4-quinolinone derivative as well as preparation method and application thereof

Abstract

The invention discloses a 4-quinolinone derivative as well as a preparation method and application thereof. The compound has a structure as shown in a general formula I. The invention also relates to a pharmaceutical composition containing the compound with the structure as shown in the formula I. An activity screening experiment shows that the compound disclosed by the invention has good anti-orthopoxvirus activity, so that the invention also provides application of the compound in preparation of anti-orthopoxvirus medicines. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis and pharmaceutical application, and specifically relates to a 4-quinolinone derivative and a preparation method thereof and application thereof as a broad-spectrum orthopoxvirus inhibitor. Background Art

[0002] The genus Orthopoxvirus belongs to the Poxviridae family, which includes monkeypox virus, smallpox virus, vaccinia virus, camelpox virus and cowpox virus. Poxvirus is a large double-stranded DNA virus with an envelope structure, with a genome size of 130 to 360kbp, and its life cycle occurs in the host's cytoplasm. Among them, monkeypox virus is the pathogen of the recent monkeypox outbreak. On August 14, 2024, the World Health Organization announced that the monkeypox outbreak constituted an international public health emergency; smallpox is an acute infectious disease caused by smallpox virus infection, with a high mortality rate, and is regarded as one of the most devastating diseases in human history; vaccinia virus is a widely used virus model in the laboratory and has been used to prepare smallpox vaccines; camelpox virus is a highly contagious pathogen for camels. The virus was first discovered in India in 1909; cowpox virus is named because of its association with pustular lesions on the nipples of cows and the hands of milkers.

[0003] Orthopoxviruses are closely related in antigenicity, immunology, and serology, and have cross-immune protection. However, since the eradication of smallpox in the 1980s, routine vaccination has been stopped, resulting in a gradual increase in the number of people susceptible to orthopoxviruses worldwide. Currently, the U.S. Food and Drug Administration (FDA) has approved the use of tecoviridad and brincidofovir for the treatment of smallpox; the European Medicines Agency (EMA) has approved tecoviridad for the treatment of monkeypox. However, they have many problems, such as: the mechanism of action of tecoviridad has limitations; brincidofovir has weak antiviral activity and is accompanied by severe hepatotoxicity. Therefore, there is an urgent need to develop new and effective drugs against monkeypox virus and other orthopoxviruses. Summary of the invention

[0004] In view of the deficiencies of the prior art, the present invention provides a 4-quinolinone derivative and a preparation method thereof; the present invention also provides the use of the 4-quinolinone derivative as a broad-spectrum orthopoxvirus (monkeypox virus, camelpox virus, vaccinia virus and cowpox virus) inhibitor in the preparation of a broad-spectrum anti-orthopoxvirus (monkeypox virus, camelpox virus, vaccinia virus and cowpox virus) drug.

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

[0006] 1.4-Quinolinone derivatives

[0007] A 4-quinolinone derivative and its tautomer, the derivative or the deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof of the present invention has a structure shown in the following 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: N or C(U);

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

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

[0015] And one and only one of X, Y and Z is N;

[0016] wherein U, V and W are each independently selected from the group consisting of hydrogen, halogen, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C6 cycloalkyl, OC3-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 combined with R 1 Connect into a ring;

[0017] R 1 is: 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 q, trifluoromethyl, substituted cycloalkyl, substituted benzene ring, substituted benzyl, substituted naphthalene 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;

[0018] 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, 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 is: 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, substituted naphthalene, 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 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 and five-membered heterocycles, various substituted six-membered and six-membered heterocycles, various substituted five-membered and five-membered heterocycles, and 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;

[0021] R is: C1-C6 alkyl, OC1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, OC3-C6 cycloalkyl, substituted benzene ring, substituted naphthalene ring, various substituted six-membered heterocycles, various substituted five-membered heterocycles, various substituted six-membered and five-membered heterocycles, various substituted six-membered and six-membered heterocycles, various substituted five-membered and five-membered heterocycles, various substituted benzo five-membered heterocycles or various substituted benzo six-membered heterocycles, and the substituents are one or more and 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 is independently selected at each occurrence from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl;

[0023] Where: R p , R q , R s and R r The C1-C4 alkyl in any of the groups is optionally substituted with 1 to 3 groups selected from halogen, cyano or hydroxy.

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

[0025] R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl,

[0026] R 2 is hydroxyl, hydroxylamine or ethoxy;

[0027] R 3 is hydrogen;

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

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

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

[0031] R is a substituted benzene ring having 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 the present invention, further preferably, the present invention provides a compound represented by Formula Ia and its tautomer, said derivative or deuterated derivative of said tautomer, or a pharmaceutically acceptable salt or prodrug derivative thereof,

[0035]

[0036] in,

[0037] R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl,

[0038] R 2 is hydroxyl, hydroxylamine or ethoxy;

[0039] R 3 is hydrogen;

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

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

[0042] R is a substituted benzene ring having 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 the present invention, further preferably, the present invention provides a compound represented by formula Ib and its tautomer, said derivative or deuterated derivative of said tautomer, or a pharmaceutically acceptable salt or prodrug derivative thereof,

[0046]

[0047] in,

[0048] R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl,

[0049] R 2 is hydroxyl, hydroxylamine or ethoxy;

[0050] R 3 is hydrogen;

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

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

[0053] is piperidine, piperazine, piperazinone or tetrahydropyrrole;

[0054] R is a substituted benzene ring having 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] Preferably according to the present invention, the pharmaceutically acceptable salt of the compound is sodium salt, hydrochloride, sulfate, tartrate or citrate.

[0058] According to the present invention, more preferably, a 4-quinolinone derivative represented by general formula I is one of the following compounds:

[0059]

[0060] 2.4-Preparation method of quinolinone derivatives

[0061] The preparation method of a 4-quinolinone derivative disclosed in the present invention can be prepared according to standard chemical practice or as described herein, including the following synthesis scheme and the representation of the compound used to prepare formula Ia and Ib, its tautomer, the deuterated derivative of the compound or the tautomer, or the pharmaceutically acceptable salt of the foregoing.

[0062] The following non-limiting reaction schemes A and B are preferred embodiments for preparing the compounds of the present invention. Based on the reaction schemes described below and the structures of the compounds of the present invention, other methods and adjustments are obvious to those skilled in the art. These methods are all included in the scope of the present invention.

[0063] The synthesis steps of general scheme A are as follows: using compounds A and B as starting materials, first reacting 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 hydrocarbonization reaction at N-1 position under alkaline conditions of potassium carbonate to generate intermediate compound E; intermediate compound E undergoes Sonogaoka coupling reaction under conditions of cuprous iodide and bis(triphenylphosphine)palladium dichloride as catalysts and triethylamine as base to obtain intermediate compound F, then intermediate compound F is subjected to trimethylsilyl removal under the action of potassium carbonate with methanol as solvent to generate key intermediate G; then key intermediate compound G is subjected to azide-alkynyl Husigen-Click cycloaddition reaction under the action of Cu(I) generated by the reaction of sodium ascorbate and copper sulfate pentahydrate to generate intermediate compound H, and finally intermediate compound H is subjected to ester hydrolysis reaction under the action of lithium hydroxide monohydrate with methanol as solvent to generate target product Ia.

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

[0065]

[0066] Reagents and conditions: (i) toluene, 90-110°C; (ii) diphenyl ether, 200-250°C; (iii) dimethylformamide, iodinated alkane or iodinated aromatic hydrocarbon or brominated alkane or brominated aromatic hydrocarbon, 60-80°C; (iv) tetrahydrofuran, cuprous iodide, bis(triphenylphosphine)palladium dichloride, triethylamine, trimethylsilyl acetylene, N2, room temperature; (v) methanol, potassium carbonate, room temperature; (vi) sodium ascorbate, copper sulfate pentahydrate, tetrahydrofuran, water, azide, 30-65°C; (vii) a) lithium hydroxide monohydrate, methanol, water, 60°C; b) potassium hydroxylamine solution, room temperature.

[0067] The synthesis steps of general scheme B are as follows: compound J is used as a starting material, first reacting with diethyl ethoxymethylenemalonate 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 alkylation reaction at N-1 position under alkaline conditions of potassium carbonate to generate intermediate compound N; intermediate compound N undergoes Buchwald-Hartwig coupling reaction under conditions of palladium acetate and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene as catalysts and cesium carbonate as a base to obtain intermediate compound The intermediate compound O is then subjected to a nucleophilic substitution reaction under the action of potassium carbonate or an amide condensation reaction under the action of O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIEA) to generate an intermediate compound Q. Finally, the intermediate compound Q is subjected to an ester hydrolysis reaction under the action of lithium hydroxide monohydrate using methanol as a solvent to generate the target product Ib.

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

[0069]

[0070] Reagents and conditions: (i) toluene, 90-110°C; (ii) diphenyl ether, 200-250°C; (iii) iodinated alkane, iodinated aromatic hydrocarbon, brominated alkane or brominated aromatic hydrocarbon, dimethylformamide, 60-80°C; (iv) palladium acetate, 4,5-bis(diphenylphosphino-9,9-dimethylxanthene, cesium carbonate, 1,4-dioxane, N2, 70-100°C; (v) trifluoroacetic acid, dichloromethane, room temperature; (vi) a) substituted benzyl bromide, 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°C; (vii) lithium hydroxide monohydrate, methanol, water, 60°C.

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

[0072] The azide is a substituted benzene ring azide, a substituted naphthalene ring azide, various substituted six-membered heterocyclic azides, various substituted five-membered heterocyclic azides, various substituted six-membered and five-membered heterocyclic azides, various substituted six-membered and six-membered heterocyclic azides, various substituted five-membered and five-membered heterocyclic azides, various substituted benzo five-membered heterocyclic azides or various substituted benzo six-membered heterocyclic azides, 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.

[0073] The room temperature described in the present invention refers to 20-30°C.

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

[0075] The present invention discloses the results of screening the broad-spectrum anti-orthopoxvirus (monkeypox virus, camelpox virus, vaccinia virus and cowpox virus) activity of 4-quinolinone derivatives and their first application as broad-spectrum orthopoxvirus inhibitors. Experiments prove that the 4-quinolinone derivatives of the present invention can be used as broad-spectrum orthopoxvirus inhibitors for preparing anti-orthopoxvirus drugs. The present invention also provides the use of the above compounds in preparing broad-spectrum orthopoxvirus drugs.

[0076] Broad-spectrum anti-orthopoxvirus (monkeypox virus, camelpox virus, vaccinia virus and cowpox virus) activity and toxicity experiments of target compounds

[0077] The 4-quinolinone derivatives synthesized according to the above method were screened for their broad-spectrum anti-orthopoxvirus activity (monkeypox virus, camelpox virus, vaccinia virus and cowpox virus). Their antiviral activity and toxicity data are listed in Table 1, with Cidofovir, Brincidofovir and Tecovirimat as positive controls.

[0078] As can be seen from Table 1, the 4-quinolinone derivatives of the present invention are a series of novel broad-spectrum orthopoxvirus inhibitors, showing significant broad-spectrum anti-orthopoxvirus activity. Among them, the anti-orthopoxvirus activity of compounds QY6259, QY6268 and QY6281 is particularly outstanding, most of the activities are less than 100nM, and the cytotoxicity is very low, which has further research and development value.

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

[0080] The 4-quinolinone derivatives of the present invention can be used as broad-spectrum orthopoxvirus inhibitors, and specifically, can be used as broad-spectrum orthopoxvirus inhibitors for preparing broad-spectrum anti-orthopoxvirus drugs.

[0081] A broad-spectrum anti-orthopoxvirus pharmaceutical composition comprises the 4-quinolinone derivatives of the present invention and one or more pharmaceutically acceptable carriers or excipients. DETAILED DESCRIPTION

[0082] The following examples are helpful for understanding the present invention, but they cannot limit the content of the present invention. In the following examples, the numbers of all target compounds are the same as those in Table 1.

[0083] Synthesis route 1:

[0084]

[0085] Synthesis route 2:

[0086]

[0087] Synthesis route three:

[0088]

[0089] Example 1. Synthesis of the key intermediate 1-(cyclobutylmethyl)-6-ethynyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (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 ethoxymethylenemalonate (25.11 mmol, 5.43 g) was added to the solution, and the mixture was heated under reflux with stirring. After the reaction was completed, the solvent was evaporated under reduced pressure, and then ether was added to the residue in the bottle, filtered, and the filter cake was washed with ether to obtain 8.10 g of a crude product of diethyl 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 of diethyl 2-(((4-iodophenyl)amino)methylene)malonate (2) (12.85 mmol, 5.0 g) obtained in the previous step was added to 50 mL of diphenyl ether solvent, and refluxed with stirring at 250° C. After the reaction was completed, the mixture was cooled to room temperature to precipitate a large amount of brown precipitate. The filter cake was filtered and washed with ethyl acetate to obtain 3.95 g of crude product of ethyl 6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (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, and then potassium carbonate (23.32 mmol, 3.22 g) was added to the solution, and stirred at room temperature for 15 min. (Iodomethyl)cyclobutane (17.49 mmol, 3.43 g) was added to the solution, and stirring was continued at 80°C for 2 h. Then 100 mL of ice water was added to the mixed solution to produce a large amount of light yellow precipitate, which was filtered and washed with water to obtain a crude product of ethyl 1-(cyclobutylmethyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (4). Recrystallization from methanol gave 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 of ethyl 1-(cyclobutylmethyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (4) (2.43 mmol, 1.0 g) was added 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) in sequence, and then nitrogen was added for protection. Then trimethylsilyl acetylene (5.35 mmol, 525.45 mg) was added to the mixed solution, and stirred at room temperature for 12 h. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and column chromatography was performed to obtain 707.9 mg of the intermediate 1-(cyclobutylmethyl)-4-oxo-6-((trimethylsilyl)ethynyl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (5), with a yield of 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 obtained 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, potassium carbonate (1.86 mmol, 256.42 mg) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the solvent was evaporated under reduced pressure, and then 60 mL of dichloromethane was added to the residue in the bottle to dissolve it, and saturated brine (3×30 mL) was added to wash three times, and the organic phase was separated and dried over anhydrous sodium sulfate; filtered, concentrated under reduced pressure, and the key intermediate 1-(cyclobutylmethyl)-6-ethynyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (6) was obtained as a pure product as 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 1-(cyclobutylmethyl)-6-ethynyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (6) (1.62 mmol, 500.0 mg) and the azide prepared from the substituted benzyl halide (4.04 mmol, 885.45 mg) were added to 10 mL of tetrahydrofuran. Then, freshly prepared aqueous sodium ascorbate (808.11 μmol, 160.09 mg) and aqueous copper sulfate pentahydrate (161.62 μmol, 40.35 mg) were added to the solution. The mixed solution was heated to 65°C and stirred vigorously for 4-12 h (TLC detection). After the reaction was completed, the solvent was evaporated under reduced pressure, and then 60 mL of dichloromethane was added to the residue in the bottle to dissolve it, and saturated brine (3×30 mL) was added to wash three times, and the organic phase was separated and dried over anhydrous sodium sulfate; filtered, concentrated under reduced pressure, subjected to column chromatography, and then recrystallized from methanol to obtain the target products QY6251 and QY6261.

[0097] Then, for different target products, the present invention adopts different synthesis methods. The target products QY6259 and QY6268 adopt method one, while the target products QY6281 and QY6285 adopt method two.

[0098] Method 1: 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), lithium hydroxide monohydrate (1.14 mmol, 47.64 mg) was added, and heated at 60°C for 2-3 h. After the reaction was completed, 1 M hydrochloric acid solution was added to adjust the pH to 10-11, and a large amount of white precipitate was precipitated. The precipitate was filtered, and the filter cake was washed with water. The filter cake was recrystallized in methanol to obtain the target products QY6259 and QY6268.

[0099] Method 2: Dissolve 14.18g KOH in 35mL methanol under ice bath to prepare a saturated solution; dissolve 11.68g NH2OH-HCl in 60mL methanol to prepare a saturated solution, then add the prepared saturated KOH methanol solution dropwise, stir and react for about 1h, filter out the precipitate, and collect the filtrate to obtain NH2OK solution. Dissolve the compounds QY6251 and QY6261 (0.1g, 0.19mmol) prepared in the previous step in NH2OK (5mL) solution, stir and react at room temperature for about 0.5h, monitor the reaction by TCL, add an appropriate amount of water after the reaction is completed, and adjust the pH to acidic with 1M hydrochloric acid solution, a white precipitate is precipitated, filter out the precipitate and dry it, 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 ethoxymethylenemalonate (31.97 mmol, 6.91 g) was added to the solution, and the mixture was heated under reflux with stirring. After the reaction was completed, the solvent was evaporated under reduced pressure, and then ether was added to the residue in the bottle, filtered, and the filter cake was washed with ether to obtain 9.34 g of a crude product of diethyl 2-(((4-bromophenyl)amino)methylene)malonate (8), with a yield of 93.9%.

[0102] The crude product of diethyl 2-(((4-bromophenyl)amino)methylene)malonate (8) (14.61 mmol, 5.0 g) obtained in the previous step was added to 50 mL of diphenyl ether solvent, and refluxed with stirring at 250° C. After the reaction was completed, the mixture was cooled to room temperature to precipitate a large amount of brown precipitate. The filter cake was filtered and washed with ethyl acetate to obtain 3.92 g of crude product of ethyl 6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylate (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] 6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (9) (13.51mmol, 4.0g) was added to 40mL of dimethylformamide, and then potassium carbonate (27.02mmol, 3.73g) and potassium iodide (13.51mmol, 2.24g) were added to the solution, and stirred at room temperature for 15min (the solution was turbid). (Bromomethyl)cyclobutane (20.26mmol, 3.02g) was added to the solution, and stirring was continued at 80℃ for 2h. Then 100mL of ice water was added to the mixed solution to produce a large amount of light yellow precipitate, which was filtered and washed with water to obtain the crude product of 1-(cyclobutylmethyl)-6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (10). Recrystallization from methanol gave 5.23g of pure product, yield: 94.1%, melting point: 135-137℃. 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 a solution of 1-(cyclobutylmethyl)-6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (10) (2.75 mmol, 1.0 g) in 10 mL of 1,4-dioxane were added 1-Boc-piperazine (4.12 mmol, 0.77 g) or tert-butyl 3-oxo-1-piperazinecarboxylate (4.12 mmol, 0.82 g), palladium acetate (0.27 mmol, 61.64 mg), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.27 mmol, 0.16 g) and cesium carbonate (5.49 mmol, 1.79 g) in sequence, and then nitrogen protection was added and the mixture was stirred at 100°C overnight. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the intermediate 6-(4-(tert-butyloxycarbonyl)azacycloalkyl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester was obtained through column chromatography. The physical properties and spectral data are as follows:

[0105] Ethyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (11a), white solid, yield: 85.7%, melting point: 160-162°C. 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-carboxylate (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] The intermediate 11a or 11b (1.0 eq) was dissolved in dichloromethane, trifluoroacetic acid (10.0 eq) was added and stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to remove the excess trifluoroacetic acid, the pH was adjusted to 9 with saturated sodium carbonate, and then 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 chromatographed to obtain the 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] Ethyl 1-(cyclobutylmethyl)-4-oxo-6-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylate (12a), white solid, yield: 89.1%, melting point: 140-142°C. 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] 1-(Cyclobutylmethyl)-4-oxo-6-(2-oxopiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (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 reaction of the raw materials is complete, the reaction solution is concentrated under reduced pressure and water is added. The aqueous phase is extracted three times with ethyl acetate, the organic phases are combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and recrystallized from methanol after column chromatography to obtain the intermediate (13a1, 13a2 or 13b1, 13b2); the intermediate 12a (0.54 mmol, 0.2 g), substituted benzoic acid (0.65 mmol, 0.14 g), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 0.65 mmol, 0.25 g) and N,N-diisopropylethylamine (DIEA, 1.08 mmol, 0.14 g) are dissolved in DCM (5 mL) and reacted at room temperature for 5 hours. After the reaction solution was cooled, 30 mL of water was added, and the mixture was extracted with dichloromethane (25 mL×3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the intermediates (13a3, 13a4).

[0111] The intermediate compound 13a1-13a4 or 13b1-13b2 prepared in the previous step was added to a mixed solvent of methanol and water (v / v=4:1, 5 mL), and lithium hydroxide monohydrate was added. The mixture was heated at 60°C for 2-3 h. After the reaction was completed, 1M hydrochloric acid solution was added to adjust the pH to 10-11, and a large amount of white precipitate was precipitated. The mixture was filtered, and the filter cake was washed with water. The filter cake was recrystallized from 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 a solution of 1-(cyclobutylmethyl)-6-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (10) (2.75 mmol, 1.0 g) in 10 mL of 1,4-dioxane were added 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(diphenylphosphino-9,9-dimethylxanthene) (0.27 mmol, 0.16 g) and cesium carbonate (5.49 mmol, 1.79 g) in sequence, and then nitrogen protection was added and the mixture was stirred at 100°C overnight. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the intermediate 6-(((tert-butyloxycarbonyl)amino)azacycloalkyl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester was obtained through column chromatography. The physical properties and spectral data are as follows:

[0114] Ethyl 6-(3-((tert-butyloxycarbonyl)amino)pyrrolidin-1-yl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (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-butyloxycarbonyl)amino)piperidin-1-yl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (14b), white solid, yield: 80.9%. ESI-MS: m / z 484.74 (M+H) + .C 26 H 33 N3O6(483.24).

[0116] The intermediate 14a or 14b (1.0 eq) was dissolved in dichloromethane, trifluoroacetic acid (10.0 eq) was added and stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to remove the excess trifluoroacetic acid, the pH was adjusted to 9 with saturated sodium carbonate, and then 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 chromatographed to obtain the intermediate 6-(3-aminoazacycloalkyl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. The physical properties and spectral data are as follows:

[0117] Ethyl 6-(3-aminopyrrolidin-1-yl)-1-(cyclobutylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (15a), white solid, yield: 81.5%, melting point: 165-167°C. 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-carboxylate (15b), white solid, yield: 82.3%, melting point: 228-230°C. 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] Substituted bromobenzene, palladium acetate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and cesium carbonate were added to a 10 mL 1,4-dioxane solution containing intermediate 15a or 15b, and then nitrogen was added for protection and stirred at 100°C overnight. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and intermediates 16a1, 16a2 or 16b1, 16b2 were obtained by column chromatography.

[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), and lithium hydroxide monohydrate was added. The mixture was heated at 60°C for 2-3 h. After the reaction was completed, 1M hydrochloric acid solution was added to adjust the pH to 10-11, and a large amount of white precipitate was precipitated. The mixture was filtered, and the filter cake was washed with water. The filter cake was recrystallized from methanol to obtain the target products QY6276, QY6277, QY6283 and QY6284.

[0121]

[0122] According to Example 2, the key intermediate (6) was treated 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 treated to obtain a white solid with a yield of 85.2% and a melting point of 228-230°C. 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 treated 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] 13a1 was treated as in Example 3 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 treated to obtain a white solid with a yield of 85.6% and a melting point of 240-242°C. 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] 13a2 was treated as in Example 3 to give 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] 13a3 was treated as in Example 3 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] 13a4 was treated as in Example 3 to give a pale 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] 16a1 was treated as in Example 4 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] 16a2 was treated as in Example 4 to give 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 treated to obtain a white solid with a yield of 50.3% and a melting point of 228-230°C. 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] 16b1 was treated as in Example 4 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] 16b2 was treated as in Example 4 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 treated to obtain a white solid with a yield of 54.6% and a melting point of 245-247°C (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] 13b1 was treated as in Example 3 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] 13b2 was treated as in Example 3 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-orthopoxvirus activity test of the target compound (HEL cells)

[0153] Test principle:

[0154] Viruses can replicate and proliferate only in susceptible living animals, chicken embryos or cells. Therefore, animals, chicken embryos or cells can be used for virus culture and antiviral testing of drugs. The antiviral test effect of drugs can be judged by observing changes in the pH of cell culture fluid, the cytopathic effect (CPE) of the virus, the plaque assay (Plaque assay, PFU), changes in the mRNA level of the viral genome, changes in chicken embryo allantoic fluid or animal serum and other corresponding indicators.

[0155] Virus plaques, also known as empty plaques, are formed after the virus infects cells. Due to the limitation of solid media, the released viruses can only spread from the initially infected cells to the periphery. After several proliferation cycles, a localized diseased cell area is formed. Combined with active dye staining, live cells are stained, and cells damaged by virus infection are not stained, forming plaques visible to the naked eye. Theoretically, one virus particle can form one plaque. Conversely, each plaque produced means that there is a live virus particle in the experimental environment. Virus plaque test is one of the most widely used methods for detecting virus titers.

[0156] Plaque Forming Units (PFU) refer to the number of infectious virus particles that can form a visible plaque in cell culture. Each plaque represents one or a group of virus particles that can infect host cells and cause cell lysis. PFU is a standard unit for quantifying virus concentration. This test uses a viral infection dose of 100 PFU.

[0157] Test method:

[0158] Virus plaque assay (PFU)

[0159] HEL cells were digested, centrifuged, counted, and plated in a 96-well plate. After culturing for 24 hours at 37°C and 5% CO2, 100 PFU of monkeypox virus (2022MPXV isolate) was added to infect the cells. After 1 hour, the residual virus was removed, and culture medium containing different concentrations of the compound was added. The cells were incubated for another 1 hour, and then covered with 1.6% carboxymethyl cellulose diluted in DMEM. After culturing for 1-3 days, when the virus plaques in the virus-infected cells in the control group were observed to be completely formed, the cells were fixed with 3.7% formaldehyde and the fixative was removed. The monolayer cells were then stained with 0.1% crystal violet and 1.5% methanol. The staining solution was removed, and the number of virus plaques in each well was observed and counted under a microscope. The concentration of the compound that reduced the formation of virus plaques by 50% was obtained as the antiviral activity of the target compound (EC 50 ).

[0160] Cytotoxicity testing is based on the inhibitory effect of the test compound on cell growth. First, 5 × 10 3 HEL cells were incubated at 37°C and 5% CO2 for 24 hours; then medium containing different concentrations of the test compound was added and incubated at 37°C and 5% CO2 for 3 days; then the number of cells in each well was measured by a Coulter counter. 50 It is the concentration of 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 compound required to cause changes in normal cell morphology visible under a microscope.

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

[0162]

[0163]

[0164] A represents compound EC 50 <100nM, B represents compound EC 50 Values ​​are 100–1000 nM, and C represents the EC of the compound. 50 >1000nM;

[0165] a EC 50 : The concentration of compound that reduces virus plaque formation by 50%, with a virus titer of 100 plaque formation units (PFU).

[0166] bMCC: The minimum concentration of a compound required to cause microscopic changes in normal cell morphology.

Claims

1. A 4-quinolinone derivative and its tautomer, the derivative or the deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof, having a structure shown in the following general formula I: in, A is: (CH2) n 、NH(CH2) n or CO(CH2) n ; n = 0, 1, 2 or 3; X is: N or C(U); Y is: N or C(V); Z is: N or C(W); And one and only one of X, Y and Z is N; wherein U, V and W are each independently selected from the group consisting of hydrogen, halogen, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C6 cycloalkyl, OC3-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 combined with R 1 Connect into a ring; R 1 is: 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 q , trifluoromethyl, substituted cycloalkyl, substituted benzene ring, substituted benzyl, substituted naphthalene 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; 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, 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; R 3 is: 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, substituted naphthalene, 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 halogen, hydroxyl, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6 alkyl or C3-C6 cycloalkyl; 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 and five-membered heterocycles, various substituted six-membered and six-membered heterocycles, various substituted five-membered and five-membered heterocycles, and 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; R is: C1-C6 alkyl, OC1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, OC3-C6 cycloalkyl, substituted benzene ring, substituted naphthalene ring, various substituted six-membered heterocycles, various substituted five-membered heterocycles, various substituted six-membered and five-membered heterocycles, various substituted six-membered and six-membered heterocycles, various substituted five-membered and five-membered heterocycles, various substituted benzo five-membered heterocycles or various substituted benzo six-membered heterocycles, and the substituents are one or more and independently selected from halogen, hydroxyl, amino, nitro, -SO2CH3, -CONH2, -CN, -CF3, -NHCH3, -COOH, -CH2OH, -CO2CH3, -OCH3, -NHCOCH3, C1-C6 alkyl or C3-C6 cycloalkyl; R p , R q , R s and R r is independently selected at each occurrence from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl; Where: R p , R q , R s and R r The C1-C4 alkyl in any of the groups is optionally substituted with 1 to 3 groups selected from halogen, cyano or hydroxy.

2. The 4-quinolinone derivative according to claim 1, characterized in that: R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, R 2 is hydroxyl, hydroxylamine or ethoxy; R 3 is hydrogen; A is -CH2-, -NH- or -CO-; X, Y, and Z are all C; T is triazole, piperidine, piperazine, piperazinone or tetrahydropyrrole; R is a substituted benzene ring having the general formula a; 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.

3. The 4-quinolinone derivative according to claim 2, characterized in that It is a compound represented by formula Ia: in, R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, R 2 is hydroxyl, hydroxylamine or ethoxy; R 3 is hydrogen; A is -CH2-, -NH- or -CO-; X, Y, and Z are all C; R is a substituted benzene ring having the general formula a; 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.

4. The 4-quinolinone derivative according to claim 2, characterized in that It is a compound shown in formula Ib: in, R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, R 2 is hydroxyl, hydroxylamine or ethoxy; R 3 is hydrogen; A is -CH2-, -NH- or -CO-; X, Y, and Z are all C; is piperidine, piperazine, piperazinone or tetrahydropyrrole; R is a substituted benzene ring having the general formula a; 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.

5. The 4-quinolinone derivative according to any one of claims 1 to 4, characterized in that The pharmaceutically acceptable salt of the compound is sodium salt, hydrochloride, sulfate, tartrate or citrate.

6. The 4-quinolinone derivative according to claim 3 or 4, characterized in that is one of the following compounds:

7. The method for preparing the 4-quinolinone derivatives according to claim 3, comprising the following steps: Compounds A and B are used as starting materials, and are first reacted in a toluene solvent to generate an intermediate compound C. Compound C is then cyclized in a diphenyl ether solvent to generate an intermediate compound D. The intermediate compound D undergoes an alkylation reaction at the N-1 position under the alkaline condition of potassium carbonate to generate an intermediate compound E. The intermediate compound E undergoes a Sonogaoka coupling reaction under the condition of cuprous iodide and bis(triphenylphosphine)palladium dichloride as catalysts and triethylamine as a base to obtain an intermediate compound F. The intermediate compound F is then subjected to a solvent, and trimethylsilyl is removed under the action of potassium carbonate to generate a key intermediate G. The key intermediate compound G is then subjected to an azide-alkyne Husigen-Click cycloaddition reaction under the action of Cu(I) generated by the reaction of sodium ascorbate and copper sulfate pentahydrate to generate an intermediate compound H. Finally, the intermediate compound H undergoes an ester hydrolysis reaction under the action of lithium hydroxide monohydrate with methanol as a solvent to generate a target product Ia. The synthetic route of general scheme A is as follows: Reagents and conditions: (i) toluene, 90-110°C; (ii) diphenyl ether, 200-250°C; (iii) dimethylformamide, iodinated alkane or iodinated aromatic hydrocarbon or brominated alkane or brominated aromatic hydrocarbon, 60-80°C; (iv) tetrahydrofuran, cuprous iodide, bis(triphenylphosphine)palladium dichloride, triethylamine, trimethylsilyl acetylene, N2, room temperature; (v) methanol, potassium carbonate, room temperature; (vi) sodium ascorbate, copper sulfate pentahydrate, tetrahydrofuran, water, azide, 30-65°C; (vii) a) lithium hydroxide monohydrate, methanol, water, 60°C; b) potassium hydroxylamine solution, room temperature; R, R 1 , R 2 , R 3 , A, X, Y, Z, are the same as those shown in the general formula Ia in claim 3; The azide is a substituted benzene ring azide, a substituted naphthalene ring azide, various substituted six-membered heterocyclic azides, various substituted five-membered heterocyclic azides, various substituted six-membered and five-membered heterocyclic azides, various substituted six-membered and six-membered heterocyclic azides, various substituted five-membered and five-membered heterocyclic azides, various substituted benzo five-membered heterocyclic azides or various substituted benzo six-membered heterocyclic azides, 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 derivatives according to claim 4, comprising the following steps: Compound J is used as a starting material, first reacting with diethyl ethoxymethylenemalonate in a toluene solvent to generate an intermediate compound L, then compound L is cyclized in a diphenyl ether solvent to generate an intermediate compound M, intermediate compound M undergoes an alkylation reaction at the N-1 position under the alkaline condition of potassium carbonate to generate an intermediate compound N; intermediate compound N undergoes a Buchwald-Hartwig coupling reaction under the conditions of palladium acetate and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene as catalysts and cesium carbonate as a base to obtain an intermediate compound O, then The intermediate compound O uses dichloromethane as a solvent and removes the tert-butyloxycarbonyl group under the action of trifluoroacetic acid to generate an intermediate P; then the key intermediate compound P undergoes a nucleophilic substitution reaction under the action of potassium carbonate or an amide condensation reaction under the action of O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIEA) to generate an intermediate compound Q; finally, the intermediate compound Q uses methanol as a solvent and undergoes an ester hydrolysis reaction under the action of lithium hydroxide monohydrate to generate the target product Ib; The synthetic route of general scheme B is as follows: Reagents and conditions: (i) toluene, 90-110°C; (ii) diphenyl ether, 200-250°C; (iii) iodinated alkane, iodinated aromatic hydrocarbon, brominated alkane or brominated aromatic hydrocarbon, dimethylformamide, 60-80°C; (iv) palladium acetate, 4,5-bis(diphenylphosphino-9,9-dimethylxanthene, cesium carbonate, 1,4-dioxane, N2, 70-100°C; (v) trifluoroacetic acid, dichloromethane, room temperature; (vi) a) substituted benzyl bromide, 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°C; (vii) lithium hydroxide monohydrate, methanol, water, 60°C. R, R 1 , R 2 , R 3 , A, X, Y, Z, are the same as those shown in the general formula Ib in claim 4. The azide is a substituted benzene ring azide, a substituted naphthalene ring azide, various substituted six-membered heterocyclic azides, various substituted five-membered heterocyclic azides, various substituted six-membered and five-membered heterocyclic azides, various substituted six-membered and six-membered heterocyclic azides, various substituted five-membered and five-membered heterocyclic azides, various substituted benzo five-membered heterocyclic azides or various substituted benzo six-membered heterocyclic azides, 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 the compound according to any one of claims 1 to 6 in the preparation of anti-orthopoxvirus drugs.

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

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