Phthalazinediones, processes for their preparation and use

Abstract

The application discloses a phthalazine dione compound and a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The phthalazine dione compound prepared by the application has extensive antibacterial activity and shows extremely low toxicity to normal cells, and has the characteristics of high efficiency and low toxicity. Functional groups in the structure of the phthalazine dione compound can be further derivatized, thereby expanding the structural diversity of the phthalazine dione compound. Therefore, the application provides an important strategy for structural modification and diversity synthesis of the phthalazine dione compound. In addition, the preparation method of the application is simple and easy to operate, avoids the cumbersome process of pre-installation of a guiding group in other synthesis methods of the phthalazine dione compound, does not need to add an additional external oxidant, significantly improves the synthesis efficiency and reduces the cost, and has the advantages of cheap and easily available raw materials, mild conditions, environmental friendliness and the like.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a phthalazine dione compound, its preparation method, and its application. Background Technology

[0002] Phthalasmine compounds are widely found in natural products and drugs, exhibiting diverse biological activities. In particular, their oxidized derivatives, phthalazine diones, possess electron-deficient phthalazine cores (two amide groups), creating a structure conducive to interactions with biomolecules such as proteins, enzymes, and nucleic acids. Therefore, these compounds show great potential in medicinal chemistry. However, efficiently obtaining structurally rich phthalazine diones is crucial for supporting subsequent biological research and drug development. Therefore, developing efficient synthetic methods for phthalazine diones has significant scientific importance and broad application prospects. Currently, the rhodium-catalyzed CH activation synthesis of phthalazine dione derivatives generally requires exogenous oxidants such as copper and silver salts, resulting in poor functional group compatibility, numerous side reactions, and environmental pollution, failing to meet the requirements of green chemistry and limiting their application in biological function research and related drug development. Summary of the Invention

[0003] To address the aforementioned shortcomings of existing technologies, the present invention aims to provide a phthalazine dione compound, its preparation method, and its applications, thereby solving the problem of the lack of structural diversity in phthalazine dione compounds in traditional synthetic methods.

[0004] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: A phthalazine dione compound is provided, the general structural formula of which is shown in formula (I) or formula (II):

[0005] (I)

[0006] (II) In equation (Ⅰ), R 1 and R 2 All are hydrogen, alkyl, alkoxy, amino, fluoroalkyl, halogen, ester, acyl, cyano, nitro, or sulfonyl groups; R 3 It can be an ester group, an acyl group, or an amide group; In formula (II), R 1 R 2 and R 4 All are hydrogen, alkyl, alkoxy, amino, fluoroalkyl, halogen, ester, acyl, cyano, nitro, or sulfonyl groups; R 3 It can be an ester group, acyl group, or amide group.

[0007] Furthermore, when R in equations (I) and (II)1 and / or R 2 When R is any one of hydrogen, alkyl, alkoxy, halogen, ester, acyl, cyano, nitro, or sulfonyl, 1 and / or R 2 Each can be individually controlled by one or more independent Rs X Substituents are substituted; when R in formula (Ⅰ) is substituted. 3 When R is any of the following: carboxylic acid ester, ketone, or amide, 3 Each can be individually controlled by one or more independent Rs X Substituents of the substituents; R X It can be alkyl, alkoxy, cycloalkyl, aryl, amino, fluoroalkyl, halogen, ester, acyl, cyano, nitro or sulfonyl.

[0008] Furthermore, R X It can be methoxy, halogen, methyl, trifluoromethyl, methyl ester, phenyl ester, ethyl ester, halophenyl ester, or methoxy-substituted phenyl ester.

[0009] Furthermore, the structural formulas of phthalazine dione compounds are shown below: .

[0010] This invention provides a method for preparing the above-mentioned phthalazin dione compounds, comprising the following steps: using 2-aryl-2,3-dihydrophthalazin-1,4-dione or 3,4-diphenylisoquinoline-1 (2 H )-ketone or 6-phenyl-2(1 H )-pyridone, ( E The product is prepared by mixing 3-phenoxyacrylic acid derivatives with transition metal catalysts and alkaline substances in an organic solvent and stirring at 0-150°C for 1-36 hours.

[0011] Furthermore, the transition metal catalyst is a rhodium catalyst, a ruthenium catalyst, an iridium catalyst, a manganese catalyst, a palladium catalyst, or a cobalt catalyst.

[0012] Furthermore, the alkaline substance is a carbonate, bicarbonate, acetate, phosphate, hydrogen phosphate, or 1,8-diazabicyclo[5.4.0]undec-7-ene; the organic solvent is methanol, ethanol, tetrahydrofuran, acetonitrile, acetone, 1,2-dichloroethane, chloroform, N , N -Dimethylformamide, N , N -Dimethylacetamide, dimethyl sulfoxide, or 1,4-dioxane.

[0013] Furthermore, 2-aryl-2,3-dihydrophthalazine-1,4-dione or 3,4-diphenylisoquinoline-1(2H )-ketone or 6-phenyl-2(1 H )-pyridone, ( E The molar ratio of 3-phenoxypropene carboxylic acid derivative, transition metal catalyst and basic substance is 1:1-5:0.001-0.1:1-5.

[0014] This invention provides an application of the above-mentioned phthalazinide dione compounds in the preparation of antibacterial drugs.

[0015] The present invention also provides an antibacterial drug comprising the above-mentioned phthalazin dione compounds or their stereoisomers, tautomers, salts or prodrug molecules having the same function.

[0016] The present invention offers the following advantages: the phthalazine dione compounds prepared by this invention exhibit broad-spectrum antibacterial activity and extremely low toxicity to normal cells, demonstrating high efficiency and low toxicity. The functional groups in their structure can be further derivatized, thereby expanding the structural diversity of phthalazine dione compounds. Therefore, this invention provides an important strategy for the structural modification and diverse synthesis of phthalazine dione compounds. Furthermore, the preparation method of this invention is simple and easy to operate, avoiding the cumbersome process of pre-installing directing groups in other phthalazine dione compound synthesis methods, eliminating the need for additional external oxidants, significantly improving synthesis efficiency and reducing costs, and possessing advantages such as inexpensive and readily available raw materials, mild conditions, and environmental friendliness. Attached Figure Description

[0017] Figure 1 The proton / proton NMR spectrum of P1; Figure 2 The carbon spectrum / carbon-13 NMR spectrum of P1; Figure 3 The proton / proton NMR spectrum of P8; Figure 4 The carbon spectrum / carbon-13 NMR spectrum of P8; Figure 5 The proton / proton NMR spectrum of P12; Figure 6 The carbon spectrum / carbon-13 NMR spectrum of P12; Figure 7 The proton / proton NMR spectrum of P21; Figure 8 The carbon spectrum / carbon-13 NMR spectrum of P21; Figure 9 The proton / proton NMR spectrum of P22; Figure 10 The carbon spectrum / carbon-13 NMR spectrum of P22; Figure 11 A schematic diagram of the preparation process of the phthalazine dione compounds of the present invention. Detailed Implementation

[0018] The examples given below are for illustrative purposes only and are not intended to limit the scope of the invention. Unless otherwise specified, conditions in the examples are performed under standard conditions or as recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0019] A schematic diagram of the preparation process of the phthalazine dione compounds of the present invention is shown below. Figure 11 .

[0020] Example 1: (1) 2-(6,11-dioxo-6,11-dihydro-13) H Synthesis of methyl 2-indazolo[1,2-b]phthalazin-13-yl)acetate (P1): 2-phenyl-2,3-dihydrophthalazin-1,4-dione (60 mg, 0.25 mmol, 1 equiv.) and methyl ( E 3-phenoxyacrylate (53 mg, 0.3 mmol, 1.2 equiv.), [Cp*RhCl2]2 (8 mg, 12.5 μmol, 5 mol%), and sodium acetate (42 mg, 0.5 mmol, 2 equiv.) were added to a sealed tube, and acetone (4 mL) was added as solvent. The mixture was stirred at 80 °C for 12 hours. Subsequently, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10:1:1, v / v) to give phthalazine dione product P1 (77 mg, 95% yield).

[0021] The NMR data for P1 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.53-8.20 (m,3H), 7.99 – 7.64 (m, 2H), 7.60 – 7.37 (m, 2H), 7.36 – 7.07 (m, 1H), 6.17 (dd, J = 7.4, 3.6 Hz, 1H), 3.66 (s, 3H), 3.48 (dd, J = 16.4, 3.7 Hz, 1H), 3.14 (dd, J = 16.4, 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.13, 155.36, 154.86, 136.81, 133.70, 133.65, 130.05, 129.96, 128.75, 127.83, 127.45, 126.96, 126.44, 123.08, 115.95, 59.16, 52.11, 37.51. Proton / proton NMR spectrum of P1 ( 1 H NMR) and carbon / carbon-13 NMR spectrum ( 13 (C NMR) see Figure 1-2 .

[0022] (2) Effect of different types of catalysts on the yield of P1 synthesis: Referring to the synthesis method in step (1), when the photosensitizer [Cp*RhCl2]2 was replaced with [RuCl2(p-cymene)]2, [Cp*IrCl2]2, MnBr(CO)5 and CoCp2*PF6 respectively, the yields of P1 were 13%, 21%, 0% and 0% respectively.

[0023] (3) Effect of different types of alkaline substances on the yield of P1 synthesis: Referring to the synthesis method in step (1), when the alkaline substances are replaced with KOAc, CsOAc, Na2CO3 and K2CO3, the yields of P1 are 91%, 92%, 84% and 72%, respectively.

[0024] (4) Effect of different types of organic solvents on the yield of P1 synthesis: Referring to the synthesis method in step (1), when the solvent is replaced with DCE, 1,4-Dioxane, THF, MeCN, DMSO, MeOH, EtOH, H2O, the yields of P1 are 0%, 0%, 47%, 90%, 0%, 94%, 82% and 84%, respectively.

[0025] (5) Effect of different amounts of NaOAc on the yield of P1 synthesis: Referring to the synthesis method in step (1), the yields of P1 were 54%, 94% and 85% when the amount of sodium acetate was 1 equivalent, 3 equivalent and 4 equivalent, respectively.

[0026] Example 2: 2-(2-Fluoro-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P2): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-(4-fluorophenyl)-2,3-dihydrophthalazine-1,4-dione is reacted with ( EThe reaction of methyl 3-phenoxyacrylate yielded product P2 (78 mg, 92% yield).

[0027] The structural formula is:

[0028] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.63-8.22 (m, 3H),8.01-7.67 (m, 2H), 7.24-7.13 (m, 2H), 6.16 (dd, J = 7.9, 3.4 Hz, 1H), 3.69 (s,3H), 3.54 (dd, J = 16.7, 3.5 Hz, 1H), 3.11 (dd, J = 16.7, 7.9 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d ) δ 170.04, 160.84 (d, J = 246.7 Hz), 155.37, 154.62,133.79 (d, J = 1.7 Hz), 133.02 (d, J = 2.1 Hz), 129.91, 128.99, 128.90, 128.62,127.80, 127.49, 117.28 (d, J = 8.4 Hz), 116.81 (d, J = 23.4 Hz), 111.02 (d, J =26.1 Hz), 58.89 (d, J = 2.5 Hz), 52.26, 37.15.

[0029] Example 3: 2-(2-chloro-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P3): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-(4-chlorophenyl)-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P3 (78 mg, 88% yield).

[0030] The structural formula is:

[0031] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.51-8.21 (m, 3H),7.98-7.78 (m, 2H), 7.51-7.36 (m, 2H), 6.14 (dd, J = 7.7, 3.3 Hz, 1H), 3.69 (s,2H), 3.50 (dd, J = 16.9, 3.4 Hz, 1H), 3.14 (dd, J = 16.8, 7.7 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d ) δ 170.00, 155.27, 154.79, 135.39, 133.90, 133.80,131.76, 130.11, 129.78, 128.76, 128.66, 127.85, 127.51, 123.59, 116.86,58.77, 52.27, 37.12..

[0032] Example 4: 2-(2-bromo-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P4): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-(4-bromophenyl)-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P4 (80 mg, 90% yield).

[0033] The structural formula is:

[0034] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.44-8.39 (m, 1H),8.38-8.33 (m, 1H), 8.30 (d, J = 8.5 Hz, 1H), 7.91-7.76 (m, 2H), 7.63-7.52 (m,2H), 6.13 (dd,J = 7.6, 3.4 Hz, 1H), 3.68 (s, 3H), 3.46 (d, J = 3.4 Hz, 1H), 3.15 (dd, J = 16.8, 7.6 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d ) δ 169.98,155.25, 154.85, 135.90, 133.91, 133.80, 133.03, 129.80, 129.07, 128.71,127.87, 127.53, 126.45, 119.24, 117.19, 58.67, 52.27, 37.17.

[0035] Example 5: 2-(2-methyl-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P5): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-(4-methylphenyl)-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P5 (77 mg, 91% yield).

[0036] The structural formula is:

[0037] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.46-8.40 (m, 1H),8.39-8.33 (m, 1H), 8.29 (d, J = 8.2 Hz, 1H), 7.91-7.77 (m, 2H), 7.31-7.18 (m,2H), 6.12 (dd, J = 7.4, 3.6 Hz, 1H), 3.67 (s, 3H), 3.47 (dd, J = 16.5, 3.6 Hz, 1H), 3.13 (dd, J = 16.4, 7.4 Hz, 1H), 2.40 (s, 3H); 13 C NMR (101 MHz, Chloroform- d) δ 170.22, 155.37, 154.51, 136.63, 134.58, 133.62, 133.56,130.53, 130.11, 128.68, 127.74, 127.41, 127.09, 123.51, 115.67, 59.10, 52.14,37.46, 21.50.

[0038] Example 6: 2-(2-methoxy-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P6): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-(4-methoxyphenyl)-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P6 (80 mg, 91% yield).

[0039] The structural formula is:

[0040] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.43-8.37 (m, 1H),8.33 (dd, J = 8.9, 6.5 Hz, 2H), 7.91-7.74 (m, 2H), 7.04-6.76 (m, 2H), 6.11(dd, J = 7.7, 3.5 Hz, 1H), 3.83 (s, 3H), 3.66 (s, 3H), 3.49 (dd, J = 16.5, 3.6Hz, 1H), 3.09 (dd, J = 16.5, 7.6 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d ) δ170.17, 158.34, 155.35, 154.06, 133.58, 133.40, 130.35, 130.09, 128.57,128.50, 127.58, 127.34, 116.91, 114.77, 109.03, 59.07, 55.89, 52.13, 37.31.

[0041] Example 7: 2-(3-chloro-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P7): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-(3-chlorophenyl)-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P7 (76 mg, 85% yield).

[0042] The structural formula is:

[0043] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.45 (d, J = 2.0 Hz, 1H), 8.44-8.39(m, 1H), 8.38-8.30 (m, 1H), 7.97-7.79 (m, 2H), 7.38 (dd, J = 8.2, 1.0 Hz, 1H),7.28-7.18 (m, 1H), 6.19-6.05 (m, 1H), 3.66 (s, 3H), 3.48 (dd, J = 16.7, 3.5Hz, 1H), 3.13 (dd, J = 16.6, 7.5 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d ) δ170.04, 155.24, 154.95, 137.60, 135.82, 133.98, 133.79, 129.66, 128.68,127.92, 127.50, 126.48, 125.39, 124.02, 116.15, 58.85, 52.20, 37.20..

[0044] Example 8: 2-(3-bromo-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P8): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-(3-bromophenyl)-2,3-dihydrophthalazine-1,4-dione is reacted with (E The reaction of methyl 3-phenoxyacrylate yielded product P8 (75 mg, yield 84%).

[0045] The structural formula is:

[0046] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.62 (d, J = 1.8 Hz, 1H), 8.49-8.39(m, 1H), 8.39-8.33 (m, 1H), 7.98-7.74 (m, 2H), 7.41 (dd, J = 8.1, 1.8 Hz, 1H), 7.32 (dd, J = 8.1, 1.1 Hz, 1H), 6.10 (ddd, J = 7.6, 3.6, 1.0 Hz, 1H), 3.66 (s,3H), 3.48 (dd, J = 16.6, 3.5 Hz, 1H), 3.13 (dd, J = 16.6, 7.5 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d ) δ 170.02, 155.27, 154.98, 137.78, 134.00, 133.81, 129.70, 129.42, 128.73, 127.95, 127.54, 125.98, 124.37, 123.62, 118.95, 58.93, 52.20, 37.19. P8 1 H NMR and 13 The C NMR spectrum is shown in Figure 3-4 .

[0047] Example 9: 2-(3-methyl-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P9): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-(3-methylphenyl)-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P9 (75 mg, 89% yield).

[0048] The structural formula is:

[0049] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.50-8.40 (m, 1H), 8.39-8.32 (m,1H), 8.27 (s, 1H), 7.99-7.71 (m, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.14-7.03 (m,1H), 6.11 (dd, J = 7.4, 3.6 Hz, 1H), 3.65 (s, 3H), 3.46 (dd, J = 16.4, 3.6 Hz, 1H), 3.11 (dd, J = 16.4, 7.4 Hz, 1H), 2.44 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 170.50, 155.65, 155.10, 140.71, 137.24, 133.95, 133.91,130.37, 129.02, 128.10, 127.71, 127.54, 124.44, 122.99, 116.73, 59.32, 52.40,37.82, 22.18.

[0050] Example 10: 2-(3-trifluoromethyl-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P10): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-(3-trifluoromethylphenyl)-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P10 (84 mg, yield 86%).

[0051] The structural formula is:

[0052] The nuclear magnetic resonance data are as follows: 1H NMR (400 MHz, Chloroform- d ) δ 8.73 (s, 1H), 8.53-8.30 (m, 2H), 8.02-7.76 (m, 2H), 7.69-7.47 (m, 2H), 7.26 (d, J = 1.9 Hz, 1H), 6.36-6.02 (m,1H), 3.67 (s, 3H), 3.52 (dd, J = 17.0, 2.8 Hz, 1H), 3.18 (dd, J = 16.8, 7.5 Hz, 1H). 13 C NMR (101 MHz, Chloroform- d ) δ 169.93, 155.22 (d, J = 16.0 Hz), 137.23, 134.03 (d, J = 20.3 Hz), 132.74, 132.41, 132.08, 130.57, 129.66, 128.73,127.99, 127.60, 123.74, 123.65 (q, J = 272.8 Hz), 123.36 (d, J = 4.1 Hz), 113.06 (d, J = 3.9 Hz) 59.01, 52.27, 37.13.

[0053] Example 11: 2-(4-bromo-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P11): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-(4-bromophenyl)-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P11 (71 mg, 80% yield).

[0054] The structural formula is:

[0055] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d) δ 8.55-8.28 (m, 2H), 7.91-7.68 (m,2H), 7.57-7.40 (m, 1H), 7.34-7.15 (m, 1H), 6.17 (dd, J = 7.6, 3.7 Hz, 1H), 3.66 (s, 3H), 3.48 (dd, J = 16.5, 3.7 Hz, 1H), 3.14 (dd, J = 16.4, 7.4 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d ) δ 170.16, 155.37, 154.85, 136.77, 133.73,133.68, 130.00, 129.97, 128.69, 127.83, 127.45, 126.93, 126.47, 123.08,115.95, 59.16, 52.15, 37.46..

[0056] Example 12: 2-(4-methyl-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P12): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-(4-methylphenyl)-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P12 (72 mg, 85% yield).

[0057] The structural formula is:

[0058] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.49-8.21 (m, 2H),7.84 (dd, J = 5.9, 3.3 Hz, 2H), 7.39-7.10 (m, 3H), 6.02 (dd, J = 6.3, 3.7 Hz,1H), 3.55 (s, 3H), 3.32 (dd, J = 16.3, 6.2 Hz, 1H), 3.24 (dd, J= 16.3, 3.7 Hz,1H), 2.57 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 170.04, 156.48, 156.42, 135.91,133.52, 133.51, 133.11, 130.73, 129.17, 128.78, 127.94, 127.31, 127.26,126.96, 120.18, 59.12, 52.06, 37.06, 22.57. P12 1 H NMR and 13 The C NMR spectrum is shown in Figure 5-6 .

[0059] Example 13: 2-(8,9-dichloro-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P13): The synthesis process is the same as the synthesis method (1) in Example 1, where 6,7-dichloro-2-phenyl-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P13 (79 mg, 81% yield).

[0060] The structural formula is:

[0061] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.49 (s, 1H), 8.42(s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 7.55-7.39 (m, 2H), 7.31 (td, J = 7.6, 1.1Hz, 1H), 6.14 (dd, J = 7.2, 3.6 Hz, 1H), 3.65 (s, 3H), 3.42 (dd, J = 16.5, 3.6Hz, 1H), 3.18 (dd, J = 16.5, 7.2 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d) δ169.93, 153.68, 153.02, 139.13, 136.50, 130.11, 129.76, 129.44, 129.27,127.91, 126.86, 126.80, 123.10, 116.02, 59.42, 52.20, 37.19.

[0062] Example 14: 2-(8,9-dimethoxy-6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of methyl phthalazine-13-yl)acetate (P14): The synthesis process is the same as the synthesis method (1) in Example 1, where 6,7-dimethoxy-2-phenyl-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P14 (84 mg, yield 88%).

[0063] The structural formula is:

[0064] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.40 (d, J = 8.1 Hz,1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.55-7.38 (m, 2H), 7.32-7.26 (m, 1H), 6.16(dd, J = 7.4, 3.7 Hz, 1H), 4.07 (s, 3H), 4.06 (s, 3H), 3.66 (s, 3H), 3.48 (dd, J = 16.4, 3.7 Hz, 1H), 3.13 (dd, J = 16.4, 7.4 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d ) δ 170.20, 155.15, 154.67, 153.95, 153.85, 136.96, 129.94,126.97, 126.23, 124.35, 123.19, 123.07, 115.78, 108.12, 107.80, 59.12, 56.75(2C), 52.12, 37.55.

[0065] Example 15: 2-(6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of ethyl phthalazine-13-yl) (P15): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-phenyl-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The product P15 (78 mg, 93% yield) was obtained by reacting ethyl 3-phenoxyacrylate.

[0066] The structural formula is:

[0067] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.50-8.41 (m, 2H),8.41-8.31 (m, 1H), 7.92-7.80 (m, 2H), 7.59-7.42 (m, 2H), 7.35-7.27 (m, 1H),6.17 (dd, J = 7.2, 3.5 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.43 (dd, J = 16.3, 3.5 Hz, 1H), 3.22 (dd, J = 16.3, 7.2 Hz, 1H), 1.12 (t, J = 7.1 Hz, 3H). 13 C NMR(100 MHz, CDCl3) δ 169.61, 155.32, 154.86, 136.87, 133.72, 133.65, 130.04,129.95, 128.78, 127.82, 127.45, 126.93, 126.43, 123.12, 115.94, 61.09, 59.21,37.53, 14.14.

[0068] Example 16: 2-(6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of phthalazine-13-yl)phenyl acetate (P16): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-phenyl-2,3-dihydrophthalazine-1,4-dione is reacted with ( EThe product P16 (86 mg, 90% yield) was obtained by reacting phenyl 3-phenoxyacrylate.

[0069] The structural formula is:

[0070] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.49-8.34 (m, 3H),7.87 (dd, J = 6.0, 3.3 Hz, 2H), 7.64-7.44 (m, 2H), 7.33 (td, J = 7.9, 2.4 Hz, 3H), 7.20 (t, J = 7.4 Hz, 1H), 6.95 (dd, J = 7.7, 1.6 Hz, 2H), 6.27 (dd, J =6.8, 3.9 Hz, 1H), 3.66 (dd, J = 16.4, 3.9 Hz, 1H), 3.49 (dd, J = 16.4, 6.7 Hz, 1H). 13 C NMR (101 MHz, Chloroform- d ) δ 168.32, 155.43, 154.83, 150.31, 136.90,133.75, 133.72, 130.15, 130.02, 129.61, 128.65, 127.85, 127.45, 126.52(2C),126.22, 123.19, 121.48, 116.04, 59.14, 37.76.

[0071] Example 17: 2-(6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of phthalazine-13-yl)acetic acid-4-chlorophenyl ester (P17): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-phenyl-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The product P17 (91 mg, 87% yield) was obtained by reacting 3-phenoxyacrylate-4-chlorophenyl ester.

[0072] The structural formula is:

[0073] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.49 – 8.42 (m, 2H), 8.42 – 8.36 (m, 1H), 7.93 – 7.84 (m, 2H), 7.55 – 7.48 (m, 2H), 7.37 – 7.28(m, 3H), 6.95 – 6.89 (m, 2H), 6.30 – 6.24 (m, 1H), 3.61 (dd, J = 16.4, 4.2 Hz, 1H), 3.50 (dd, J = 16.4, 6.3 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d ) δ 168.13,155.51, 154.86, 148.79, 136.91, 133.82, 133.80, 131.66, 130.25, 130.03,129.68, 128.62, 127.90, 127.49, 126.55, 126.39, 123.12, 122.90, 116.09,59.13, 37.99.

[0074] Example 18: 2-(6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of phthalazine-13-yl)acetic acid-4-bromophenyl ester (P18): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-phenyl-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The product P18 (107 mg, 92% yield) was obtained by reacting 3-phenoxyacrylate-4-bromophenyl ester.

[0075] The structural formula is:

[0076] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d) δ 8.50 – 8.42 (m, 2H), 8.42 – 8.36 (m, 1H), 7.93 – 7.83 (m, 2H), 7.56 – 7.48 (m, 2H), 7.48 – 7.41(m, 2H), 7.33 (td, J = 7.6, 1.0 Hz, 1H), 6.92 – 6.80 (m, 2H), 6.32 – 6.22 (m,1H), 3.61 (dd, J = 16.4, 4.2 Hz, 1H), 3.49 (dd, J = 16.4, 6.3 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d ) δ 168.04, 155.51, 154.85, 149.35, 136.91, 133.81,133.80, 132.67, 130.25, 130.03, 128.62, 127.90, 127.49, 126.55, 126.38,123.33, 123.12, 119.38, 116.09, 59.12, 38.01.

[0077] Example 19: 2-(6,11-dioxo-6,11-dihydro-13) H -Indazolo[1,2- b Synthesis of phthalazine-13-yl)acetic acid-4-methoxyphenyl ester (P19): The synthesis process is the same as the synthesis method (1) in Example 1, where 2-phenyl-2,3-dihydrophthalazine-1,4-dione is reacted with ( E The product P19 (99 mg, 96% yield) was obtained by reacting 3-phenoxyacrylate-4-methoxyphenyl ester.

[0078] The structural formula is:

[0079] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 8.38 – 8.24 (m, 3H), 8.04 –7.95 (m, 2H), 7.68 (d, J = 7.8 Hz, 1H), 7.54 (td, J = 8.2, 1.2 Hz, 1H), 7.40(td, J= 7.6, 1.1 Hz, 1H), 7.17 (ddd, J = 8.2, 6.9, 2.2 Hz, 1H), 7.02 (dd, J =8.3, 1.3 Hz, 1H), 6.90 – 6.81 (m, 2H), 6.18 (t, J = 4.8 Hz, 1H), 3.66 (dd, J =4.9, 3.2 Hz, 2H), 3.54 (s, 3H); 13 C NMR (101 MHz, DMSO- d 6) δ 168.57, 156.90,154.49, 154.01, 143.39, 136.51, 133.94, 133.76, 129.51, 129.39, 128.45,127.14, 126.97, 126.78, 126.10, 123.47, 122.21, 114.72, 114.40, 59.05, 55.38,36.87. Example 20: 2-(6,9-dioxo-6,9-dihydro-11) H -pyridazine[1,2- a Synthesis of indazole-11-yl)methyl acetate (P20): The synthesis process is the same as the synthesis method (1) in Example 1, where 1-phenyl-1,2-dihydropyridazine-3,6-dione is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P20 (56 mg, yield 82%).

[0080] The structural formula is:

[0081] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.32 (d, J = 8.1 Hz,1H), 7.54-7.38 (m, 2H), 7.37-7.27 (m, 1H), 7.03 (d, J = 10.3 Hz, 1H), 6.94 (d, J = 10.2 Hz, 1H), 6.01 (dd, J = 7.4, 3.6 Hz, 1H), 3.65 (s, 3H), 3.43 (dd,J =16.5, 3.6 Hz, 1H), 3.11 (dd, J = 16.5, 7.4 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ169.89, 154.44, 153.89, 136.36, 136.15, 134.18, 130.03, 126.94, 126.64,123.06, 115.68, 59.53, 52.19, 36.46.

[0082] Example 21: 2-(5-oxo-12-phenyl-5,7-dihydroisoindolo[2,1- b Synthesis of isoquinoline-7-yl)methyl acetate (P21): The synthesis process is the same as the synthesis method (1) in Example 1, where 3,4-diphenylisoquinoline-1(2H)-one is reacted with ( E The reaction of methyl 3-phenoxyacrylate yielded product P21 (67 mg, 70% yield).

[0083] The structural formula is:

[0084] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.67-8.38 (m, 1H),7.66-7.54 (m, 4H), 7.54-7.49 (m, 2H), 7.48-7.42 (m, 1H), 7.39-7.30 (m, 2H),7.23-7.17 (m, 1H), 7.15-7.00 (m, 1H), 6.39 (d, J = 8.0 Hz, 1H), 6.02 (dd, J =7.8, 3.7 Hz, 1H), 3.78 (dd, J = 16.3, 3.7 Hz, 1H), 3.69 (s, 3H), 2.98 (dd, J =16.2, 7.8 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d) δ 171.10, 161.06, 141.83,138.88, 138.05, 135.32, 133.67, 132.31, 131.32, 131.10, 129.64, 128.62,128.60, 127.50, 126.54, 125.39, 124.96, 124.14, 123.01, 114.71, 77.48, 77.16,76.84, 60.11, 51.99, 36.75. P21 1 H NMR and 13 The C NMR spectrum is shown in Figure 7-8 .

[0085] Example 22: 2-(4-oxo-4,6-dihydropyrido[2,1-) a Synthesis of isoindole-6-yl)methyl acetate (P22): The synthesis process is the same as the synthesis method (1) in Example 1, using 6-phenyl-2(1 H )-Pyridone and ( E The reaction of methyl 3-phenoxyacrylate yielded product P22 (48 mg, 75% yield).

[0086] The structural formula is:

[0087] The nuclear magnetic resonance data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.76-7.66 (m, 1H),7.60-7.54 (m, 1H), 7.54-7.40 (m, 3H), 6.69 (dd, J = 6.9, 1.0 Hz, 1H), 6.51(dd, J = 9.1, 1.1 Hz, 1H), 5.85 (dd, J = 7.9, 3.7 Hz, 1H), 3.77 (dd, J = 16.5,3.8 Hz, 1H), 3.65 (s, 3H), 2.93 (dd, J = 16.5, 8.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 170.78, 162.17, 147.84, 141.59, 140.35, 132.97, 130.74, 129.10,123.42, 121.35, 118.61, 98.68, 61.28, 51.99, 35.17. P22 1 H NMR and 13 The C NMR spectrum is shown in Figure 9-10 .

[0088] Experimental example: Antibacterial activity of phthalazinide compounds Using the broth microdilution method recommended by the Clinical Laboratory Standards Institute (CLSI, formerly the National Committee for Clinical Laboratory Standards, NCCLS), the prepared phthalazine dione compounds were tested for their effectiveness against methicillin-resistant Gram-positive bacterial strains (methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300)) and Escherichia coli. E. coli The inhibitory activity of ATCC25922 was measured, and the data are expressed as the minimum inhibitory concentration (MIC, in μg / mL) required to inhibit pathogen growth. The readings were taken at 600 nm using a microplate reader, and the results are shown in Table 1.

[0089] Table 1 shows that the phthalazinide core is an essential skeleton for the antibacterial activity of this class of compounds. Replacing it with an isoquinolinone or pyridinone core significantly reduces antibacterial activity, while the pyridazininazole skeleton retains some antibacterial activity. The electronegativity and position of the aromatic ring substituents significantly affect the inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA): the introduction of electron-withdrawing substituents (Cl, Br, F, CF3) at the 3-position of the benzene ring can greatly enhance antibacterial activity, among which the 3-chloro-substituted compound (P7) has the best activity (MIC=1 μg / mL), which is better than the positive control linezolid (MIC=2 μg / mL); 2-F and 3-CF3 substitutions also show good activity (MIC=2 μg / mL), while electron-withdrawing substitutions at the 2 / 4 positions have the next best activity; electron-donating substituents such as methyl and methoxy decrease the activity. The substitution positions generally show an activity order of 3 > 2 > 4. Introducing electron-withdrawing disubstituents (8,9-dichloro) onto the parent benzene ring maintains good activity, while electron-donating disubstituents (8,9-dimethoxy) lead to decreased activity. Among the ester side chains, methyl esters are the optimal group, while ethyl esters and various aromatic esters show reduced activity. Furthermore, these compounds exhibit significantly better inhibitory effects against Gram-positive bacteria MRSA than against Gram-negative bacteria Escherichia coli (E. coli). E. coli Overall, the phthalazine dione compounds synthesized in this invention exhibited good antibacterial activity against the two bacteria mentioned above, with a MIC of 1-32 μg / mL against MRSA. E. coliIt exhibits moderate inhibitory activity and has potential development value in the application of antibiotics against drug-resistant bacteria in animals and humans, providing important evidence for subsequent synthesis and structure-activity relationship studies.

[0090] Table 1. Antibacterial activity of some phthalazinide dione compounds

[0091] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A phthalazinide dione compound, characterized in that, The general structural formulas of the phthalazine dione compounds are shown in formula (I) or formula (II): （Ⅰ） （Ⅱ） In equation (Ⅰ), R 1 and R 2 All are hydrogen, alkyl, alkoxy, amino, fluoroalkyl, halogen, ester, acyl, cyano, nitro, or sulfonyl groups; R 3 It can be an ester group, an acyl group, or an amide group; In formula (II), R 1 R 2 and R 4 All are hydrogen, alkyl, alkoxy, amino, fluoroalkyl, halogen, ester, acyl, cyano, nitro, or sulfonyl groups; R 3 It can be an ester group, acyl group, or amide group.

2. The phthalazinide dione compound according to claim 1, characterized in that, When R in equations (I) and (II) 1 and / or R 2 When R is any one of hydrogen, alkyl, alkoxy, halogen, ester, acyl, cyano, nitro, or sulfonyl, 1 and / or R 2 Each can be individually controlled by one or more independent Rs X Substituents are substituted; when R in formula (Ⅰ) is substituted. 3 When R is any of the following: carboxylic acid ester, ketone, or amide, 3 Each can be individually controlled by one or more independent Rs X Substituents of the substituents; The R X It can be alkyl, alkoxy, cycloalkyl, aryl, amino, fluoroalkyl, halogen, ester, acyl, cyano, nitro or sulfonyl.

3. The phthalazinide dione compound according to claim 2, characterized in that, The R X It can be methoxy, halogen, methyl, trifluoromethyl, methyl ester, phenyl ester, ethyl ester, halophenyl ester, or methoxy-substituted phenyl ester.

4. The phthalazinide dione compound according to claim 3, characterized in that, The structural formula of the phthalazine dione compound is shown below: 。 5. The method for preparing the phthalazine dione compound according to any one of claims 1-4, characterized in that, Includes the following steps: using 2-aryl-2,3-dihydrophthalazine-1,4-dione or 3,4-diphenylisoquinoline-1 (2 H )-ketone or 6-phenyl-2(1 H )-pyridone, ( E The product is prepared by mixing 3-phenoxyacrylic acid derivatives with transition metal catalysts and alkaline substances in an organic solvent and stirring at 0-150°C for 1-36 hours.

6. The preparation method according to claim 5, characterized in that, The transition metal catalyst is a rhodium catalyst, ruthenium catalyst, iridium catalyst, manganese catalyst, palladium catalyst, or cobalt catalyst.

7. The preparation method according to claim 5, characterized in that, The alkaline substance is a carbonate, bicarbonate, acetate, phosphate, hydrogen phosphate, or 1,8-diazabicyclo[5.4.0]undec-7-ene; the organic solvent is methanol, ethanol, tetrahydrofuran, acetonitrile, acetone, 1,2-dichloroethane, chloroform, etc. N , N -Dimethylformamide, N , N -Dimethylacetamide, dimethyl sulfoxide, or 1,4-dioxane.

8. The preparation method according to claim 5, characterized in that, The 2-aryl-2,3-dihydrophthalazine-1,4-dione or 3,4-diphenylisoquinoline-1(2 H )-ketone or 6-phenyl-2(1 H )-pyridone, ( E The molar ratio of 3-phenoxypropene carboxylic acid derivative, transition metal catalyst and basic substance is 1:1-5:0.001-0.1:1-5.

9. The use of the phthalazine dione compounds according to any one of claims 1-4 in the preparation of antibacterial drugs.

10. An antibacterial drug, characterized in that, This includes phthalazine dione compounds as described in any one of claims 1-4, or stereoisomers, tautomers, or salts or prodrug molecules having the same function.

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