of diphenyl ether solvent and stirred under reflux at 250 °C. After the reaction was completed, it was cooled to room temperature, and a large amount of brown precipitate was precipitated. The precipitate was filtered and washed with ethyl acetate to obtain 3.92 g of crude 6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (9), with a yield of 90.5% and a melting point of >300 °C. 1HNMR(400MHz,DMSO-d6)δ8.60(s,1H),8.22(d,J=2.3Hz,1H),7.87(dd,J=8.8,2.4Hz, 1H),7.60(d,J=8.8Hz,1H),4.22(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H).ESI-MS:m / z 296.59(M+H) + .C 12 H 10 BrNO3 (294.98).

[0103] Ethyl 6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylate (9) (13.51 mmol, 4.0 g) was added to 40 mL of dimethylformamide, followed by the addition of potassium carbonate (27.02 mmol, 3.73 g) and potassium iodide (13.51 mmol, 2.24 g). The mixture was stirred at room temperature for 15 min (the solution became turbid). Then, (bromomethyl)cyclobutane (20.26 mmol, 3.02 g) was added to the solution, and stirring was continued at 80 °C for 2 h. Finally, 100 mL of ice water was added to the mixture, producing a large amount of pale yellow precipitate. This precipitate was filtered, washed with water, and crude ethyl 1-(cyclobutylmethyl)-6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylate (10) was obtained. Recrystallization from methanol yielded 5.23 g of pure product, with a yield of 94.1% and a melting point of 135-137 °C. 1 HNMR (400MHz, DMSO-d6) δ8.73(s,1H),8.30(d,J=2.5Hz,1H),7.93(dd,J=9.1,2.5Hz,1H),7.83(d,J=9.1Hz,1H),4.43(d,J=7.4Hz,2 H),4.24(q,J=7.1Hz,2H),2.77(p,J=7.6Hz,1H),1.92(dt,J=6.5,3.5Hz,2H),1.86–1.79(m,4H),1.29(t,J=7.1Hz,3H).ESI-MS:m / z 748.66(2M+Na) + 766.44 (2M+K) + .C 17 H 18 BrNO3 (363.05).

[0104] To 10 mL of 1,4-dioxane solution containing ethyl 1-(cyclobutylmethyl)-6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylate (10) (2.75 mmol, 1.0 g), 1-Boc-piperazine (4.12 mmol, 0.77 g) or tert-butyl 3-oxo-1-piperazine carboxylate (4.12 mmol, 0.82 g), palladium acetate (0.27 mmol, 61.64 mg), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (0.27 mmol, 0.16 g), and cesium carbonate (5.49 mmol, 1.79 g) were added sequentially, followed by nitrogen protection and stirring overnight at 100 °C. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and column chromatography was used to obtain the intermediate ethyl 6-(4-(tert-butoxycarbonyl)azacycloalkyl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate. The physical properties and spectral data are as follows:

[0105] 6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (11a), white solid, yield: 85.7%, melting point: 160-162℃. 1 H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 7.71 (d, J = 9.4Hz, 1H), 7.60 (d, J = 3.0Hz, 1H) ,7.50(dd,J=9.3,3.0Hz,1H),4.39(d,J=7.4Hz,2H),4.21(q,J=7.1Hz,2H),3.50( t,J=4.9Hz,4H),3.20(t,J=5.2Hz,4H),2.78(q,J=7.7Hz,1H),1.91(td,J=8.5,7. 6,4.0Hz,2H),1.85–1.77(m,4H),1.43(s,9H),1.28(t,J=7.1Hz,3H).ESI-MS:m / z 470.94(M+H) + 939.08 (2M+H) + .C 26 H 35 N3O5(469.26).

[0106] Ethyl 6-(4-(tert-butyloxycarbonyl)-2-oxopiperazin-1-yl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (11b), white solid, yield: 81.5%. ESI-MS: m / z 484.90 (M+H) + 506.73 (M+Na) + 989.12(2M+Na) + .C26 H 33 N3O6(483.24).

[0107] Intermediate 11a or 11b (1.0 eq) was dissolved in dichloromethane, and trifluoroacetic acid (10.0 eq) was added followed by stirring at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to remove excess trifluoroacetic acid, the pH was adjusted to 9 with saturated sodium carbonate, and the solution was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was subjected to column chromatography to obtain intermediate 1-(cyclobutylmethyl)-4-oxo-6-azacycloalkyl-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. The physical properties and spectral data are as follows:

[0108] 1-(cyclobutylmethyl)-4-oxo-6-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (12a), white solid, yield: 89.1%, melting point: 140-142℃. 1 H NMR (400MHz, DMSO-d6) δ8.58(s,1H),7.69(d,J=9.4Hz,1H),7.57(d,J=3.0Hz,1 H),7.48(dd,J=9.3,3.0Hz,1H),4.38(d,J=7.4Hz,2H),4.22(q,J=7.1Hz,2H),3 .13(t,J=5.0Hz,4H),2.86(dd,J=6.3,3.7Hz,4H),2.78(q,J=7.6Hz,1H),1.94– 1.89(m,2H),1.85–1.77(m,4H),1.28(t,J=7.1Hz,3H).ESI-MS:m / z370.19(M+H) + .C 26 H 35 N3O5(369.21).

[0109] Ethyl 1-(cyclobutylmethyl)-4-oxo-6-(2-oxoperpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylate (12b), white solid, yield: 85.2%. ESI-MS: m / z 384.13 (M+H) + .C 21 H 25 N3O4 (383.18).

[0110] Intermediate 12a or 12b (1.0 equiv), potassium carbonate (2.0 equiv) and substituted benzyl bromide (1.2 equiv) were dissolved in anhydrous DMF, and the reaction solution was stirred at room temperature for 4-7 hours. After the reactants had reacted completely, the reaction solution was concentrated under reduced pressure and water was added. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and recrystallized from methanol by column chromatography to obtain intermediates (13a1, 13a2 or 13b1, 13b2). Intermediate 12a (0.54 mmol, 0.2 g), substituted benzoic acid (0.65 mmol, 0.14 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 0.65 mmol, 0.25 g) and N,N-diisopropylethylamine (DIEA, 1.08 mmol, 0.14 g) were dissolved in DCM (5 mL) and reacted at room temperature for 5 hours. After cooling the reaction solution, 30 mL of water was added, followed by extraction with dichloromethane (25 mL × 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain intermediates (13a3, 13a4).

[0111] The intermediate compounds 13a1-13a4 or 13b1-13b2 prepared in the previous step were added to a mixed solvent of methanol and water (v / v = 4:1, 5 mL), lithium hydroxide monohydrate was added, and the mixture was heated at 60 °C for 2-3 h until the reaction was complete. The pH was adjusted to 10-11 by adding 1 M hydrochloric acid solution, and a large amount of white precipitate was formed. The precipitate was filtered, washed with water, and recrystallized in methanol to obtain the target products QY6265, QY6270, QY6271, QY6272, QY6299, and QY62100.

[0112] Example 4. Synthesis of target products QY6276, QY6277, QY6283 and QY6284

[0113] To 10 mL of 1,4-dioxane solution containing ethyl 1-(cyclobutylmethyl)-6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylate (10) (2.75 mmol, 1.0 g), 3-(Boc-amino)pyrrolidine (4.12 mmol, 0.77 g) or 4-Boc-aminopiperidine (4.12 mmol, 0.82 g), palladium acetate (0.27 mmol, 61.64 mg), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (0.27 mmol, 0.16 g), and cesium carbonate (5.49 mmol, 1.79 g) were added sequentially, followed by nitrogen protection and stirring overnight at 100 °C. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and column chromatography was used to obtain intermediate 6-(((tert-butoxycarbonyl)amino)azacycloalkyl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. The physical properties and spectroscopic data are as follows:

[0114] Ethyl 6-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-yl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (14a), white solid, yield: 83.6%. ESI-MS: m / z 471.12 (M+H) + 492.91(M+Na) + 961.56 (2M+Na) + .C 26 H 35 N3O5(469.26).

[0115] Ethyl 6-(4-((tert-Butoxycarbonyl)amino)piperidin-1-yl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (14b), white solid, yield: 80.9%. ESI-MS: m / z 484.74 (M+H) + .C 26 H 33 N3O6(483.24).

[0116] Intermediate 14a or 14b (1.0 eq) was dissolved in dichloromethane, and trifluoroacetic acid (10.0 eq) was added followed by stirring at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to remove excess trifluoroacetic acid, the pH was adjusted to 9 with saturated sodium carbonate, and the solution was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was subjected to column chromatography to obtain intermediate ethyl 6-(3-aminoazacycloalkyl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. The physical properties and spectral data are as follows:

[0117] 6-(3-aminopyrrolidone-1-yl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (15a), white solid, yield: 81.5%, melting point: 165-167℃. 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),7.68(d,J=9.3Hz,1H),7.18(d,J=3.0Hz,1H),7.06(dd,J= 9.3,3.0Hz,1H),4.38(d,J=7.4Hz,2H),4.20(q,J=7.1Hz,2H),3.82–3.78(m,1H),3.55(dd,J=1 0.2,6.2Hz,2H),3.48(t,J=7.1Hz,2H),3.38–3.33(m,2H),3.21–3.16(m,1H),2.80–2.73(m,1H ),2.26–2.19(m,1H),1.94–1.85(m,2H),1.86–1.81(m,4H),1.28(t,J=7.1Hz,3H).ESI-MS:m / z 370.58(M+H) + .C 26 H 35 N3O5(369.21).

[0118] Ethyl 6-(4-aminopiperidin-1-yl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (15b), white solid, yield: 82.3%, melting point: 228-230℃. 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H),7.67(d,J=9.3Hz,1H),7.59(d,J=3.0Hz,1H), 7.49(dd,J=9.4,3.1Hz,1H),4.38(d,J=7.3Hz,2H),4.20(q,J=7.1Hz,2H),3.80–3. 76(m,2H),2.95(q,J=6.3,5.3Hz,1H),2.86–2.80(m,2H),2.76(q,J=7.7Hz,1H),1. 93–1.85(m,6H),1.81(m,4H),1.50–1.42(m,2H),1.28(t,J=7.1Hz,3H).ESI-MS:m / z 384.54(M+H) + 789.14(2M+Na) + .C 21 H 25 N3O4(383.22).

[0119] To 10 mL of a 1,4-dioxane solution containing intermediate 15a or 15b, substituted bromobenzene, palladium acetate, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene), and cesium carbonate were added sequentially. The mixture was then protected with nitrogen and stirred overnight at 100°C. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and column chromatography was used to obtain intermediates 16a1, 16a2 or 16b1, 16b2, respectively.

[0120] The intermediate compounds 16a1, 16a2 or 16b1, 16b2 prepared in the previous step were added to a mixed solvent of methanol and water (v / v = 4:1, 5 mL), lithium hydroxide monohydrate was added, and the mixture was heated at 60 °C for 2-3 h until the reaction was complete. The pH was adjusted to 10-11 by adding 1 M hydrochloric acid solution, and a large amount of white precipitate was formed. The precipitate was filtered, washed with water, and recrystallized in methanol to obtain the target products QY6276, QY6277, QY6283 and QY6284.

[0121]

[0122] According to Example 2, the key intermediate (6) was processed to obtain a white solid with a yield of 88.7% and a melting point of 236-238°C. 1 H NMR(400MHz,DMSO-d6)δ8.88(d,J=4.0Hz,1H),8.74–8.69(m,2H),8.25–8.22(m,1 H),7.92(d,J=8.9Hz,1H),7.82–7.78(m,1H),7.68–7.65(m,1H),7.61(t,J=7.6Hz, 1H),5.85(s,2H),4.45(dd,J=7.5,2.3Hz,2H),4.25(q,J=7.1Hz,2H),2.82(p,J=7. 7Hz,1H),1.98–1.92(m,2H),1.91–1.85(m,4H),1.30(t,J=7.1Hz,3H).ESI-MS:m / z 529.21(M+H) + 551.23(M+Na) + 1078.87 (2M+Na) + .C 27 H 24 F4N4O3(528.18).

[0123]

[0124] According to Method 1, QY6251 was processed to obtain a white solid with a yield of 85.2% and a melting point of 228-230℃. 1H NMR(400MHz,DMSO-d6,)δ9.02(s,1H),8.97(s,1H),8.82(s,1H),8.38(s,1H),8.12(s,1H),7.81( s,1H),7.66(s,2H),5.87(s,2H),4.62(s,2H),2.85(s,1H),1.95(s,2H),1.85(s,4H).ESI-MS:m / z 501.57(M+H) + .C 25 H 20 F4N4O3(500.15).

[0125]

[0126] According to Example 2, the key intermediate (6) was processed to obtain a white solid with a yield of 87.5% and a melting point of 260-262°C. 1 H NMR(400MHz,DMSO-d6)δ8.89(d,J=3.9Hz,1H),8.74–8.68(m,2H),8.23(dt,J=9.1,1.6Hz,1 H),7.92(d,J=8.9Hz,1H),7.83(t,J=7.9Hz,1H),7.56(d,J=11.6Hz,1H),7.36(d,J=8.1Hz, 1H),5.82(s,2H),4.45(dd,J=7.5,2.4Hz,2H),4.24(q,J=7.1Hz,2H),2.82(p,J=7.6Hz,1H) ,1.95(d,J=7.4Hz,2H),1.88–1.79(m,4H),1.29(t,J=7.1Hz,3H).ESI-MS:m / z529.19(M+H) + 551.16(M+Na) + .C 27 H 24 F4N4O3(528.18).

[0127]

[0128] According to Example 3, 13a1 was treated to obtain a white solid with a yield of 83.7% and a melting point of 242-244°C. 1HNMR(400MHz,DMSO-d6,)δ15.51(s,1H),8.96(s,1H),8.02–7.92(m,3H),7.74–7.66(m,3H),4.61(d,J=7.4Hz,2H),4.53(s,2H),4. 24–4.04(m,2H),3.37–3.46(m,2H),3.41–3.33(m,2H),3.32–3.22(m,2H),3.01–2.80(m,1H),1.93–1.88(m,2H),1.87–1.78(m,4H). 13 C NMR (125MHz, DMSO-d6) δ177.33, 166.92, 159.04 (d, J = 252.8Hz), 147.99, 147.38, 133.48, 128.68, 128.31, 127.04, 124. 34,124.02,121.86,120.22,108.38,107.02,57.90,57.46(d,J=8.9Hz),50.64,45.22,34.69,25.54,18.10.ESI-MS:m / z 518.24(M+H) + .C 27 H 27 F4N3O3(517.20).

[0129]

[0130] According to Method 1, QY6261 was processed to obtain a white solid with a yield of 85.6% and a melting point of 240-242℃. 1 H NMR(400MHz, DMSO-d6,)δ15.23(s,1H),9.08(s,1H),9.02(s,1H),8.82(d,J=2.1Hz,1H),8.41(d,J=9.0Hz,1H),8.17(d,J=9.0Hz,1H),7.85(t,J=7.9 Hz,1H),7.59(d,J=11.5Hz,1H),7.39(d,J=8.1Hz,1H),5.84(s,2H),4.66( d,J=7.5Hz,2H),2.90–2.80(m,1H),1.97–1.90(m,2H),1.88–1.79(m,4H). 13C NMR (150MHz, DMSO-d6) δ178.46, 166.76, 159.41 (d, J = 255.8Hz), 144.28 (d, J = 6.4Hz), 139.19, 128.49, 125.03,123.95,123.11,122.15,117.23(d,J=21.6Hz),57.30,52.48,34.74,25.74,18.24.ESI-MS:m / z 501.97(M+H) + .C 25 H 20 F4N4O3(500.15).

[0131]

[0132] According to Example 3, 13a2 was processed to obtain a yellow solid with a yield of 88.3% and a melting point of 225-227°C. 1 HNMR(400MHz,DMSO-d6,)δ11.36(s,1H),8.96(s,1H),8.07(t,J=7.5Hz,1H),8.00(d,J =9.5Hz,1H),7.89(d,J=9.6Hz,1H),7.78(d,J=8.0Hz,1H),7.73(dd,J=9.5,3.0Hz,1H), 7.67(d,J=3.0Hz,1H),4.62(d,J=7.4Hz,2H),4.55(s,2H),4.15–4.06(m,2H),3.75–3. 54(m,2H),3.34–3.27(m,4H),2.79–2.65(m,1H),2.01–1.91(m,2H),1.80–1.75(m,4H). 13 C NMR(125MHz,DMSO-d6)δ177.34,166.93,147.99,147.42,135.98,133.52,127.03,12 4.39,120.22,108.38,107.03,57.91,50.85,45.36,34.69,25.54,18.10.ESI-MS:m / z 519.00(M+H) + .C 27 H 27 F4N3O3(517.20).

[0133]

[0134] According to Example 3, 13a3 was processed to obtain a light yellow solid with a yield of 90.4% and a melting point of 228-230°C.1 H NMR(400MHz, DMSO-d6,)δ15.56(s,1H),8.93(s,1H),7.97(d,J=9.5Hz,1H),7.89(d,J=9.4Hz,1H),7.75–7.71(m,3H),7.64(d,J=2.9Hz,1H),4. 61(d,J=7.5Hz,2H),3.87(t,J=5.3Hz,2H),3.47–3.42(m,4H),3.32–3. 28(m,2H),2.79(q,J=7.8Hz,1H),1.94–1.88(m,2H),1.86–1.79(m,4H). 13 C NMR (125MHz, DMSO-d6) δ177.35, 166.98, 163.20, 157.94 (d, J = 248.3Hz), 149.01, 147.15, 133.20, 130.78 (d, J = 4.1Hz), 128.54 (d, J = 18 .1Hz),127.05,124.36,122.54,120.04,114.23(d,J=22.4Hz),108.05,106.93,57.90,46.48,41.63,34.69,25.55,18.10.ESI-MS:m / z 532.71(M+H) + 1084.85 (2M+Na) + .C 27 H 25 F4N3O4(531.18).

[0135]

[0136] According to Example 3, 13a4 was treated to obtain a light yellow solid with a yield of 83.6% and a melting point of 195-197°C. 1 H NMR (400MHz, DMSO-d6) δ15.54(d,J=19.8Hz,1H),8.95(d,J=10.9Hz,1H),8.01–7.91(m,3H),7.76–7.50(m,3H),4.61(dd,J=7.5,4.4Hz ,2H),3.82(s,1H),3.57–3.52(m,2H),3.50–3.44(m,2H),3.32–3.26(m,3H),2.83–2.76(m,1H),1.94–1.87(m,2H),1.87–1.77(m,4H). 13C NMR (125MHz, DMSO-d6) δ177.35, 166.99, 166.91, 159.23 (d, J = 254.9Hz), 149.05, 148.47, 147.3 9,147.10,133.32(d,J=48.8Hz),128.43(d,J=4.5Hz),127.04(d,J=5.1Hz),126.19(d,J=3.8Hz) ,124.34(d,J=13.3Hz),120.06(d,J=16.0Hz),117.99(d,J=21.7Hz),116.33(d,J=21.9Hz),108 .15(d,J=51.3Hz),106.98(d,J=14.3Hz),57.89,45.39,42.96,34.70,25.55,18.10.ESI-MS:m / z 532.37(M+H) + .C 27 H 25 F4N3O4(531.18).

[0137]

[0138] According to Example 4, 16a1 was processed to obtain a yellow solid with a yield of 87.1% and a melting point of 258-260°C. 1 HNMR (400MHz, DMSO-d6) δ15.72(s,1H),8.84(s,1H),7.91(d,J=9.2Hz,1H),7.40(t,J=8.6Hz,1H),7.29( d,J=8.8Hz,1H),7.23(d,J=2.7Hz,1H),7.07(d,J=6.5Hz,1H),6.62(d,J=14.4Hz,1H),6.57(d,J=8.8Hz, 1H),4.59(d,J=7.4Hz,2H),4.27(s,1H),3.78(t,J=8.0Hz,1H),3.58–3.43(m,2H),3.26(s,1H),2.80(t, J=7.8Hz,1H),2.37(dd,J=12.7,6.3Hz,1H),2.04(d,J=5.6Hz,1H),1.94–1.88(m,2H),1.86–1.79(m,4H). 13C NMR (125MHz, DMSO-d6) δ177.18, 167.29, 153.71 (d, J = 11.8Hz), 146.12, 145.77, 130.80, 128.14, 127.40, 125.34, 123.19, 120. 57,119.94,108.55,106.27,103.62,99.14(d,J=24.8Hz),57.95,53.57,52.22,46.40,34.75,31.15,25.57,18.10.ESI-MS:m / z 504.15(M+H) + .C 26 H 25 F4N3O3(503.18).

[0139]

[0140] According to Example 4, 16a2 was processed to obtain a yellow solid with a yield of 83.9% and a melting point of 240-242°C. 1 HNMR (400MHz, DMSO-d6) δ15.73(s,1H),8.84(s,1H),7.91(d,J=9.4Hz,1H),7.43(dd,J=12.1,2.1Hz,1H),7.38(d,J=7. 8Hz,1H),7.28(dd,J=9.4,3.0Hz,1H),7.22(d,J=2.9Hz,1H),7.02(t,J=8.6Hz,1H),6.48(dd,J=6.7,2.2Hz,1H),4.59( d,J=7.4Hz,2H),4.34(q,J=5.9Hz,1H),3.80(dd,J=9.9,6.3Hz,1H),3.57(q,J=7.9,7.4Hz,1H),3.48(t,J=7.6Hz,1H), 3.39(s,1H),2.84–2.77(m,1H),2.43–2.35(m,1H),2.17(dt,J=12.1,6.4Hz,1H),1.93–1.87(m,2H),1.86–1.78(m,4H). 13C NMR (125MHz, DMSO-d6) δ177.20,167.26,146.18,145.78,130.77,127.43,122.91,120.56,119.93,112 .45(d,J=4.4Hz),106.27,103.61,57.93,53.28,52.27,46.49,34.76,31.03,25.57,18.11.ESI-MS:m / z 504.38(M+H) + .C 26 H 25 F4N3O3(503.18).

[0141]

[0142] According to Method 2, QY6261 was processed to obtain a white solid with a yield of 50.3% and a melting point of 228-230℃. 1 H NMR(400MHz,DMSO-d6)δ11.75(s,1H),9.25(s,1H),8.94(s,1H),8.88(s,1H), 8.79(d,J=2.1Hz,1H),8.30(dd,J=9.0,2.2Hz,1H),8.03(d,J=9.0Hz,1H),7.8 5(t,J=7.9Hz,1H),7.58(d,J=11.6Hz,1H),7.38(d,J=8.1Hz,1H),5.83(s,2H) ,4.58(d,J=7.4Hz,2H),2.84(p,J=7.5Hz,1H),1.97–1.92(m,2H),1.85(s,4H). 13 C NMR(125MHz,DMSO-d6)δ174.98,162.94,159.35(d,J=254.0Hz),147.79,14 6.10,144.17(d,J=8.2Hz),138.98,130.35,128.46(d,J=4.8Hz),127.87,1 27.69,124.98(d,J=3.5Hz),122.97(q,J=74.1Hz),119.07,117.19(d,J=21 .2Hz),110.90,57.49,52.46,34.61,25.63,18.18.ESI-MS:m / z516.14(M+H) + .C 25 H 21 F4N5O3(515.16).

[0143]

[0144] According to Example 4, 16b1 was treated to obtain a light yellow solid with a yield of 89.2% and a melting point of 160-162°C. 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),7.86(s,1H),7.66(s,1H),7.36(t,J=8.8Hz, 1H),6.73(d,J=7.8Hz,1H),6.59(dd,J=14.5,2.1Hz,1H),6.53(dd,J=8.7,2.2Hz, 1H),4.56(s,2H),3.85(s,2H),3.58(s,1H),3.03(s,2H),2.84–2.75(m,1H),2.03 (d,J=12.5Hz,2H),1.95–1.89(m,2H),1.88–1.77(m,4H),1.52(q,J=10.7Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ167.21,161.22(d,J=247.9Hz),153.65,153.56,132.57,128.08,125.38,123.24,108.41,102.50 (d,J=13.0Hz),102.24(d,J=12.4Hz),98.86(d,J=24.3Hz),57.60,48.90,47.49,34.71,30.98,25.61,18.13.ESI-MS:m / z 518.21(M+H) + 540.35 (M+Na) + .C 27 H 27 F4N3O3(517.20).

[0145]

[0146] According to Example 4, 16b2 was processed to obtain a light yellow solid with a yield of 87.3% and a melting point of 188-189°C. 1H NMR (400MHz, DMSO-d6) δ15.62(s,1H),8.90(s,1H),7.92(d,J=9.4Hz,1H),7.72(d,J=9.4Hz,1H),7.64(d ,J=2.9Hz,1H),7.40(dd,J=12.1,2.1Hz,1H),7.33(d,J=8.7Hz,1H),6.99(t,J=8.6Hz,1H),6.06(dd,J=8 .6,2.5Hz,1H),4.60(d,J=7.4Hz,2H),3.95(d,J=12.7Hz,2H),3.66(s,1H),3.02(t,J=12.3Hz,2H),2.82 (q,J=7.8Hz,1H),2.01(d,J=12.5Hz,2H),1.95–1.89(m,2H),1.88–1.80(m,4H),1.65(q,J=11.3Hz,2H). 13 C NMR (125MHz, DMSO-d6) δ177.27,167.10,151.12,149.21,139.64(d,J=11.3Hz),132.46,126.00,123.87,122.83,119.87,115.32(d, J=7.0Hz),115.06(d,J=7.1Hz),112.34,112.10(d,J=5.3Hz),107.47,57.85,49.28,47.59,34.70,30.88,25.57,18.11.ESI-MS:m / z 518.23(M+H) + 540.41 (M+Na) + .C 27 H 27 F4N3O3(517.20).

[0147]

[0148] According to Method 2, QY6251 was processed to obtain a white solid with a yield of 54.6% and a melting point of 245-247℃ (decomposition). 1H NMR (400MHz, DMSO-d6) δ11.75(s,1H),9.25(s,1H),8.93(s,1H),8.88(s,1H),8.78(d,J=2.1Hz,1H),8.30(dd,J=8.9,2.2Hz,1H),8.02(d,J=9.0Hz, 1H),7.81(dd,J=10.0,1.7Hz,1H),7.69–7.60(m,2H),5.85(s,2H),4.57( d,J=7.4Hz,2H),2.89–2.80(m,1H),1.98–1.91(m,2H),1.88–1.80(m,4H). 13 C NMR (125MHz, DMSO-d6) δ174.98, 162.94, 160.36 (d, J = 249.9Hz), 147.78, 145.97, 138.97,132.39(d,J=3.8Hz),130.36,127.94(d,J=14.5Hz),127.85,127.69,124 .74(d,J=2.8Hz),123.21,122.66,122.33(d,J=4.1Hz),119.05,113.87(d,J=3.7 Hz),113.67(d,J=3.8Hz),110.89,57.49,47.35,34.60,25.63,18.18.ESI-MS:m / z 516.24(M+H) + 537.59 (M+Na) + 553.52(M+K) + .C 25 H 21 F4N5O3(515.16).

[0149]

[0150] According to Example 3, 13b1 was treated to obtain a white solid with a yield of 84.3% and a melting point of 178-180°C. 1HNMR (400MHz, DMSO-d6) δ9.09(s,1H),8.31(d,J=2.6Hz,1H),8.13(d,J=9.3Hz,1H),7.95(dd,J=9.2,2.6Hz,2H),7.83(d,J=9.6Hz,1H),7.73(d,J=8. 1Hz,1H),4.65(d,J=7.5Hz,2H),4.34(s,2H),3.98(s,2H),3.60(s,2H),3. 47–3.38(m,2H),2.88–2.81(m,1H),1.96–1.91(m,2H),1.88–1.82(m,4H). 13 C NMR (125MHz, DMSO-d6) δ177.70, 170.82, 166.42, 161.41 (d, J = 250.2Hz), 149.70, 139.54, 138.25, 132.53, 126.48, 124.72, 122. 55,122.45,122.15,120.00,113.90(d,J=25.7Hz),107.91,60.23,58.07,51.64,34.49,25.52,21.23,18.11,14.55.ESI-MS:m / z 532.73(M+H) + 1084.92 (2M+Na) + .C 27 H 25 F4N3O4(531.18).

[0151]

[0152] According to Example 3, 13b2 was treated to obtain a white solid with a yield of 87.2% and a melting point of 154-156°C. 1 HNMR(400MHz,DMSO-d6)δ9.09(s,1H),8.32(d,J=2.5Hz,1H),8.12(d,J=9.3H z,1H),7.98(dd,J=9.2,2.6Hz,1H),7.86(t,J=7.9Hz,1H),7.68(d,J=10.8Hz, 1H),7.56(s,1H),4.65(d,J=7.5Hz,2H),4.07(s,2H),3.92(s,2H),3.59(s,2 H),3.17(s,2H),2.84(p,J=7.5Hz,1H),1.97–1.91(m,2H),1.89–1.81(m,4H). 13C NMR (125MHz, DMSO-d6) δ177.72, 166.46, 159.32 (d, J = 253.8Hz), 149.59, 139.97, 138.01, 132.47, 128 .03,126.42,124.18,122.10,122.02,119.77,107.84,58.05,48.66,34.50,25.53,18.11.ESI-MS:m / z 532.34(M+H) + .C 27 H 25 F4N3O4 (531.18). Example 5. In vitro anti-poxvirus activity assay of the target compound (HEL cell)

[0153] Test principle:

[0154] Viruses can only replicate and multiply within susceptible live animals, chicken embryos, or cells. Therefore, animals, chicken embryos, or cells can be used for virus culture and antiviral drug testing. The antiviral efficacy of drugs can be assessed by observing changes in cell culture medium pH, viral cytopathic effect (CPE), viral plaque assay (PFU), viral genome mRNA levels, and changes in relevant indicators such as chicken embryo allantoic fluid or animal serum.

[0155] Viral plaques, also known as empty plaques, occur when a virus infects a cell. Due to the limitations of the solid medium, the released virus can only spread from the initially infected cell to the surrounding area. After several proliferation cycles, a localized lesion cell area is formed. Combined with staining with reactive dyes, live cells are stained, while cells damaged by viral infection remain unstained, forming a visible plaque. Theoretically, one viral particle can form one plaque. Conversely, each plaque indicates the presence of one live viral particle in the experimental environment. The viral plaque assay is one of the most widely used methods for detecting viral titers.

[0156] Plaque forming units (PFUs) refer to the number of infectious viral particles sufficient to form a visible plaque in a cell culture. Each plaque represents one or a group of viral particles capable of infecting host cells and causing cell lysis. PFU is a standard unit used to quantify viral concentration. This experiment used a viral infection dose of 100 PFU.

[0157] Test method:

[0158] Viral plaque assay (PFU)

[0159] HEL cells were digested, centrifuged, counted, and seeded into 96-well plates. After 24 hours of incubation at 37°C and 5% CO2, 100 PFU of monkeypox virus (2022MPXV isolate) was added to infect the cells. One hour later, residual virus was removed, and culture medium containing different concentrations of compounds was added. Incubation continued for another hour, followed by covering the cells with 1.6% carboxymethyl cellulose diluted in DMEM. After 1-3 days of incubation, when viral plaques were fully formed in the control group infected cells, the cells were fixed with 3.7% formaldehyde, and the fixative was removed. The monolayer of cells was then stained with 0.1% crystal violet and 1.5% methanol. The staining solution was removed, and the number of viral plaques in each well was observed and counted under a microscope. The concentration of the compound that reduced viral plaque formation by 50% was considered the antiviral activity (EC50) of the target compound. 50 ).

[0160] The cytotoxicity test is based on the inhibitory effect of the test compound on cell growth. First, 5 × 10⁵ cells / well are seeded into each well of a 96-well microtiter plate. 3 HEL cells were incubated at 37°C and 5% CO2 for 24 hours; then culture medium containing different concentrations of the test compound was added, and the cells were incubated at 37°C and 5% CO2 for 3 days; then the number of cells per well was determined using a Coulter counter. 50 This indicates the concentration of a compound required to reduce cell proliferation by 50% relative to the number of cells in the untreated control group. Cytotoxicity can also be expressed as MCC, which is the minimum concentration of a compound required to produce a visible change in the morphology of normal cells under a microscope.

[0161] Table 1. Structures of some 4-quinolinone compounds and their activity and toxicity against orthopoxvirus (HEL cells)

[0162]

[0163]

[0164] A represents compound EC 50 <100nM, B represents compound EC 50 Values ​​range from 100 to 1000 nM, where C represents the compound EC. 50 >1000nM;

[0165] a EC 50 The concentration of the compound that reduces viral plaque formation by 50% is used when the viral titer is 100 plaque formation units (PFU).

[0166] bMCC: The minimum concentration of a compound required to cause a change in the morphology of normal cells visible under a microscope.

Claims

1. A 4-quinolinone derivative and its tautomers, deuterated derivatives of said derivative or tautomers, or a pharmaceutically acceptable salt thereof, having the structure of the general formula I: ###0001### wherein, n = 0, 1, 2 or 3; T is: C5-C6 cycloalkyl, C4-C5 heterocycloalkyl, -CO(Ci-C6 alkyl)NH-, -(Ci-C6 alkyl)CONH- or -CO(Ci-C6 alkyl)CONH-, various substituted six-membered heterocycles, various substituted five-membered heterocycles, various substituted six-membered fused five-membered heterocycles, various substituted six-membered fused six-membered heterocycles, various substituted five-membered fused five-membered heterocycles, said substituents being one or more, independently selected from halogen, hydroxy, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, Ci-C6 alkyl or C3-C6 cycloalkyl; R is: Ci-C6 alkyl, OCi-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, OC3-C6 cycloalkyl, substituted phenyl ring, substituted naphthyl ring, various substituted six-membered heterocycles, various substituted five-membered heterocycles, various substituted six-membered fused five-membered heterocycles, various substituted six-membered fused six-membered heterocycles, various substituted five-membered fused five-membered heterocycles, various substituted benzofused five-membered heterocycles or various substituted benzofused six-membered heterocycles, said substituents being one or more, independently selected from halogen, hydroxy, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, Ci-C6 alkyl or C3-C6 cycloalkyl. I 2. The 4-quinolinone derivative according to claim 1, wherein: A is -CH2-, -NH- or -CO-; T is triazole, piperidine, piperazine, piperazinone or tetrahydropyrrole; R is a substituted phenyl ring having the formula a; ###0002### is a compound of the formula la: ###0003### la wherein, A is -CH2-, -NH- or -CO-; R is a substituted phenyl ring having the formula a; is a compound of the formula lb: ###0004### lb wherein, A is -CH2-, -NH- or -CO-; R is a substituted phenyl ring having the formula a; and the pharmaceutically acceptable salt of said compound is a sodium salt, a hydrochloride salt, a sulfate salt, a tartrate salt or a citrate salt. A is: (CH2) n , NH(CH2) n or CO(CH2) n ; is one of the following compounds: ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###0112### ###0113### ###0114### ###0115### ###0116### ###0117### ###0118### ###0119### ###0120### ###0121### ###0122### ###0123### ###0124### ###0125### ###0126### ###0127### ###0128### ###0129### ###0130### ###0131### ###0132### ###0133### ###0134### ###0135### ###0136### ###0137### ###0138### ###0139### ###0140### ###0141### ###0142### ###0143### ###0144### ###0145### ###0146### ###0147### ###0148### ###0149### ###0150### ###0151### ###0152### ###0153### ###0154### ###0155### ###0156### ###0157### ###0158### ###0159### ###0160### ###0161### ###0162### ###0163### ###0164### ###0165### ###0166### ###0167### ###0168### ###0169### ###0170### ###0171### ###0172### ###0173### ###0174### ###0175### ###0176### ###0177### ###0178### ###0179### ###0180### ###0181### ###0182### ###0183### ###0184### ###0185### ###0186### ###0187### ###0188### ###0189### ###0190### ###0191### ###0192### ###0193### ###0194### ###0195### ###0196### ###0197### ###0198### ###0199### ###0200### ###0201### ###0202### ###0203### ###0204### ###0205### ###0206### ###0207### ###0208### ###0209### ###0210### ###0211### ###0212### ###0213### ###0214### ###0215### ###0216### ###0217### ###0218### ###0219### ###0220### ###0221### ###0222### ###0223### ###0224### ###0225### ###0226### ###0227### ###0228### ###0229### ###0230### ###0231### ###0232### ###0233### ###0234### ###0235### ###0236### ###0237### ###0238### ###0239### ###0240### ###0241### ###0242### ###0243### ###0244### ###0245### ###0246### ###0247### ###0248### ###0249### ###0250### ###0251### ###0252### ###0253### ###0254### ###0255### ###0256### ###0257### ###0258### ###0259### ###0260### ###0261### ###0262### ###0263### ###0264### ###0265### ###0266### ###0267### ###0268### ###0269### ###0270### ###0271### ###0272### ###0273### ###0274### ###0275### ###0276### ###0277### ###0278### ###0279### ###0280### ###0281### ###0282### ###0283### ###0284### ###0285### ###0286### ###0287### ###0288### ###0289### ###0290### ###0291### ###0292### ###0293### ###0294### ###0295### ###0296### ###0297### ###0298### ###0299### ###0300### ###0301### ###0302### ###0303### ###0304### ###0305### ###0306### ###0307### ###0308### ###0309### ###0310### ###0311### ###0312### ###0313### ###0314### ###0315### ###0316### ###0317### ###0318### ###0319### ###0320### ###0321### ###0322### ###0323### ###0324### ###0325### ###0326### ###0327### ###0328### ###0329### ###0330### ###0331### ###0332### ###0333### ###0334### ###0335### ###0336### ###0337### ###0338### ###0339### ###0340### ###0341### ###0342### ###0343### ###0344### R 1 R is hydrogen, hydroxyl, C1-C6alkyl, halogenated C1-C6alkyl, heteroatom-containing C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, OC3-C6cycloalkyl, -C(=O)(C1-C6alkyl), trifluoromethyl, substituted cycloalkyl, substituted phenyl ring, substituted benzyl, substituted naphthyl ring, various substituted six-membered heterocyclic rings, various substituted five-membered heterocyclic rings, or various substituted four-membered heterocyclic rings, the substituents being one or more, independently selected from halogen, hydroxyl, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6alkyl, or C3-C6cycloalkyl; R 2 is: O-R4, NH-R4, HON-R4, or CH=C(OH)COOR4, wherein R4 is hydrogen, C1-C6 alkyl, phenyl, benzyl, substituted phenyl, or substituted benzyl, said substituents being one or more, independently selected from halogen, hydroxy, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6 alkyl, or C3-C6 cycloalkyl; R 3 is: hydrogen, C1-C6alkyl, halogenated C1-C6alkyl, heteroatom-containing C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C3-C6cycloalkyl or substituted cycloalkyl, OC3-C6cycloalkyl, trifluoromethyl, substituted phenyl ring, substituted benzyl, substituted naphthalene ring, various substituted six-membered heterocyclic ring, various substituted five-membered heterocyclic ring, or various substituted four-membered heterocyclic ring, the substituents being one or more, independently selected from halogen, hydroxyl, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6alkyl or C3-C6cycloalkyl; ​ ​ ​ R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, , , , , , , , or ; R 2 is hydroxyl, hydroxylamino or ethoxy; R 3 is hydrogen; ​ ​ ​ a wherein R is F, CI, Br, CH3, OCH3, CN, NO2, NH2, 2,6-diF, 2,5-diF, 3,4-diF, 2,4-diF, 2-F-4-CF3-Ph, 3-F-4-CF3-Ph, CONH2, SO2NH2, SO2CH3, NHCH3, NHCOCH3, NHSO2CH3, or NHSO2CF3. 4 wherein R is F, CI, Br, CH3, OCH3, CN, NO2, NH2, 2,6-diF, 2,5-diF, 3,4-diF, 2,4-diF, 2-F-4-CF3-Ph, 3-F-4-CF3-Ph, CONH2, SO2NH2, SO2CH3, NHCH3, NHCOCH3, NHSO2CH3, or NHSO2CF3 3. The 4-quinolinone derivative as described in claim 2, characterized in that... ​ ​ ​ R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, , , , , , , , or ; R 2 is hydroxyl, hydroxylamino or ethoxy; R 3 is hydrogen; ​ ​ a wherein R is F, CI, Br, CH3, OCH3, CN, NO2, NH2, 2,6-diF, 2,5-diF, 3,4-diF, 2,4-diF, 2-F-4-CF3-Ph, 3-F-4-CF3-Ph, CONH2, SO2NH2, SO2CH3, NHCH3, NHCOCH3, NHSO2CH3, or NHSO2CF3. 4 wherein R is F, CI, Br, CH3, OCH3, CN, NO2, NH2, 2,6-diF, 2,5-diF, 3,4-diF, 2,4-diF, 2-F-4-CF3-Ph, 3-F-4-CF3-Ph, CONH2, SO2NH2, SO2CH3, NHCH3, NHCOCH3, NHSO2CH3, or NHSO2CF3 4. The 4-quinolinone derivative as described in claim 2, characterized in that... ​ ​ ​ R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, , , , , , , , or ; R 2 is hydroxyl, hydroxylamino or ethoxy; R 3 is hydrogen; ​ is piperidine, piperazine, piperazinone or tetrahydropyrrole; ​ a wherein R is F, CI, Br, CH3, OCH3, CN, NO2, NH2, 2,6-diF, 2,5-diF, 3,4-diF, 2,4-diF, 2-F-4-CF3-Ph, 3-F-4-CF3-Ph, CONH2, SO2NH2, SO2CH3, NHCH3, NHCOCH3, NHSO2CH3, or NHSO2CF3. 4 wherein R is F, CI, Br, CH3, OCH3, CN, NO2, NH2, 2,6-diF, 2,5-diF, 3,4-diF, 2,4-diF, 2-F-4-CF3-Ph, 3-F-4-CF3-Ph, CONH2, SO2NH2, SO2CH3, NHCH3, NHCOCH3, NHSO2CH3, or NHSO2CF3 5. The 4-quinolinone derivative as described in any one of claims 1-4, characterized in that... ​ 6. The 4-quinolinone derivative as described in claim 3 or 4, characterized in that... ​ 。 ​ The compound A and B are used as starting materials, first reacted in toluene solvent to generate intermediate compound C, then compound C is cyclized in diphenyl ether solvent to generate intermediate compound D, and the intermediate compound D is subjected to N-1 hydrocarbonation under the alkaline condition of potassium carbonate to generate intermediate compound E; the intermediate compound E is subjected to Sonogashira coupling reaction under the condition of cuprous iodide and bis(triphenylphosphine)palladium dichloride as catalyst and triethylamine as base to generate intermediate compound F, then the intermediate compound F is subjected to trimethylsilane removal under the action of potassium carbonate with methanol as solvent to generate key intermediate G; then the key intermediate compound G is subjected to azide-alkynyl Husigen-Click cycloaddition under the action of Cu(I) generated by the reaction of sodium ascorbate and copper sulfate pentahydrate to generate intermediate compound H, and finally the intermediate compound H is subjected to ester hydrolysis under the action of lithium hydroxide monohydrate with methanol as solvent to generate target product Ia; The synthetic route of general scheme A is as follows: Reagents and conditions: (i) toluene, 90-110 DEG C; (ii) diphenyl ether, 200-250 DEG C; (iii) dimethylformamide, iodoalkane or iodoaromatic hydrocarbon or bromoalkane or bromoaromatic hydrocarbon, 60-80 DEG C; (iv) tetrahydrofuran, cuprous iodide, bis(triphenylphosphine)palladium dichloride, triethylamine, trimethylsilylethynyl, N2, room temperature; (v) methanol, potassium carbonate, room temperature; (vi) sodium ascorbate, copper sulfate pentahydrate, tetrahydrofuran, water, azide, 30-65 DEG C; (vii) a) lithium hydroxide monohydrate, methanol, water, 60 DEG C; b) potassium hydroxylamine solution, room temperature; R, R 1 , R 2 , R 3 , A is as indicated in claim 3 for formula la; The azide is a substituted benzene ring azide, and the substituent is one or more, independently selected from halogen, hydroxyl, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6 alkyl or C3-C6 cycloalkyl.

8. The method for preparing the 4-quinolinone derivative according to claim 4, comprising the following steps: With compound J as starting material, first reacted with diethyl ethoxymalonate in toluene solvent to form intermediate compound L, then cyclized to form intermediate compound M in diphenyl ether solvent, and then reacted with potassium carbonate to form intermediate compound N; intermediate compound N was subjected to Buchwald-Hartwig coupling reaction with palladium acetate and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene as catalyst and cesium carbonate as base to form intermediate compound O, then intermediate compound O was subjected to removal of tert-butyloxycarbonyl in the presence of trifluoroacetic acid in dichloromethane to form intermediate compound P; then key intermediate compound P was subjected to nucleophilic substitution reaction in the presence of potassium carbonate or amide condensation reaction in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIEA) to form intermediate compound Q, and finally intermediate compound Q was subjected to ester hydrolysis reaction in the presence of lithium hydroxide monohydrate in methanol to form target product Ib; The synthetic route of general scheme B is as follows: Reagents and conditions: (i) toluene, 90-110 ℃; (ii) diphenyl ether, 200-250 ℃; (iii) iodoalkane, iodoaromatic, bromoalkane or bromoaromatic, dimethylformamide, 60-80 ℃; (iv) palladium acetate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, cesium carbonate, 1,4-dioxane, N2, 70-100 ℃; (v) trifluoroacetic acid, dichloromethane, room temperature; (vi) a) substituted bromobenzene, potassium carbonate, dimethylformamide, room temperature; b) substituted benzoic acid, HATU, DIEA, dichloromethane, room temperature; c) substituted bromobenzene, palladium acetate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, cesium carbonate, 1,4-dioxane, N2, 70-100 ℃; (vii) lithium hydroxide monohydrate, methanol, water, 60 ℃; R, R 1 , R 2 , R 3 , A is as indicated in claim 4 for formula Ib; The azide is a substituted benzene ring azide, and the substituent is one or more, independently selected from halogen, hydroxyl, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6 alkyl or C3-C6 cycloalkyl.

9. Use of a compound according to any one of claims 1-6 for the preparation of a medicament for the treatment of orthopoxvirus.

10. A pharmaceutical composition comprising a compound according to any one of claims 1-6 and one or more pharmaceutically acceptable carriers or excipients.

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