Indazole hydrazide compound as well as preparation method and application thereof

Abstract

The invention discloses an indazole hydrazide compound as well as a preparation method and application thereof. The preparation method of the indazole hydrazide compound disclosed by the invention is simple to operate, no precious metal participates in the reaction, and the reaction is efficient. The indazole hydrazide compound disclosed by the invention has good fungicidal activity, and the indazole hydrazide compound shows efficient or broad-spectrum bacteriostatic activity and can be effectively applied to prevention and treatment of pathogenic fungi of crops.

Description

Technical Field

[0001] This invention belongs to the field of compound technology, specifically relating to an indazole hydrazine compound, its preparation method, and its application. Background Technology

[0002] Plant diseases caused by various pathogenic microorganisms such as fungi and oomycetes are important factors affecting crop yield and quality. Currently, the fungicides widely used in agricultural production mainly include triazoles, methoxyacrylates, benzimidazoles, and pyrazolamides. Long-term and repeated use of these fungicides with single mechanisms of action has led to varying degrees of resistance in many pathogens, resulting in a gradual decline in their control efficacy. At the same time, some traditional fungicides have problems such as narrow spectrum of action, limited duration of action, or potential risks to non-target organisms, making it difficult to meet the needs of sustainable development in modern agriculture. Therefore, developing fungicidal active molecules with novel structural features and potential new modes of action has become an important research direction in this field.

[0003] Indazole compounds, as an important class of nitrogen-containing heterocyclic structures, possess excellent structural modifiability and exhibit diverse biological activities in the pharmaceutical and pesticide fields. Current research mainly focuses on the pharmaceutical applications of indazole compounds, while studies on agricultural fungicides, particularly on systematically enhancing their fungicidal performance through the introduction of specific functional groups, are relatively limited.

[0004] Due to their unique molecular conformation and multiple hydrogen bonding capabilities, acylhydrazine groups have potential advantages in interacting with biological targets. However, there are limited reports on existing technologies that combine acylhydrazine structures with indazole skeletons for the control of plant pathogens, and their fungicidal activity and application potential are not systematically revealed.

[0005] Therefore, it is necessary to develop a class of indazole hydrazine compounds with novel structures, excellent fungicidal activity, and low potential resistance risk to enrich the existing fungicide product system and provide new technical options for plant disease control. Summary of the Invention

[0006] Objective of the Invention: The objective of this invention is to provide a class of novel compounds with excellent antibacterial and bacteriostatic activities, addressing the problems of limited structural types, easy development of resistance, and limited potential for activity enhancement in existing bactericides. To achieve the above objective, this invention employs a molecular design strategy combining active unit substructure splicing and skeleton migration, introducing phenylhydrazine fragments into the indazole skeleton to construct a series of novel indazole-1-acetylhydrazine compounds and novel indazoleformylhydrazine compounds.

[0007] Another technical problem to be solved by the present invention is to provide a series of novel indazole-1-acetylhydrazine compounds and methods for preparing novel indazole-formylhydrazine compounds.

[0008] The technical problem that this invention also aims to solve is to provide the application of novel indazole-1-acetylhydrazine compounds and novel indazole-formylhydrazine compounds in the preparation of products that inhibit or kill pathogens.

[0009] Technical solution: To solve the above-mentioned technical problems, the first aspect of the present invention provides an indazole-1-acetylhydrazine compound, the structure of which is shown in Formula I:

[0010]

[0011] in, Selected from , , or R1 is selected from 1-CH3, 3-Br, 5-Br, 5-Cl, 5-CH3, 6-Cl, 6-Br, or 6-NO2; R is selected from H, 4-F, 3-F, 2-F, 4-Cl, 3-Cl, 2-Cl, 4-Br, 3-Br, 2-Br, 4-Me, 4-CF3, 2-CF3, 4-CF3O, 3-CF3O, 4-CH3O, 2-CH3O, 4-CN, 4-BnO, 2,4-di-F, 2,5-di-F, 3,4-di-F, 3,5- R1 is selected from one or more of di-Cl, 2,4,6-tri-Cl, 1,2,3,4,5-F, and 3-Cl-4-F; preferably, R1 is selected from 1-CH3, 3-Br, 5-Br, 5-Cl, and 6-Br; preferably, R is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 4-Br, 4-CF3, 2,4-di-F, 2,5-di-F, 3,4-di-F, or 2,4,6-tri-Cl.

[0012] The structure of the compound is shown in Formula II:

[0013] ,

[0014] Wherein, R1 is selected from 3-Br, 5-Br, 5-Cl, 6-Br, or 6-NO2; R is selected from one or more of H, 4-F, 3-F, 2-F, 4-Cl, 3-Cl, 4-Br, 4-Me, 4-CF3, 2-CF3, 4-CF3O, 3-CF3O, 4-CH3O, 2-CH3O, 2,4-di-F, 2,5-di-F, 3,5-di-Cl, and 3-Cl-4-F. Preferably, R is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 4-Br, 4-CF3, 2,4-di-F, and 2,5-di-F.

[0015] The structure of the compound is shown in Formula III:

[0016] ,

[0017] Wherein, R1 is selected from 1-CH3, 5-Br, 6-CH3, 6-Cl; R is selected from H, 4-F, 3-F, 2-F, 4-Cl, 3-Cl, 2-Cl, 4-Br, 3-Br, 2-Br, 4-Me, 4-CF3, 2-CF3, 4-CF3O, 3-CF3O, 4-CH3O, 2-CH3O, 4-CN, 4-BnO, 2,4-di-F, 2,5-di-F, 3,4-di-F, 3,5- One or more of di-Cl, 2,4,6-tri-Cl, 1,2,3,4,5-F, and 3-Cl-4-F; preferably, R1 is selected from H, 1-CH3, 5-Br, and 6-Cl; preferably, R is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 4-Br, 4-CF3, 2,4-di-F, 2,5-di-F, or 3,4-di-F.

[0018] The structure of the compound is shown in Formula IV:

[0019] ,

[0020] R is selected from one or more of H, 4-F, 4-Cl, 4-Br, 4-CF3, 3-F, 4-CF3O, 4-CN, 3-Cl, 3-Br, 3-CF3O, 2-F, and 2-Cl; preferably, R is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 4-Br, or 4-CF3.

[0021] The structure of the compound is shown in Formula V:

[0022] ,

[0023] R is selected from one or more of 4-F, 4-Cl, 4-Br, 4-CF3, 3-F, 4-CF3O, 3-Cl, 3-Br, 2-F, and 2-Cl; preferably, R is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, or 4-Br.

[0024] A second aspect of this invention provides a method for preparing indazole acetylhydrazine compounds, comprising the following steps:

[0025]

[0026] (1) A substituted indazole was prepared by sequentially adding acetic anhydride, potassium acetate, isoamyl nitrite, sodium hydroxide solution, and tetrapropylammonium hydroxide to o-methylaniline as a raw material. Preferably, the molar ratio of o-methylaniline to isoamyl nitrite is 1:2.

[0027] (2) The intermediate N-ethyl acetate indazole derivative is prepared by reacting the substituted indazole with ethyl bromoacetate. Preferably, the molar ratio of the substituted indazole, potassium carbonate and ethyl bromoacetate is 1:1:1.5.

[0028] (3) Add potassium hydroxide solution to N-ethyl acetate indazole derivative, dissolve and stir, then heat and stir to prepare intermediate 1-N-ethyl acetate indazole derivative.

[0029] (4) The 1-N-acetic acid indazole derivative and the substituted phenylhydrazine were dissolved in acetonitrile solution, and then O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (TBTU) was added. Triethylamine was then added dropwise, and the reaction was stirred at room temperature and monitored by TLC to prepare a series of target compounds, indazole-1-acetylhydrazine. Preferably, the molar ratio of 1-N-acetic acid indazole derivative to substituted phenylhydrazine, TBTU and triethylamine was 1:1.2:1.2:1.2.

[0030] A third aspect of this invention provides a method for preparing indazole-3-formylhydrazide compounds, comprising the following steps:

[0031]

[0032] (1) Using substituted methyl anthranilate as a raw material, glacial acetic acid and tert-butyl nitrite were added to acetonitrile solvent and stirred at room temperature to prepare methyl 1H-indazole-3-carboxylate derivative. Preferably, the molar ratio of substituted methyl anthranilate, glacial acetic acid and tert-butyl nitrite is 1:2:1.5.

[0033] (2) The methyl ester derivative of 1H-indazole-3-carboxylic acid was placed in an aqueous sodium hydroxide solution and stirred at room temperature to completely hydrolyze it. Then, the pH of the system was adjusted to weak acidity with dilute hydrochloric acid to precipitate the product. After filtration, washing and drying, the 1H-indazole-3-carboxylic acid derivative was obtained.

[0034] (3) Dissolve the 1H-indazole-3-carboxylic acid derivative and the substituted phenylhydrazine hydrochloride in acetonitrile, add TBTU, and then add triethylamine as a base, and stir the reaction at room temperature. Preferably, the molar ratio of 1H-indazole-3-carboxylic acid derivative, substituted phenylhydrazine hydrochloride, TBTU and triethylamine is 1:1.2:1.2:1.2.

[0035] A fourth aspect of this invention provides a method for preparing indazole 5-formylhydrazine compounds, comprising the following steps:

[0036]

[0037] (1) Using methyl 4-amino-3-methylbenzoate as raw material, add tetrafluoroboric acid aqueous solution, then add sodium nitrite aqueous solution, stir and react at room temperature for 15 minutes to obtain methyl 4-diazotetrafluoroborate-3-methylbenzoate.

[0038] (2) Methyl 4-diazotetrafluoroborate-3-methylbenzoate was added to chloroform solvent along with potassium acetate and 18-crown-6. After the reaction was completed, the reaction solution was extracted in a mixed solvent of water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and the solvent was concentrated by rotary evaporation to obtain methyl 5-indazolecarboxylate.

[0039] (3) Mix methyl 5-indazole carboxylate with sodium hydroxide solution, heat the reaction solution to 40°C and stir for 1 hour. After the reaction is completed, remove the methanol solvent by vacuum distillation, extract the aqueous phase three times with ethyl acetate, and then adjust the pH to 7 with 1 M hydrochloric acid solution to precipitate a yellow solid. 5-indazole carboxylic acid is obtained by filtration and drying.

[0040] (4) 5-Indazole carboxylic acid, substituted phenylhydrazine hydrochloride, TBTU, and triethylamine were dissolved in acetonitrile and reacted at room temperature for 10 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the indazole-5-carboxyhydrazine derivative was obtained by column chromatography. Preferably, the molar ratio of 5-indazole carboxylic acid, substituted phenylhydrazine hydrochloride, TBTU, and triethylamine was 1:1.2:1.2:1.2.

[0041] The fifth aspect of this invention provides a method for preparing indazole-6-formylhydrazide compounds, comprising the following steps:

[0042]

[0043] (1) Using methyl 4-amino-3-methylbenzoate as raw material, add tetrafluoroboric acid aqueous solution, then add sodium nitrite aqueous solution, stir and react at room temperature for 15 minutes to obtain 3-diazotetrafluoroborate-4-methylbenzonitrile.

[0044] (2) 3-diazotetrafluoroborate-4-methylbenzonitrile, potassium acetate, and 18-crown-6 were added to chloroform solvent and stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was extracted in a mixed solvent of water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and the solvent was concentrated by rotary evaporation to obtain 6-cyanoinazole.

[0045] (3) Mix 6-cyanoindazole with sodium hydroxide solution, heat the reaction solution to 70°C and stir for 1 hour. After the reaction is completed, remove the ethanol solvent by vacuum distillation, and then adjust the pH to 7 with 1 M hydrochloric acid solution to precipitate a yellow solid. 6-indazole carboxylic acid is obtained by filtration and drying.

[0046] (4) 6-Indazole carboxylic acid, substituted phenylhydrazine hydrochloride, TBTU, and triethylamine were dissolved in acetonitrile and reacted at room temperature for 10 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and then the indazole-6-carboxyhydrazide derivative was obtained by column chromatography. Preferably, the molar ratio of 5-indazole carboxylic acid, substituted phenylhydrazine hydrochloride, TBTU, and triethylamine was 1:1.2:1.2:1.2.

[0047] The preparation method of the novel indazole hydrazine compound described in this invention also includes the purification of the target compound. There are no special requirements for the purification method. Those skilled in the art can use various conventional purification methods, such as extraction with an extractant, drying with a drying agent, and removing impurities by column chromatography to obtain the target compound in high purity.

[0048] The sixth aspect of this invention provides the application of the novel indazole hydrazine compounds in the preparation of products that inhibit or kill pathogens.

[0049] The pathogens include, but are not limited to, crop pathogenic fungi, which include, but are not limited to, one or more of the following: *Botrytis cinerea* (strawberry gray mold), *Alternaria solani* (tomato early blight), *Rhizoctonia solani* (rice sheath blight), *Fusarium graminearum* (wheat scab), *Colletotrichum orbiculare* (cucumber anthracnose), *Valsa mali* (apple rot), *Fusarium oxysporum f. sp. lycopersici* (tomato wilt), and *Magnaporthe oryzae* (rice blast).

[0050] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0051] 1. This invention relates to a novel indazole-1-acetylhydrazine compound prepared by a five-step simple reaction using o-methylaniline, acetic anhydride, potassium acetate, isoamyl nitrite, ethyl bromoacetate, and tetrapropylammonium hydroxide as raw materials. The preparation method of this novel indazole-1-acetylhydrazine compound is simple to operate, operates under mild reaction conditions, involves no precious metals, is highly efficient, and produces a high-purity product. This method also has strong scalability.

[0052] 2. This invention utilizes various substituted methyl o-aminophenylacetate, methyl 4-amino-3-methylbenzoate, ethyl bromoacetate, TBTU, and tetrafluoroboric acid aqueous solution as raw materials to prepare novel indazole carbamoyl hydrazides with different substitution positions through a four-step reaction process. The preparation method of the novel indazole carbamoyl hydrazides of this invention is simple to operate, involves no precious metals, has high reaction efficiency, and produces high-purity products.

[0053] 3. The novel indazole hydrazine compounds described in this invention show excellent application prospects in the agricultural field, especially in the control of pathogenic fungi in crops. These compounds have significant inhibitory effects on a variety of fungal diseases, exhibit a broad fungicidal spectrum, and can effectively control many important agricultural pathogenic fungi such as rice blast fungus, tomato early blight fungus, and wheat scab fungus, demonstrating potential development value as novel agricultural fungicides.

[0054] In summary, the acylhydrazine compounds designed and prepared using indazole as the lead structure in this invention exhibit excellent, broad-spectrum, and highly efficient activity against plant pathogenic fungi, and can be effectively used to control various plant diseases caused by plant pathogenic microorganisms. Furthermore, the research results of this invention show that the acylhydrazine compounds with indazole as the lead structure have significant inhibitory effects on various plant pathogenic fungi, providing important scientific basis and potential application value for the research and development of novel agricultural fungicides. Attached Figure Description

[0055] Figure 1 The study aimed to investigate the in vivo inhibitory effects of target compounds 57, 70, and 79 on Fusarium graminearum, the causal agent of wheat blight. Detailed Implementation

[0056] Example 1: Preparation of novel indazole-1-acetylhydrazine compounds

[0057] The synthetic route for indazole-1-acetylhydrazine compounds is as follows:

[0058]

[0059] Wherein, R1 is selected from H, 3-Br, 5-Br, 5-Cl, 6-Br, 6-NO2; R is selected from H, 4-F, 3-F, 2-F, 4-Cl, 3-Cl, 4-Br, 4-Me, 4-CF3, 4-CF3O, 4-CH3O, 2-CH3O, 2,4-F, 2,5-F, 3-Cl-4-F, 3,5-Cl.

[0060] The specific steps are as follows:

[0061] 1. Preparation of substituted indazole: Weigh 10 mmol of substituted o-methylaniline (A) and place it in a 50 mL round-bottom flask. Dissolve it in 5 mL of acetic anhydride and stir in an ice bath for 0.5–1 h. Add 1.4 g of potassium acetate and stir until completely dissolved. Continue stirring for 1 h until the mixture becomes very viscous. Using a constant-pressure dropping funnel, slowly add 2.4 mL of isoamyl nitrite (20 mmol) at 0–5 °C. After the addition is complete, heat the reaction mixture to 80 °C and stir for 8–10 h. Monitor the reaction progress by thin-layer chromatography (TLC). After the reaction is complete, cool to room temperature and add 4.15 mol / L sodium hydroxide (24 mL) and 1 mol / L tetrapropylammonium hydroxide methanol solution (1 mL). React the mixture with stirring for 4 h, and monitor the reaction progress by TLC. Cool the reaction mixture to room temperature, separate the layers, and wash the organic layer with 3 × 50 mL of water. The organic layer was concentrated to obtain a solid residue, which was dissolved in 20 mL of dichloromethane (DCM), and 20 mL of heptane was added. The mixture was concentrated to approximately 20 mL, then cooled to room temperature, and the solid was filtered. The filtered solid was washed with 20 mL of heptane and dried to give the product, the indazole derivative (C).

[0062] 2. Preparation of N-ethyl acetate indazole derivative (D): 10 mmol of indazole derivative (C), 15 mL of DMF, 1.4 g of potassium carbonate, and 15 mmol of ethyl bromoacetate were sequentially added to a 50 mL round-bottom flask. The reaction was heated to 60 °C and stirred vigorously. The reaction progress was monitored by TLC until the reaction was complete. After the reaction was complete, the reaction solution was poured into 50 mL of water and extracted with 3 × 15 mL of ethyl acetate, and the organic phase was combined. Finally, the target product, N-ethyl acetate indazole derivative (D), was obtained by column chromatography.

[0063] 3. Preparation of 1-N-acetic acid indazole derivative (E): Weigh 10 mmol of 1-N-acetic acid indazole derivative (D) into a 50 mL round-bottom flask, add 20 mL of 1 M NaOH solution, and react at room temperature until complete hydrolysis. Adjust the pH to 5 using 1 M dilute hydrochloric acid. At this point, the 1-N-acetic acid indazole derivative precipitates from the aqueous phase, and the solid is filtered. The filtered solid is washed with 20 mL of ice water and dried to obtain the target product, 1-N-acetic acid indazole derivative (E).

[0064] 4. Preparation of indazole-1-acetylhydrazine compounds: Weigh 1 mmol of 1-N-acetic acid indazole derivative (E) into a 50 mL round-bottom flask, add 1.2 mmol of substituted phenylhydrazine hydrochloride, 1.2 mmol of O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (TBTU), add 15 mL of acetonitrile as solvent, and then add 0.5 mL of triethylamine as base. React at room temperature for 10 h. Monitor the reaction progress by TLC. After the reaction is complete, evaporate the reaction solution to dryness and then perform column chromatography to obtain the product. The substituent groups of each compound are shown in Table 1. The indazole-1-acetylhydrazine compounds represented by Formula II are shown in Table 1.

[0065] Table 1 Indazole-1-acetylhydrazine compounds

[0066] The structural characterization data of the target compounds indazole-1-acetylhydrazine 1~51 are as follows:

[0067] Compound 1: 2-(1H-indazol-1-yl)-N′-phenylacetylhydrazine

[0068] White solid, melting point 192-193℃, yield 72%. 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (d, J= 2.2 Hz, 1H), 8.14 (s, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 8.1 Hz,1H), 7.70 (d, J = 8.5 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.7 Hz, 3H), 6.81 (d, J = 7.9 Hz, 2H), 6.74 (t, J = 7.3 Hz, 1H), 5.28 (s, 2H). 13 C NMR(100 MHz, DMSO-d6) δ 167.23, 149.11, 140.49, 133.71, 128.99, 126.44, 123.86,121.06, 120.80, 119.05, 112.50, 110.11, 50.10. HRMS (ESI) m / z: [M + H] + calcdfor C 15 H 15 N4O 267.1240, found 267.1248.

[0069] Compound 2: N′-(4-fluorophenyl)-2-(1H-indazol-1-yl)acetylhydrazine:

[0070] White solid, melting point 202-203℃, yield 69%. 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s,1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.3Hz, 1H), 7.40 (t, J = 7.4 Hz, 1H), 7.20 – 7.11 (m, 1H), 7.00 (t, J = 8.5 Hz, 2H), 6.78 (dd, J = 8.8, 4.6 Hz, 2H), 5.25 (s, 2H). 13 C NMR (100 MHz, DMSO-d6)δ 167.22, 145.63, 140.46, 133.66, 126.40, 123.80, 121.00, 120.75, 115.47,115.24, 113.69 (d, J = 7.7 Hz), 110.08, 50.05. HRMS (ESI) m / z: [M + H] + calcdfor C 15 H 14 FN4O 285.1146, found 285.1150.

[0071] Compound 3: N′-(3-fluorophenyl)-2-(1H-indazol-1-yl)acetylhydrazine:

[0072] White solid, melting point 200-201℃, yield 60%. 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s,1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.5Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.19 (tt, J = 8.3, 4.3 Hz, 2H), 6.67 (d, J= 8.5 Hz, 1H), 6.63 (d, J = 12.0 Hz, 1H), 6.54 (t, J = 7.9 Hz, 1H), 5.33 (s,2H). 13C NMR (100 MHz, DMSO-d6) δ 167.19, 163.40 (d, J = 240.4 Hz), 151.38,140.43, 133.61, 130.41 (d, J = 10.0 Hz), 126.26, 123.76, 120.90, 120.64,109.99, 108.43, 104.84 (d, J = 21.4 Hz), 98.88 (d, J = 26.0 Hz), 50.01. HRMS(ESI) m / z: [M + H] + calcd for C 15 H 14 FN4O 285.1146, found 285.1156.

[0073] Compound 4: N′-(2-fluorophenyl)-2-(1H-indazol-1-yl)acetylhydrazine:

[0074] White solid, melting point 188-189℃, yield 48%. 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s,1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.4Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.05 (dd, J =11.8, 8.3 Hz, 1H), 7.00 (t, J = 7.7 Hz, 1H), 6.91 (t, J = 8.1 Hz, 1H), 6.72(q, J = 6.7 Hz, 1H), 5.31 (s, 1H). 13 C NMR (125 MHz, DMSO-d6) δ 167.12,140.33, 136.56 (d, J = 13.2 Hz), 133.42, 126.13, 124.50, 123.66, 120.78,120.54, 118.86 (d, J = 5.9 Hz), 114.93, 114.79, 113.77, 110.06, 49.92. HRMS(ESI) m / z: [M + H] + calcd for C 15 H 14FN4O 285.1146, found 285.1151.

[0075] Compound 5: N′-(4-chlorophenyl)-2-(1H-indazol-1-yl)acetylhydrazine:

[0076] White solid, melting point 208-209℃, yield 67%. 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s,1H), 8.11 (d, J = 9.3 Hz, 2H), 7.73 (dd, J = 37.0, 8.3 Hz, 2H), 7.41 (t, J =7.8 Hz, 1H), 7.18 (t, J = 9.7 Hz, 3H), 6.80 (d, J = 8.3 Hz, 2H), 5.27 (s,2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.31, 148.12, 140.50, 133.75, 128.75,126.47, 123.86, 122.36, 121.06, 120.82, 114.01, 110.08, 50.07. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 14 ClN4O 301.0851, found 301.0858.

[0077] Compound 6: N′-(3-chlorophenyl)-2-(1H-indazol-1-yl)acetylhydrazine

[0078] White solid, melting point 206-207℃, yield 40%. 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (d, J= 2.4 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 7.79 (d, J = 8.0 Hz,1H), 7.71 (d, J = 8.5 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.17 (td, J = 7.8,2.6 Hz, 2H), 6.84 (s, 1H), 6.76 (d, J = 7.0 Hz, 2H), 5.30 (s, 2H). 13C NMR(100 MHz, DMSO-d6) δ 167.14, 150.64, 140.35, 133.72, 133.57, 130.41, 126.24,123.73, 120.87, 120.61, 118.21, 111.58, 111.01, 109.94, 50.01. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 14 ClN4O 301.0851, found 301.0861.

[0079] Compound 7: N′-(4-bromophenyl)-2-(1H-indazol-1-yl)acetylhydrazine

[0080] White solid, melting point 215-216℃, yield 35%. 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (d, J= 2.6 Hz, 1H), 8.10 (d, J = 7.1 Hz, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.67 (d, J= 8.5 Hz, 1H), 7.44 – 7.36 (m, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.15 (t, J =7.4 Hz, 1H), 6.73 (d, J = 8.7 Hz, 2H), 5.25 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.26, 148.50, 140.47, 133.72, 131.55, 126.45, 123.82, 121.04, 120.79,114.47, 110.07, 109.79, 50.02. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 14 BrN4O345.0346, found 345.0351.

[0081] Compound 8: 2-(1H-indazol-1-yl)-N′-(p-tolyl)acetylhydrazine

[0082] White solid, melting point 199-200℃, yield 59%. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s,1H), 8.11 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.73 – 7.66 (m, 2H), 7.41 (t, J= 7.9 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 7.9 Hz, 2H), 6.70 (d, J= 7.9 Hz, 2H), 5.26 (s, 2H), 2.18 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ167.06, 146.79, 140.41, 133.57, 129.30, 127.56, 126.32, 123.79, 120.96,120.70, 112.68, 110.08, 50.07, 20.31. HRMS (ESI) m / z: [M + H] + calcd forC 16 H 17 N4O 281.1397, found 281.1399.

[0083] Compound 9: 2-(1H-indazol-1-yl)-N′-(4-trifluoromethylphenyl)acetylhydrazine

[0084] White solid, melting point 222-223℃, yield 65%. 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (d, J= 1.8 Hz, 1H), 8.60 (d, J = 1.7 Hz, 1H), 8.16 (s, 1H), 7.80 (d, J = 8.0 Hz,1H), 7.73 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.49 – 7.39 (m, 1H), 7.18 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 5.35 (s, 2H). 13C NMR (100MHz, DMSO-d6) δ 167.25, 152.25, 147.56, 140.45, 133.63, 126.27, 126.24,123.79, 120.88, 120.64, 111.71, 109.99, 50.00. HRMS (ESI) m / z: [M + H] + calcdfor C 16 H 14 F3N4O 335.1114, found 335.1118.

[0085] Compound 10: 2-(1H-indazol-1-yl)-N′-(4-trifluoromethoxyphenyl)acetylhydrazine

[0086] White solid, melting point 185-186℃, yield 61%. 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (d, J= 2.3 Hz, 1H), 8.17 (d, J = 2.2 Hz, 1H), 8.13 (s, 1H), 7.79 (d, J = 8.0 Hz,1H), 7.69 (d, J = 8.5 Hz, 1H), 7.46 – 7.38 (m, 1H), 7.21 – 7.12 (m, 3H), 6.85(d, J = 8.9 Hz, 2H), 5.28 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.13,148.28, 140.56, 140.37, 133.53, 126.19, 123.69, 121.96, 120.82, 120.56,112.93, 109.97, 49.92. HRMS (ESI) m / z: [M + H] + calcd for C 16 H 14 F3N4O2 350.0991, found 350.0991.

[0087] Compound 11: 2-(1H-indazol-1-yl)-N′-(4-methoxyphenyl)acetylhydrazine

[0088] White solid, melting point 210-211℃, yield 30%. 1H NMR (500 MHz, DMSO-d6) δ 10.12 (d, J= 3.1 Hz, 1H), 8.13 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.5 Hz,1H), 7.58 (d, J = 3.2 Hz, 1H), 7.48 – 7.35 (m, 1H), 7.17 (t, J = 7.4 Hz, 1H), 6.88 – 6.55 (m, 4H), 5.25 (s, 2H), 3.67 (s, 3H). 13 C NMR (125 MHz, DMSO-d6) δ166.91, 152.84, 142.85, 140.34, 133.45, 126.17, 123.69, 120.82, 120.55,114.27, 113.83, 109.99, 55.31, 50.02. HRMS (ESI) m / z: [M + H] + calcd forC 16 H 17 N4O2 297.1346, found 297.1346.

[0089] Compound 12: 2-(1H-indazol-1-yl)-N′-(2-methoxyphenyl)acetylhydrazine

[0090] White solid, melting point 208-209℃, yield 46%. 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (d, J= 2.6 Hz, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.23 ​​(s, 1H), 7.85 (d, J = 8.0 Hz,1H), 7.71 (d, J = 8.5 Hz, 1H), 7.46 – 7.38 (m, 1H), 7.21 – 7.12 (m, 3H), 6.85(d, J = 8.9 Hz, 2H), 5.18 (s, 2H). 3.67 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ167.99, 151.88, 134.44, 128.43, 127.62, 125.13, 123.82, 121.58, 116.41,113.87, 110.05, 70.75, 52.08. HRMS (ESI) m / z: [M + H] + calcd for C 16 H 17 N4O2297.1346, found 297.1351.

[0091] Compound 13: N′-(2,4-difluorophenyl)-2-(1H-indazol-1-yl)acetylhydrazine

[0092] White solid, melting point 212-213℃, yield 38%. 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s,1H), 8.10 (s, 1H), 7.77 (d, J = 10.3 Hz, 2H), 7.69 (d, J = 8.6 Hz, 1H), 7.40(t, J = 7.9 Hz, 1H), 7.14 (q, J = 9.4, 8.0 Hz, 1H), 6.91 (d, J = 7.1 Hz, 1H), 5.29 (s, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 167.41, 148.54 (d, J = 11.8 Hz), 140.49, 133.70, 133.50 (dd, J = 11.0, 3.0 Hz), 126.44, 123.83, 121.02,120.79, 114.53 (dd, J = 8.2, 4.6 Hz), 110.99 (dd, J = 21.3, 3.5 Hz), 110.14,103.89 (d, J = 4.2 Hz), 103.65 (d, J = 2.6 Hz), 50.03. HRMS (ESI) m / z: [M +H] + calcd for C 15 H 13 F2N4O 303.1052, found 303.1060.

[0093] Compound 14: N′-(2,5-difluorophenyl)-2-(1H-indazol-1-yl)acetylhydrazine

[0094] White solid, melting point 200-201℃, yield 38%. 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (s,1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.75 (dd, J = 17.8, 8.0 Hz, 2H), 7.48 – 7.32(m, 1H), 7.23 – 7.11 (m, 1H), 7.08 (s, 1H), 6.70 (s, 1H), 6.48 (s, 1H), 5.33 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.43, 159.23 (d, J = 237.7 Hz), 140.49, 133.72, 126.42, 123.83, 121.03, 120.80, 115.89 (d, J = 20.9 HRMS (ESI) m / z: [M + H] + calcd forC 15 H 13 F2N4O 303.1052, found 303.1060.

[0095] Compound 15: N′-(3-chloro-4-fluorophenyl)-2-(1H-indazol-1-yl)acetylhydrazine

[0096] White solid, melting point 188-189℃, yield 45%. 1H NMR (400 MHz, DMSO-d6) δ 10.27 (d, J= 2.4 Hz, 1H), 8.17 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J = 8.1 Hz,1H), 7.72 (d, J = 8.5 Hz, 1H), 7.50 – 7.36 (m, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.19 – 7.14 (m, 1H), 6.96 (dd, J = 6.4, 2.7 Hz, 1H), 6.80 (dt, J = 9.0, 3.4Hz, 1H), 5.32 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.25, 150.88 (d, J =236.8 Hz), 146.50, 140.38, 133.61, 126.26, 123.77, 120.89, 120.64, 119.63 (d,J = 18.4 Hz), 116.94 (d, J = 21.8 Hz), 113.16, 112.38 (d, J = 6.6 Hz), 109.94, 50.06. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 13 FClN4O 319.0756, found319.0756.

[0097] Compound 16: 2-(3-bromo-1H-indazol-1-yl)-N′-phenylacetylhydrazine

[0098] White solid, melting point 208-209℃, yield 45%. 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (d, J= 2.7 Hz, 1H), 7.93 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.2 Hz,1H), 7.52 (t, J = 7.7 Hz, 1H), 7.31 – 7.25 (m, 1H), 7.18 (t, J = 7.4 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 6.75 (t, J = 7.3 Hz, 1H), 5.31 (s, 2H).13 C NMR (100MHz, DMSO-d6) δ 166.63, 148.95, 141.67, 128.79, 127.73, 123.03, 121.81,120.17, 119.48, 118.82, 112.33, 110.69, 50.29. HRMS (ESI) m / z: [M + H] + calcdfor C 15 H 14 BrN4O 345.0346, found 345.0350.

[0099] Compound 17: 2-(3-bromo-1H-indazol-1-yl)-N′-(4-fluorophenyl)acetylhydrazine

[0100] White solid, melting point 213-214℃, yield 65%. 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (d, J= 2.8 Hz, 1H), 7.94 (d, J = 2.9 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.03 (t, J= 8.8 Hz, 2H), 6.88 (d, J = 4.6 Hz, 2H), 6.85 (d, J = 4.6 Hz, 1H), 5.34 (s,2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.80, 154.96, 145.56, 141.71, 127.77,123.11, 121.84, 120.25, 119.51, 115.26 (d, J = 22.1 Hz), 113.69 (d, J = 7.7Hz), 110.71, 50.38. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 13 BrFN4O 363.0251, found 363.0261.

[0101] Compound 18: 2-(3-bromo-1H-indazol-1-yl)-N′-(3-fluorophenyl)acetylhydrazine

[0102] White solid, melting point 208-209℃, yield 56%. 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s,1H), 8.24 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.57 –7.49 (m, 1H), 7.32 – 7.25 (m, 1H), 7.17 (q, J = 8.0 Hz, 1H), 6.63 (d, J = 8.1Hz, 1H), 6.58 (d, J = 11.7 Hz, 1H), 6.51 (td, J = 8.5, 2.5 Hz, 1H), 5.32 (s,2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.72, 163.31 (d, J = 240.8 Hz), 151.20 (d,J = 10.4 Hz), 141.69, 130.40, 127.75, 123.03, 121.82, 120.24, 119.49, 110.67,108.36, 104.81 (d, J = 21.8 Hz), 98.80 (d, J = 25.3 Hz), 50.24. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 13 BrFN4O 363.0251, found 363.0251.

[0103] Compound 19: 2-(3-bromo-1H-indazol-1-yl)-N′-(2-fluorophenyl)acetylhydrazine

[0104] White solid, melting point 195-196℃, yield 59%. 1H NMR (400 MHz, DMSO-d6) δ 10.26 (d, J= 2.1 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.2 Hz,1H), 7.52 (ddd, J = 8.2, 6.9, 1.0 Hz, 1H), 7.27 (t, J = 7.4 Hz, 1H), 7.11 –7.05 (m, 1H), 7.05 – 7.00 (m, 1H), 6.95 (td, J = 8.4, 1.7 Hz, 1H), 6.75 (tdd,J = 7.6, 4.8, 1.7 Hz, 1H), 5.32 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.73,150.22 (d, J = 239.4 Hz), 141.69, 136.50 (d, J = 10.6 Hz), 127.74, 124.53 (d,J = 2.7 Hz), 123.04, 121.82, 120.21, 119.47, 119.01 (d, J = 6.4 Hz), 114.93 (d, J = 17.5 Hz), 113.78 (d, J = 2.9 Hz), 110.73, 50.25. HRMS (ESI) m / z: [M +H] + calcd for C 15 H 13 BrFN4O 363.0251, found 363.0260.

[0105] Compound 20: 2-(3-bromo-1H-indazol-1-yl)-N′-(4-chlorophenyl)acetylhydrazine

[0106] White solid, melting point 216–217 °C, yield 59%. 1H NMR (400 MHz, DMSO-d6) δ 10.33(s, 1H), 8.14 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H),7.56–7.45 (m, 1H), 7.30–7.23 (m, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.85 (d, J =8.3 Hz, 2H), 5.33 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.19, 148.38, 142.11,129.00, 128.19, 123.50, 122.67, 122.24, 120.68, 119.93, 114.30, 111.10,50.74. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 13 BrClN4O 378.9956, found378.9960.

[0107] Compound 21: 2-(3-bromo-1H-indazol-1-yl)-N′-(4-bromophenyl)acetylhydrazine

[0108] White solid, melting point 225-226℃, yield 55%. 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (d, J= 2.4 Hz, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.60 (d, J= 8.1 Hz, 1H), 7.57 – 7.47 (m, 1H), 7.33 (d, J = 8.6 Hz, 2H), 7.27 (t, J =7.4 Hz, 1H), 6.79 (d, J = 8.6 Hz, 2H), 5.32 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.68, 148.33, 141.65, 131.36, 127.73, 123.01, 121.80, 120.19, 119.47,114.31, 110.66, 109.65, 50.25. HRMS (ESI) m / z: [M + H] +calcd for C 15 H 13 Br2N4O422.9451, found 422.9458.

[0109] Compound 22: 2-(3-bromo-1H-indazol-1-yl)-N′-(p-tolyl)acetylhydrazine

[0110] White solid, melting point 210-211℃, yield 60%. 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s,1H), 7.86 – 7.56 (m, 3H), 7.51 (t, J = 7.9 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 7.9 Hz, 2H), 6.72 (d, J = 7.9 Hz, 2H), 5.31 (s, 2H), 2.18 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 166.55, 146.67, 141.65, 135.96, 129.11,127.67, 123.14, 122.99, 121.78, 119.42, 112.59, 110.72, 50.32, 20.21. HRMS(ESI) m / z: [M + H] + calcd for C 16 H 16 BrN4O 359.0502, found 359.0509.

[0111] Compound 23: 2-(3-bromo-1H-indazol-1-yl)-N′-(4-trifluoromethylphenyl)acetylhydrazine

[0112] White solid, melting point 213-214℃, yield 56%. 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s,1H), 8.57 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.54 –7.50 (m, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 7.5 Hz, 1H), 6.90 (d, J= 8.4 Hz, 2H), 5.34 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 166.78, 152.12,141.69, 128.97 (q, J = 5.6 Hz), 127.77, 126.17 (q, J = 4.8, 4.1 Hz), 123.02,121.82, 120.20, 119.47, 118.08 (q, J = 51.7 Hz), 111.63, 110.70, 50.21. HRMS(ESI) m / z: [M + H] + calcd for C 16 H 13 BrF3N4O 413.0219, found 413.0226.

[0113] Compound 24: 2-(3-bromo-1H-indazol-1-yl)-N′-(4-trifluoromethoxyphenyl)acetylhydrazine

[0114] White solid, melting point 180-181℃, yield 45%. 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s,1H), 8.19 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.52(t, J = 7.9 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 5.31 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.79,148.23, 141.70, 140.60, 127.75, 123.04, 121.94, 121.81, 120.19, 119.45,112.99, 110.71, 50.25. HRMS (ESI) m / z: [M + H] + calcd for C 16 H 13 BrF3N4O2429.0168, found 429.0174.

[0115] Compound 25: 2-(3-bromo-1H-indazol-1-yl)-N′-(4-methoxyphenyl)acetylhydrazine

[0116] White solid, melting point 194-195℃, yield 62%. 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s,1H), 7.64 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.55 – 7.47 (m, 1H),7.32 – 7.21 (m, 1H), 7.12 (s, 1H), 6.95 (t, J = 6.9 Hz, 1H), 6.86 (d, J = 7.0Hz, 1H), 6.81 – 6.76 (m, 1H), 6.78 – 6.72 (m, 1H), 5.26 (s, 2H), 3.77 (s,3H). 13 C NMR (100 MHz, DMSO-d6) δ 167.77, 143.88, 141.10, 137.12, 125.15,123.44, 122.26, 121.16, 120.53, 119.87, 119.64, 114.02, 113.21, 110.91,55.88, 52.70. HRMS (ESI) m / z: [M + H] + calcd for C 16 H 16 BrN4O2 375.0451, found375.0451.

[0117] Compound 26: 2-(3-bromo-1H-indazol-1-yl)-N′-(2-methoxyphenyl)acetylhydrazine

[0118] White solid, melting point 195-196℃, yield 56%. 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s,1H), 7.74 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.55 – 7.47 (m, 1H),7.32 – 7.21 (m, 1H), 7.11 (s, 1H), 6.95 (t, J = 6.9 Hz, 1H), 6.86 (d, J = 7.0Hz, 1H), 6.83 – 6.78 (m, 1H), 6.78 – 6.72 (m, 1H), 5.26 (s, 2H), 3.77 (s,3H). 13C NMR (100 MHz, DMSO-d6) δ 166.77, 146.88, 142.10, 138.12, 128.15,123.44, 122.26, 121.16, 120.53, 119.87, 119.64, 112.02, 111.21, 110.91,55.88, 50.70. HRMS (ESI) m / z: [M + H] + calcd for C 16 H 16 BrN4O2 375.0451, found375.0458.

[0119] Compound 27: 2-(3-bromo-1H-indazol-1-yl)-N′-(2,4-difluorophenyl)acetylhydrazine

[0120] White solid, melting point 252-253℃, yield 68%. 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s,1H), 7.81 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.51(t, J = 7.6 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.14 (t, J = 10.3 Hz, 1H), 6.92 (dd, J = 7.2, 3.6 Hz, 2H), 5.28 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ166.76, 141.68, 133.29 (dd, J = 10.8, 2.7 Hz), 127.74, 123.00, 121.82,120.16, 119.61 (d, J = 4.0 Hz), HRMS (ESI) m / z: [M + H] + calcd for C 15 H 12 BrF2N4O 381.0157, found381.0163.

[0121] Compound 28: 2-(3-bromo-1H-indazol-1-yl)-N′-(3,5-dichlorophenyl)acetylhydrazine

[0122] White solid, melting point 218-219℃, yield 45%. 1 H NMR (400 MHz, DMSO-d6) δ 10.53 (s,1H), 8.57 (s, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.50(t, J = 8.0 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 6.95 – 6.67 (m, 3H), 5.38 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.93, 151.42, 141.64, 134.58, 127.78,123.14, 121.83, 120.41, 119.55, 117.54, 110.60, 110.52, 50.39. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 12 BrCl2N4O 412.9566, found 412.9570.

[0123] Compound 29: 2-(5-bromo-1H-indazol-1-yl)-N′-(4-fluorophenyl)acetylhydrazine

[0124] White solid, melting point 221-222℃, yield 57%. 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (d, J= 2.9 Hz, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.69 (d, J = 8.9 Hz,1H), 7.52 (d, J = 8.2 Hz, 1H), 6.99 (t, J = 8.7 Hz, 2H), 6.80 – 6.68 (m, 2H), 5.28 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 166.86, 154.82, 145.55, 139.25,133.05, 128.93, 124.23 (d, J = 212.6 Hz), 115.23 (d, J = 22.3 Hz), 113.53 (d,J = 7.5 Hz), 112.99, 112.27, 50.13. 19 F NMR (376 MHz, DMSO-d6) δ -126.25. HRMS(ESI) m / z: [M + H] + calcd for C 15 H 13 BrFN4O 363.0251, found 363.0258.

[0125] Compound 30: 2-(5-bromo-1H-indazol-1-yl)-N′-(3-fluorophenyl)acetylhydrazine

[0126] White solid, melting point 211-212℃, yield 59%. 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s,1H), 8.21 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.60– 7.43 (m, 1H), 7.14 (q, J = 7.7 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 6.53 (d,J = 11.7 Hz, 1H), 6.48 (t, J = 8.5 Hz, 1H), 5.31 (s, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 166.93, 163.30 (d, J = 240.3 Hz), 151.24 (d, J = 10.4 Hz), 139.27,133.09, 130.37 (d, J = 9.6 Hz), 128.94, 125.29, 123.19, 113.01, 112.27,108.35, 104.74 (d, J = 21.3 Hz), 98.79 (d, J = 25.6 Hz), 50.11. 19F NMR (376MHz, DMSO-d6) δ -113.02. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 13 BrFN4O363.0251, found 363.0258.

[0127] Compound 31: 2-(5-bromo-1H-indazol-1-yl)-N′-(4-chlorophenyl)acetylhydrazine

[0128] White solid, melting point 220-221℃, yield 60%. 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s,1H), 8.10 (s, 2H), 8.00 (s, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 7.40 – 7.09 (m,2H), 6.77 (s, 2H), 5.29 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.32, 148.42,139.68, 133.49, 129.37, 128.99, 125.72, 123.61, 122.48, 114.22, 113.43,112.68, 50.53. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 13 BrClN4O 378.9956, found378.9960.

[0129] Compound 32: 2-(5-bromo-1H-indazol-1-yl)-N′-(4-bromophenyl)acetylhydrazine

[0130] White solid, melting point 224-225℃, yield 45%. 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s,1H), 8.09 (s, 2H), 8.00 (s, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 8.9Hz, 1H), 7.29 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 5.27 (s, 2H). 13CNMR (100 MHz, DMSO-d6) δ 166.85, 148.37, 139.25, 133.08, 131.40, 128.95,125.28, 123.18, 114.27, 113.00, 112.23, 109.57, 50.08. HRMS (ESI) m / z: [M +H] + calcd for C 15 H 13 Br2N4O 422.9451, found 422.9458.

[0131] Compound 33: 2-(5-chloro-1H-indazol-1-yl)-N′-phenylacetylhydrazine

[0132] White solid, melting point 211-212℃, yield 59%. 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s,1H), 8.11 (s, 1H), 7.89 (s, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.74 (d, J = 8.9Hz, 1H), 7.44 (dd, J = 8.9, 1.9 Hz, 1H), 7.16 (t, J = 7.8 Hz, 2H), 6.77 (d, J= 7.8 Hz, 2H), 6.72 (t, J = 7.3 Hz, 1H), 5.28 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.76, 148.95, 139.05, 133.11, 128.76, 126.48, 125.10, 124.51, 119.94,118.73, 112.25, 111.89, 50.13. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 14 ClN4O301.0851, found 301.0858.

[0133] Compound 34: 2-(5-chloro-1H-indazol-1-yl)-N′-(4-fluorophenyl)acetylhydrazine

[0134] White solid, melting point 215-216℃, yield 50%. 1H NMR (400 MHz, DMSO-d6) δ 10.31 (d, J= 2.8 Hz, 1H), 8.10 (s, 1H), 7.91 – 7.81 (m, 2H), 7.74 (d, J = 8.9 Hz, 1H), 7.48 – 7.36 (m, 1H), 6.99 (t, J = 8.8 Hz, 2H), 6.78 (dd, J = 8.7, 4.6 Hz, 2H), 5.29 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.07, 155.03, 145.61,139.18, 133.35, 126.72, 125.32, 124.70, 120.15, 115.38 (d, J = 22.3 Hz), 113.74 (d, J = 7.5 Hz), 111.99, 50.27. HRMS (ESI) m / z: [M + H] + calcd forC 15 H 13 FClN4O 319.0756, found 319.0761.

[0135] Compound 35: 2-(5-chloro-1H-indazol-1-yl)-N′-(3-fluorophenyl)acetylhydrazine

[0136] White solid, melting point 210-211℃, yield 71%. 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s,1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.42(d, J = 8.7 Hz, 1H), 7.15 (q, J = 7.7 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 11.6 Hz, 1H), 6.49 (t, J = 8.1 Hz, 1H), 5.36 (s, 2H). 13C NMR (100MHz, DMSO-d6) δ 167.00, 151.22, 139.10, 133.19, 130.40, 126.53, 125.21,124.58, 119.99, 111.90, 108.41 (d, J = 2.1 Hz), 104.77 (d, J = 21.0 Hz),98.75, 50.19. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 13 FClN4O 319.0756, found319.0761.

[0137] Compound 36: 2-(5-chloro-1H-indazol-1-yl)-N′-(2-fluorophenyl)acetylhydrazine

[0138] White solid, melting point 223-224℃, yield 59%. 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s,1H), 8.13 (s, 1H), 7.90 – 7.83 (m, 2H), 7.78 (d, J = 8.9 Hz, 1H), 7.43 (dd, J= 9.0, 2.0 Hz, 1H), 7.02 (ddt, J = 31.7, 15.6, 8.0 Hz, 3H), 6.74 (tdd, J =7.5, 4.7, 1.8 Hz, 1H), 5.38 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.04,150.28 (d, J = 239.2 Hz), 139.09, 136.58 (d, J = 10.4 Hz), 133.17, 126.53,125.23, 124.61, 124.57, 119.98, 119.03 (d, J = 7.4 Hz), 114.93 (d, J = 18.1Hz), 113.86, 111.95, 50.22. 13C NMR (125 MHz, DMSO-d6) δ 166.85, 150.15 (d, J= 239.0 Hz), 139.04, 136.48 (d, J = 10.3 Hz), 133.11, 126.46, 125.09, 124.51,119.92, 118.89 (d, J = 6.9 Hz), 114.95, 114.81, 113.69 (d, J = 1.3 Hz), 111.92, 50.08. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 13 FClN4O 319.0756, found319.0760.

[0139] Compound 37: 2-(5-chloro-1H-indazol-1-yl)-N′-(4-chlorophenyl)acetylhydrazine

[0140] White solid, melting point 209-210℃, yield 59%. 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (d, J= 2.4 Hz, 1H), 8.10 (s, 2H), 7.85 (t, J = 2.8 Hz, 1H), 7.74 (d, J = 8.9 Hz,1H), 7.43 (dd, J = 8.8, 1.9 Hz, 1H), 7.30 (dd, J = 9.0, 2.9 Hz, 2H), 6.73 (d,J = 8.8 Hz, 2H), 5.28 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.09, 148.46,139.21, 133.43, 131.60, 126.79, 125.37, 124.73, 120.21, 114.50, 111.98,109.87, 50.24. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 13 Cl2N4O 335.0461, found335.0468.

[0141] Compound 38: 2-(5-chloro-1H-indazol-1-yl)-N′-(4-bromophenyl)acetylhydrazine

[0142] White solid, melting point 217-218℃, yield 66%. 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s,1H), 8.12 – 7.99 (m, 2H), 7.85 (s, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.42 (d, J= 8.6 Hz, 1H), 7.18 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 5.29 (s,2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.84, 147.96, 139.04, 133.12, 128.52,126.50, 125.11, 124.51, 122.01, 119.94, 113.75, 111.87, 50.09. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 13 BrClN4O 378.9956, found 378.9961.

[0143] Compound 39: 2-(5-chloro-1H-indazol-1-yl)-N′-(p-tolyl)acetylhydrazine

[0144] White solid, melting point 202-203℃, yield 68%. 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s,1H), 8.13 (s, 1H), 7.81 (d, J = 25.7 Hz, 3H), 7.43 (s, 1H), 6.99 (s, 2H),6.78 (s, 2H), 5.35 (s, 2H), 2.21 (s, 3H). 13 C NMR (125 MHz, DMSO-d6) δ 166.88,146.82, 139.14, 133.16, 129.28, 127.51, 126.56, 125.26, 124.67, 120.04,112.72, 112.01, 50.33, 20.32. HRMS (ESI) m / z: [M + H] + calcd for C 16 H 16 ClN4O315.1007, found 315.1015.

[0145] Compound 40: 2-(5-chloro-1H-indazol-1-yl)-N′-(4-trifluoromethylphenyl)acetylhydrazine

[0146] White solid, melting point 229-230℃, yield 70%. 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s,1H), 8.58 (s, 1H), 8.14 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 8.9Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.45 (dd, J = 8.9, 2.0 Hz, 1H), 6.94 (d, J= 8.3 Hz, 2H), 5.36 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.06, 152.18,139.14, 133.26, 126.61, 126.24 (q, J = 5.7, 4.3 Hz), 125.31, 124.64, 123.77(q, J = 3.5 Hz), 120.00, 118.74 (q, J = 32.3 Hz), 111.83, 111.70, 50.19. HRMS(ESI) m / z: [M + H] + calcd for C 16 H 13 ClF3N4O 369.0724, found 369.0729.

[0147] Compound 41: 2-(5-chloro-1H-indazol-1-yl)-N′-(2,4-difluorophenyl)acetylhydrazine

[0148] White solid, melting point 215-216℃, yield 68%. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (d, J= 2.1 Hz, 1H), 8.09 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.74 (d,J = 9.0 Hz, 1H), 7.42 (dd, J = 8.9, 2.0 Hz, 1H), 7.12 (ddd, J = 11.4, 9.0,1.9 Hz, 1H), 6.96 – 6.87 (m, 2H), 5.30 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ168.10, 147.60, 140.29, 133.97, 133.44 (d, J = 2.0 Hz), 123.75, 121.68,122.64, 119.93, 119.81, 114.44 (d, J = 7.7 Hz), 114.04, 110.69, 50.08. HRMS(ESI) m / z: [M + H] + calcd for C 15 H 12 BrF2N4O 337.0662, found 337.0669.

[0149] Compound 42: 2-(6-bromo-1H-indazol-1-yl)-N′-(4-fluorophenyl)acetylhydrazine

[0150] White solid, melting point 214-215℃, yield 70%. 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (d, J= 2.9 Hz, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.87 (d, J = 2.9 Hz, 1H), 7.73 (d,J = 8.6 Hz, 1H), 7.28 (dd, J = 8.6, 1.7 Hz, 1H), 7.00 (t, J = 8.9 Hz, 2H), 6.77 (dd, J = 9.0, 4.5 Hz, 2H), 5.26 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ167.02, 145.59, 141.37, 134.15, 123.89, 122.85, 122.77, 120.04, 115.47,115.25, 113.67 (d, J = 7.4 Hz), 113.05, 50.13. HRMS (ESI) m / z: [M + H] + calcdfor C 15 H 13 BrFN4O 363.0251, found 363.0257.

[0151] Compound 43: 2-(6-bromo-1H-indazol-1-yl)-N′-(3-fluorophenyl)acetylhydrazine

[0152] White solid, melting point 204-205℃, yield 49%. 1 H NMR (500 MHz, DMSO-d6) δ 10.23 (d, J= 9.2 Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 8.02 (d, J= 9.3 Hz, 1H), 7.69 (t, J = 9.3 Hz, 1H), 7.25 (t, J = 9.4 Hz, 1H), 7.17 –7.07 (m, 1H), 6.63 – 6.50 (m, 2H), 6.49 – 6.43 (m, 1H), 5.27 (s, 2H). 13 C NMR(125 MHz, DMSO-d6) 166.94, 164.27, 162.35, 151.25 (d, J = 9.1 Hz), 141.29,134.01, 130.35 (d, J = 7.9 Hz), 123.74, 122.65, 119.92, 112.97, 108.35,104.78 (d, J = 22.0 Hz), 98.80 (d, J = 25.9 Hz), 50.02. HRMS (ESI) m / z: [M +H] + calcd for C 15 H 13 BrFN4O 363.0251, found 363.0257.

[0153] Compound 44: 2-(6-bromo-1H-indazol-1-yl)-N′-(2-fluorophenyl)acetylhydrazine

[0154] White solid, melting point 192-193℃, yield 72%. 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s,1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.32– 7.23 (m, 1H), 7.06 (dd, J = 12.2, 8.3 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.90 (t, J = 8.0 Hz, 1H), 6.72 (q, J = 6.5 Hz, 1H), 5.31 (s, 1H). 19 F NMR (376MHz, DMSO-d6) δ -132.85. 13 C NMR (125 MHz, DMSO-d6) δ 166.87, 151.06, 149.16,141.19, 136.47 (d, J = 10.8 Hz), 133.88, 124.45, 123.65, 122.58, 119.78,118.87 (d, J = 6.6 Hz), 114.83 (d, J = 17.8 Hz), 113.69, 112.96, 49.95. HRMS(ESI) m / z: [M + H] + calcd for C 15 H 13 BrFN4O 363.0251, found 363.0258.

[0155] Compound 45: 2-(6-bromo-1H-indazol-1-yl)-N′-(4-chlorophenyl)acetylhydrazine

[0156] White solid, melting point 216-217℃, yield 56%. 1H NMR (400 MHz, DMSO-d6) δ 10.16 (d, J= 2.4 Hz, 1H), 8.13 (s, 1H), 8.08 (d, J = 2.1 Hz, 1H), 8.02 (s, 1H), 7.73 (d,J = 8.6 Hz, 1H), 7.28 (dd, J = 8.5, 1.4 Hz, 1H), 7.22 – 7.13 (m, 2H), 6.83 –6.70 (m, 2H), 5.26 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.07, 148.06,141.39, 134.21, 128.72, 123.94, 122.90, 122.80, 122.33, 120.08, 113.96,113.05, 50.12. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 13 BrClN4O 378.9956, found378.9961.

[0157] Compound 46: 2-(6-bromo-1H-indazol-1-yl)-N′-(4-bromophenyl)acetylhydrazine

[0158] White solid, melting point 220-221℃, yield 59%. 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s,1H), 8.12 (d, J = 10.1 Hz, 2H), 8.03 (s, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.29(t, J = 7.5 Hz, 3H), 6.73 (d, J = 8.5 Hz, 2H), 5.28 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.87, 148.38, 141.25, 133.97, 131.35, 123.71, 122.67, 122.60,119.85, 114.26, 112.97, 109.52, 49.97. HRMS (ESI) m / z: [M + H] + calcd forC 15 H 13Br2N4O 422.9451, found 422.9458.

[0159] Compound 47: 2-(6-bromo-1H-indazol-1-yl)-N′-(p-tolyl)acetylhydrazine

[0160] White solid, melting point 245-246℃, yield 65%. 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s,1H), 8.12 (s, 1H), 8.04 (s, 1H), 7.84 – 7.59 (m, 2H), 7.27 (d, J = 8.2 Hz,1H), 6.94 (d, J = 7.9 Hz, 2H), 6.68 (d, J = 7.9 Hz, 2H), 5.27 (s, 2H), 2.16(s, 3H). 13 C NMR (125 MHz, DMSO-d6) δ 166.67, 146.69, 141.17, 133.82, 129.09,127.25, 123.64, 122.60, 119.75, 112.99, 112.50, 45.22, 8.38. HRMS (ESI) m / z:[M + H] + calcd for C 16 H 16 BrN4O 359.0502, found 359.0510.

[0161] Compound 48: 2-(6-bromo-1H-indazol-1-yl)-N′-(2,4-difluorophenyl)acetylhydrazine

[0162] White solid, melting point 240-241℃, yield 70%. 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s,1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.27(d, J = 7.8 Hz, 1H), 7.13 (t, J = 10.1 Hz, 1H), 6.97 – 6.86 (m, 2H), 5.29 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 167.10, 148.60, 141.29, 133.97, 133.44 (d, J= 2.0 Hz), 123.75, 122.68, 122.64, 119.93, 119.81, 114.44 (d, J = 7.7 Hz),113.04, 110.69, 50.08. HRMS (ESI) m / z: [M + H] + calcd for C 15 H 12 BrF2N4O381.0157, found 381.0151.

[0163] Compound 49: 2-(6-bromo-1H-indazol-1-yl)-N′-(3,5-dichlorophenyl)acetylhydrazine

[0164] White solid, melting point 221-222℃, yield 70%. 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s,1H), 8.51 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.28(d, J = 8.4 Hz, 1H), 6.81 (s, 1H), 6.73 (s, 2H), 5.32 (s, 2H). 13 C NMR (100MHz, DMSO-d6) δ 167.00, 151.44, 141.24, 134.46, 134.05, 123.78, 122.69,122.62, 119.95, 117.33, 112.92, 110.34, 49.98. HRMS (ESI) m / z: [M + H] + calcdfor C 15 H 12 BrCl2N4O 412.9566, found 412.9571.

[0165] Compound 50: 2-(6-nitro-1H-indazol-1-yl)-N′-(4-chlorophenyl)acetylhydrazine

[0166] White solid, melting point 248-249℃, yield 69%. 1H NMR (400 MHz, DMSO-d6) δ 10.25 (d, J= 2.4 Hz, 1H), 8.80 (s, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.98 (d, J = 6.8 Hz,2H), 7.19 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 5.48 (s, 2H). 13 C NMR(100 MHz, DMSO-d6) δ 166.74, 147.92, 146.04, 139.33, 134.34, 128.54, 126.80,122.22, 122.13, 115.06, 113.76, 107.29, 50.36. HRMS (ESI) m / z: [M + H] + calcdfor C 15 H 13 ClN5O3 346.0701, found 346.0711.

[0167] Compound 51: 2-(6-nitro-1H-indazol-1-yl)-N′-(4-bromophenyl)acetylhydrazine

[0168] White solid, melting point 246-247℃, yield 58%. 1 H NMR (400 MHz, DMSO-d6) δ 10.27 (s,1H), 8.78 (s, 1H), 8.33 (s, 1H), 8.13 (s, 1H), 7.95 (d, J = 3.4 Hz, 2H), 7.30(d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 5.49 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.77, 148.34, 146.04, 139.31, 134.34, 131.40, 126.81, 122.20, 115.05, 114.30, 109.71, 107.26, 50.39. HRMS (ESI) m / z: [M + H] + calcd forC 15 H 13 BrN5O3 390.0196, found 390.0199.

[0169] Example 2 Preparation of novel indazole carbamoyl hydrazide compounds

[0170] The synthetic route for indazole-3-formylhydrazide compounds is as follows:

[0171]

[0172] Wherein, R1 is selected from H, 1-Me, ​​5-Br, 5-Cl, 5-CH3, 6-Cl; R is selected from H, 4-F, 4-Cl, 4-Br, 4-CH3, 4-CF3, 4-CN, 4-CF3O, 4-BnO, 3-F, 3-Cl, 3-Br, 3-CF3O, 2-F, 2-Cl, 2-Br, 2-CF3, 2-CH3O, 2,4-di-F, 3,5-di-Cl, 2,4,6-tri-Cl, 1,2,3,4,5-F.

[0173] The specific steps are as follows:

[0174] 1. Preparation of 1H-indazole-3-carboxylate derivative: 10 mmol of substituted o-aminophenylacetic acid methyl ester (F) was weighed into a 50 mL round-bottom flask, and 20 mL of acetonitrile was added. The mixture was stirred at room temperature until the solid was completely dissolved. Then, 1.15 mL (20 mmol) of glacial acetic acid was added, and the mixture was stirred at room temperature for 5 min. Next, 1.8 mL (15 mmol) of tert-butyl nitrite was added, and the mixture was stirred at room temperature for 5 h. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, 10 mL of distilled water was added to the system, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration to remove the drying agent, the solvent was removed by rotary evaporation. The crude product was purified by column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the 1H-indazole-3-carboxylate derivative (G).

[0175] 2. Preparation of 1H-indazole-3-carboxylic acid derivative (H): 10 mmol of methyl 1H-indazole-3-carboxylic acid derivative (G) was weighed and placed in a 50 mL round-bottom flask. 20 mL of 1 M NaOH solution was added, and the mixture was stirred at room temperature until the substrate was completely hydrolyzed. After the reaction was complete, the pH of the solution was adjusted to approximately 5 using 1 M dilute hydrochloric acid, and the product 1H-indazole-3-carboxylic acid derivative gradually precipitated from the aqueous phase. The precipitate was filtered, the filter cake was washed with ice water (20 mL), and dried to obtain the target product 1H-indazole-3-carboxylic acid derivative (H).

[0176] 3. Preparation of indazole-3-carboxyhydrazide derivatives: 1 mmol of indazole-3-carboxylic acid derivative (H) was weighed into a 50 mL round-bottom flask, and 1.2 mmol of substituted phenylhydrazine hydrochloride and 1.2 mmol of TBTU were added, along with 15 mL of acetonitrile as solvent. Subsequently, 0.5 mL of triethylamine was added as base, and the reaction was carried out at room temperature for 10 h. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the solvent was removed by rotary evaporation, and the target product was obtained by column chromatography. The substituent groups of each compound are shown in Table 2. The indazole-3-carboxyhydrazide compounds represented by Formula II are shown in Table 2.

[0177] Table 2. Indazole-3-formylhydrazide compounds

[0178] The structural characterization data of the target compounds, indazole carbamoyl hydrazide derivatives 52-85, are as follows:

[0179] Compound 52: N′-(4-fluorophenyl)-1H-indazole-3-formylhydrazine:

[0180] White solid, melting point 259-260℃, yield 65%. 1 H NMR (400 MHz, DMSO-d6) δ 13.76 (s,1H), 10.43 (d, J = 3.1 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 2.9Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.5Hz, 1H), 7.01 (t, J = 8.7 Hz, 2H), 6.87 (dd, J = 8.8, 4.7 Hz, 2H). 13 C NMR(100 MHz, DMSO-d6) δ 162.67, 154.87, 146.33, 141.08, 137.25, 126.73, 122.35,121.96, 121.44, 115.26 (d, J = 22.3 Hz), 113.65 (d, J = 7.8 Hz), 110.91. HRMS(ESI) m / z: [M + H]⁺ calcd for C 14 H 12 FN4O⁺ 271.0990, found 271.0988.

[0181] Compound 53: N′-(4-bromophenyl)-1H-indazole-3-formylhydrazide

[0182] White solid, melting point 225-226℃, yield 72%. 1 H NMR (400 MHz, DMSO-d6) δ 13.71 (s,1H), 10.38 (d, J = 2.5 Hz, 1H), 8.17 – 8.08 (m, 2H), 7.65 (d, J = 8.4 Hz,1H), 7.43 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.25 (t, J = 7.5 Hz, 1H), 6.76 (d, J = 8.8 Hz, 2H). 13 HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12 BrN4O + 331.0189, found 331.0188.

[0183] Compound 54: N′-(p-Tolyl)-1H-Indazole-3-Formylhydrazide

[0184] White solid, melting point 223-224℃, yield 71%. 1 H NMR (400 MHz, DMSO-d6) δ 13.78 (s,1H), 10.26 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.67(d, J = 8.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 2.27 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 162.71,147.52, 141.18, 137.41, 129.38, 127.48, 126.92, 122.50, 121.98, 121.52,112.81, 111.04, 20.38. HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 15 N4O + 267.1240, found 267.1237.

[0185] Compound 55: N′-(4-trifluoromethylphenyl)-1H-indazole-3-formylhydrazide

[0186] Pale yellow solid, melting point 241-242℃, yield 45%. 1 H NMR (400 MHz, DMSO-d6) δ 14.00 –13.46 (m, 1H), 10.69 – 10.33 (m, 1H), 8.66 – 8.53 (m, 1H), 8.23 ​​– 7.97 (m,1H), 7.67 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.06 – 6.84 (m, 2H). 13 C NMR (100 MHz, DMSO-d6)δ 162.92, 153.04, 141.37, 137.19, 127.15, 126.76, 126.55, 124.07, 122.81,122.16, 121.58, 111.95, 111.24. HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 12 F3N4O + 321.0957, found 321.0957.

[0187] Compound 56: N′-(4-cyanophenyl)-1H-indazole-3-formylhydrazine

[0188] White solid, melting point 212-213℃, yield 48%. 1H NMR (400 MHz, DMSO-d6) δ 13.79 (s,1H), 10.57 (d, J = 1.7 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 8.1Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.43 (ddd, J =8.3, 6.9, 1.2 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H). 13 CNMR (100 MHz, DMSO-d6) δ 162.41, 153.28, 141.02, 136.80, 133.48, 126.78,122.45, 121.91, 121.30, 120.23, 111.82, 110.93, 98.81. HRMS (ESI) m / z: [M +H]⁺ calcd for C 15 H 12 N5O + 278.1143, found 278.1035.

[0189] Compound 57: N′-(4-trifluoromethoxyphenyl)-1H-indazole-3-formylhydrazine:

[0190] Pale yellow solid, melting point 209-210℃, yield 53%. 1 H NMR (400 MHz, DMSO-d6) δ 13.74 (s,1H), 10.43 (d, J = 2.6 Hz, 1H), 8.22 (d, J = 2.6 Hz, 1H), 8.14 (d, J = 8.2Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 7.5Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H). 13HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 12 F3N4O2 + 337.0906, found 337.0908.

[0191] Compound 58: N′-(4-benzyloxyphenyl)-1H-indazole-3-formylhydrazine:

[0192] White solid, melting point 190-191℃, yield 63%. 1 H NMR (400 MHz, DMSO-d6) δ 13.70 (s,1H), 10.31 (d, J = 3.5 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.69 – 7.62 (m,2H), 7.48 – 7.38 (m, 3H), 7.36 (t, J = 7.4 Hz, 2H), 7.34 – 7.27 (m, 1H), 7.29– 7.21 (m, 1H), 6.87 (d, J = 9.0 Hz, 2H), 6.80 (d, J = 9.0 Hz, 2H), 4.99 (s,2H). 13 C NMR (100 MHz, DMSO-d6) δ 162.93, 152.16, 144.14, 141.39, 137.98,137.65, 129.98, 128.89, 128.12, 128.02, 127.02, 122.71, 115.83, 115.19,114.23, 111.25, 70.10. HRMS (ESI) m / z: [M + H]⁺ calcd for C 21 H 19 N4O2 + 359.1508, found 359.1498.

[0193] Compound 59: N′-(3-fluorophenyl)-1H-indazole-3-formylhydrazine:

[0194] Pale yellow solid, melting point 260-261℃, yield 63%.1 H NMR (400 MHz, DMSO-d6) δ 13.74 (s,1H), 10.41 (d, J = 2.5 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 8.2Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 7.5Hz, 1H), 7.16 (q, J = 8.1 Hz, 1H), 6.64 (dd, J = 8.2, 2.1 Hz, 1H), 6.56 –6.44 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 163.68 (d, J = 240.1 Hz), 162.88,152.38 (d, J = 10.3 Hz), 141.40, 137.42, 130.78 (d, J = 9.9 Hz), 127.12,122.75, 122.26, 121.71, 111.29, 108.70, 104.90 (d, J = 21.4 Hz), 99.10 (d, J= 25.6 Hz). 19 F NMR (376 MHz, DMSO-d6) δ -113.34. HRMS (ESI) m / z: [M + H]⁺calcd for C 14 H 12 FN4O⁺ 271.0990, found 271.0987.

[0195] Compound 60: N′-(3-chlorophenyl)-1H-indazole-3-formylhydrazine

[0196] Pale yellow solid, melting point 238-239℃, yield 63%. 1 H NMR (400 MHz, DMSO-d6) δ 13.74 (s,1H), 10.43 (s, 1H), 8.27 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.4Hz, 1H), 7.49 – 7.37 (m, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.81 – 6.67 (m, 3H). 13C NMR (100 MHz, DMSO-d6) δ 162.61, 151.42, 141.11,137.05, 133.67, 130.56, 126.85, 122.49, 121.95, 121.39, 118.03, 111.58,111.08, 111.00. HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12 ClN4O + 287.0694, found 287.0695.

[0197] Compound 61: N′-(3-bromophenyl)-1H-indazole-3-formylhydrazide

[0198] White solid, melting point 226-227℃, yield 53%. 1 H NMR (400 MHz, DMSO-d6) δ 13.75 (s,1H), 10.43 (d, J = 2.1 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 8.14 (d, J = 8.2Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 7.5Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.94 (t, J = 2.1 Hz, 1H), 6.85 (d, J = 7.8Hz, 1H), 6.80 (dd, J = 8.3, 2.2 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 162.46,151.46, 140.98, 136.96, 130.76, 126.72, 122.36, 122.13, 121.85, 121.29,120.77, 114.34, 111.33, 110.88. HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12 BrN4O + 331.0189, found 331.0186.

[0199] Compound 62: N′-(3-trifluoromethoxyphenyl)-1H-indazole-3-formylhydrazine:

[0200] Pale yellow solid D13, melting point 211-210℃, yield 53%. 1 H NMR (400 MHz, DMSO-d6) δ 13.75(s, 1H), 10.46 (s, 1H), 8.37 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.66 (d, J =8.4 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.25 (td, J = 7.8, 2.8 Hz, 2H), 6.80 (d, J = 8.2 Hz, 1H), 6.69 (s, 1H), 6.63 (d, J = 8.1 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 162.49, 151.67, 149.43, 141.00, 136.97, 130.45, 126.74, 122.37,121.87, 121.45, 121.28, 118.92, 110.92 (q, J = 5.2 Hz), 109.94, 104.11. 19 FNMR (376 MHz, DMSO-d6) δ -56.54. HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 12 F3N4O2 + 337.0906, found 337.0905.

[0201] Compound 63: N′-(2-fluorophenyl)-1H-indazole-3-formylhydrazide

[0202] Pale yellow solid, melting point 272-273℃, yield 69%. 1 H NMR (400 MHz, DMSO-d6) δ 13.74 (s,1H), 10.53 – 10.27 (m, 1H), 7.49 – 7.38 (m, 1H), 7.30 – 7.22 (m, 1H), 7.11(ddd, J = 12.1, 8.1, 1.1 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.91 – 6.83 (m,1H), 6.79 – 6.68 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 162.69, 141.15, 137.29(d, J = 26.3 Hz), 127.63, 126.94, 124.77, 122.57, 121.98, 121.45, 118.94,115.04 (d, J = 16.6 Hz), 113.87, 111.05, 106.21. HRMS (ESI) m / z: [M + H]⁺calcd for C 14 H 12 FN4O⁺ 271.0990, found 271.0988.

[0203] Compound 64: N′-(2-chlorophenyl)-1H-indazole-3-formylhydrazine:

[0204] White solid, melting point 261-260℃, yield 73%. 1 H NMR (400 MHz, DMSO-d6) δ 13.77 (s,1H), 10.51 (s, 1H), 8.15 (t, J = 7.5 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.43(t, J = 7.7 Hz, 1H), 7.31 (dd, J = 7.9, 1.4 Hz, 1H), 7.26 (t, J = 7.5 Hz,1H), 7.48 – 7.39 (m, 1H), 7.14 (t, J = 7.7 Hz, 1H), 6.89 (d, J = 6.8 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 162.36, 145.07, 140.99,136.95, 129.17, 127.78, 126.71, 122.37, 121.89, 121.29, 119.47, 117.25,113.12, 110.88. HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12 ClN4O + 287.0694, found287.0812.

[0205] Compound 65: N′-(2-bromophenyl)-1H-indazole-3-formylhydrazide

[0206] White solid, melting point 271-272℃, yield 77%. 1 H NMR (400 MHz, DMSO-d6) δ 13.76 (s,1H), 10.55 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.48(dd, J = 7.9, 1.3 Hz, 1H), 7.46 – 7.40 (m, 2H), 7.27 (t, J = 7.5 Hz, 1H), 7.24 – 7.15 (m, 1H), 6.88 (dd, J = 8.2, 1.5 Hz, 1H), 6.71 (td, J = 7.6, 1.5Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 162.51, 146.12, 141.15, 137.01, 132.54,128.57, 126.96, 122.63, 121.99, 121.41, 120.48, 113.54, 111.07, 107.22. HRMS(ESI) m / z: [M + H]⁺ calcd for C 14 H 12 BrN4O + 331.0189, found 331.0186.

[0207] Compound 66: N′-(2-trifluoromethylphenyl)-1H-indazole-3-formylhydrazine

[0208] Pale yellow solid, melting point 199-200℃, yield 66%. 1 H NMR (400 MHz, DMSO-d6) δ 13.78 (s,1H), 10.56 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.67(d, J = 8.4 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.27 (ddd, J = 7.9, 6.8, 0.9 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.87 (t, J = 7.5Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 162.35, 146.68, 141.00, 136.87, 133.43,126.71, 126.09 (q, J = 5.7 Hz), 123.41, 122.38, 121.92, 121.28, 118.12,113.20, 111.83 (q, J = 30.4 Hz), 110.88. 19 F NMR (376 MHz, DMSO-d6) δ -60.60.HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 12 F3N4O + 321.0957, found 321.0955.

[0209] Compound 67: N′-(2-methoxyphenyl)-1H-indazole-3-formylhydrazine:

[0210] White solid, melting point 178-179℃, yield 70%. 1 H NMR (400 MHz, DMSO-d6) δ 13.72 (s,1H), 10.42 (d, J = 3.6 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.4Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 3.4Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 3.4 Hz, 3H), 6.77 – 6.70 (m,1H), 3.85 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 162.41, 146.74, 141.15,138.55, 137.25, 126.92, 122.53, 121.95, 121.47, 120.94, 119.32, 111.89,111.03, 110.61, 55.68. HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 15 N4O2 + 283.1189, found 283.1188.

[0211] Compound 68: N′-(2,5-dichlorophenyl)-1H-indazole-3-formylhydrazine

[0212] Pale yellow solid, melting point 137-138℃, yield 56%. 1 H NMR (400 MHz, DMSO-d6) δ 13.80 (s,1H), 10.55 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.27 (t, J = 7.5Hz, 1H), 7.23 – 7.14 (m, 1H), 6.77 (s, 1H). 13 C NMR (125 MHz, DMSO-d6) δ162.27, 146.34, 140.98, 136.70, 132.42, 130.71, 126.79, 122.50, 121.86,121.21, 118.58, 115.53, 112.02, 110.95. HRMS (ESI) m / z: [M + H]⁺ calcd forC 14 H 11 Cl2N4O + 321.0304, found 321.0297.

[0213] Compound 69: N′-(2-chloro-4-fluorophenyl)-1H-indazole-3-formylhydrazine:

[0214] Pale yellow solid, melting point 250-251℃, yield 58%. 1 H NMR (400 MHz, DMSO-d6) δ 13.76 (s,1H), 10.51 (s, 1H), 8.11 (s, 1H), 7.63 (s, 2H), 7.43 (s, 1H), 7.29 (d, J =29.6 Hz, 2H), 7.05 (s, 1H), 6.84 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ 162.35,154.99 (d, J = 237.2 Hz), 142.05, 140.95, 136.86, 126.72, 122.38, 121.85,121.26, 117.19 (d, J = 10.6 Hz), 116.20 (d, J = 25.7 Hz), 114.59 (d, J = 22.0Hz), 113.81 (d, J = 8.2 Hz), 110.88. 19 F NMR (376 MHz, DMSO-d6) δ -124.96.HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 11 ClFN4O + 305.0600, found 305.0596.

[0215] Compound 70: N′-(2,4-difluorophenyl)-1H-indazole-3-formylhydrazide

[0216] Pale yellow solid, melting point 224-225℃, yield 66%. 1 H NMR (400 MHz, DMSO-d6) δ 13.73 (s,1H), 10.41 (d, J = 2.7 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.82 (s, 1H), 7.66(d, J = 8.4 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.21– 7.13 (m, 1H), 6.88 (q, J = 8.7, 8.1 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ162.49, 140.96, 136.97, 134.12 (d, J = 2.6 Hz), 134.01 (d, J = 3.0 Hz), 126.70, 122.34, 121.84, 121.29, 114.22 (dd, J = 8.3, 5.0 Hz), 110.86 (dd, J =21.6, 3.2 Hz), 110.86, 108.84 (d, J = 100.5 Hz), 103.68 (d, J = 4.0 Hz). 19FNMR (376 MHz, DMSO-d6) δ -124.11, -128.91. HRMS (ESI) m / z: [M + H]⁺ calcd forC 14 H 11 F2N4O + 289.0896, found 289.0890.

[0217] Compound 71: N′-(3,5-dichlorophenyl)-1H-indazole-3-formylhydrazine

[0218] Pale yellow solid, melting point 131-132℃, yield 45%. 1 H NMR (500 MHz, DMSO-d6) δ 10.51 (d,J = 2.2 Hz, 1H), 8.54 (d,J = 2.2 Hz, 1H), 8.11 (d,J = 8.2 Hz, 1H), 7.66 (d,J = 8.4 Hz, 1H), 7.49 – 7.40 (m, 1H), 7.27 (t, J = 7.5 Hz, 1H), 6.83 (q, J =1.7 Hz, 2H), 6.73 (d, J = 1.8 Hz, 2H). 13 HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 11 Cl2N4O + 321.0304, found 321.0300.

[0219] Compound 72: N′-(2,4,6-trichlorophenyl)-1H-indazole-3-formylhydrazine

[0220] White solid, melting point 272-273℃, yield 35%. 1H NMR (500 MHz, DMSO-d6) δ 10.44 (d, J= 2.1 Hz, 1H), 8.07 (dd, J = 8.1, 0.9 Hz, 1H), 7.63 (dt, J = 8.5, 1.0 Hz,1H), 7.60 (d, J = 2.1 Hz, 1H), 7.50 (s, 2H), 7.41 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 7.23 (ddd, J = 8.0, 6.9, 0.9 Hz, 1H). 13 C NMR (125 MHz, DMSO-d6) δ161.82, 141.15, 140.86, 136.47, 128.59, 126.64, 124.56, 123.78, 122.30,121.81, 121.23, 110.82. HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 10 Cl3N4O + 354.9915, found 354.9915.

[0221] Compound 73: N′-(perfluorophenyl)-1H-indazole-3-formylhydrazide

[0222] White solid, melting point 254-255℃, yield 30%. 1 H NMR (400 MHz, DMSO-d6) δ 13.74 (s,1H), 10.67 (d, J = 1.9 Hz, 1H), 8.25 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.64(d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.3 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H). 13 CNMR (100 MHz, DMSO-d6) δ 162.99, 141.34, 139.06 (dd, J = 5.4, 3.4 Hz), 136.96, 136.65 (d, J = 4.6 Hz), 135.33 (d, J = 7.7 Hz), 127.04, 125.88 –125.29 (m), 122.28, 121.59, 111.23. 19F NMR (376 MHz, DMSO-d6) δ -158.03 (dd,J = 19.2, 5.5 Hz, 2F), -165.05 – -165.29 (m, 2F), -170.89 (tt, J = 23.3, 5.9Hz, 1F). HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H8F5N4O + 343.0613, found 343.0609.

[0223] Compound 74: N′-(4-chlorophenyl)-1-methyl-1H-indazole-3-formylhydrazide

[0224] White solid, melting point 158-159℃, yield 60%. 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s,1H), 8.15 (d, J = 2.5 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 8.5 Hz,1H), 7.48 (t, J = 7.7 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 4.18 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ162.04, 148.67, 140.76, 135.59, 128.53, 126.72, 122.58, 122.50, 121.68,121.45, 113.73, 110.54, 36.07. HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 14 ClN4O + 301.0851, found 301.0850.

[0225] Compound 75: N′-(4-bromophenyl)-1-methyl-1H-indazole-3-formylhydrazide

[0226] White solid, melting point 172-173℃, yield 45%. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s,1H), 8.15 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.48(t, J = 7.6 Hz, 1H), 7.34 – 7.21 (m, 3H), 6.75 (d, J = 8.9 Hz, 2H), 4.17 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 162.01, 149.04, 140.75, 135.58, 134.62,131.35, 126.70, 122.55, 121.44, 114.23, 110.51, 109.18, 36.06. HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 14 BrN4O + 345.0345, found 345.0340.

[0227] Compound 76: N′-(3-bromophenyl)-1-methyl-1H-indazole-3-formylhydrazide

[0228] White solid, melting point 165-166℃, yield 45%. 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (d, J= 2.5 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.74 (d, J= 8.4 Hz, 1H), 7.47 (t, J = 4.17 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 162.31, 151.54, 140.93,135.59, 130.95, 126.95, 122.84, 122.67, 122.33, 121.58, 121.06, 114.53,111.55, 110.63, 36.23. HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 14 BrN4O + 345.0345, found 345.0345.

[0229] Compound 77: N′-(2,4-difluorophenyl)-1-methyl-1H-indazole-3-formylhydrazide

[0230] White solid, melting point 176-177℃, yield 48%. 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s,1H), 8.11 (d, J = 8.2 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.46(ddd, J = 8.3, 6.8, 1.1 Hz, 1H), 7.31 – 7.23 (m, 1H), 7.14 (ddd, J = 11.5,9.4, 2.3 Hz, 1H), 6.93 – 6.80 (m, 2H), 4.15 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 162.37, 155.01 (d, J = 247.7 Hz), 140.94, 135.63, 134.18 (d, J = 13.5Hz), 130.24 (d, J = 76.4 Hz), 126.98, 122.87, 122.67, 121.60, 119.13, 114.44(d, J = 4.7 Hz), 111.07 (d, J = 24.8 Hz), 110.69, 36.24. HRMS (ESI) m / z: [M +H]⁺ calcd for C 15 H 13 F2N4O + 303.1052, found 303.1050.

[0231] Compound 78: N′-(2,5-difluorophenyl)-1-methyl-1H-indazole-3-formylhydrazide

[0232] White solid, melting point 181-182℃, yield 39%. 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (d, J= 2.0 Hz, 1H), 8.25 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.5 Hz,1H), 7.48 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.14 (ddd, J = 11.3,8.8, 5.0 Hz, 1H), 6.51 (dddt, J = 14.9, 8.4, 6.4, 3.1 Hz, 2H), 4.18 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 162.03, 159.04 (d, J = 237.4 Hz), 146.24 (d, J =236.9 Hz), 140.79, 139.00 (d, J = 11.1 Hz), 135.39, 126.76, HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 13 F2N4O + 303.1052, found 303.1050.

[0233] Compound 79: N′-(3,4-difluorophenyl)-1-methyl-1H-indazole-3-formylhydrazide

[0234] White solid, melting point 180-181℃, yield 56%. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (d, J= 2.8 Hz, 1H), 8.16 (d, J = 2.8 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.78 (d, J= 8.5 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.21 (dt,J = 10.7, 9.0 Hz, 1H), 6.68 (ddd, J = 13.0, 6.9, 2.7 Hz, 1H), 6.57 (d, J =9.3 Hz, 1H), 4.17 (s, 3H). 13 C NMR (125 MHz, DMSO-d6) δ 162.05, 149.75 (d, J =242.4 Hz), 147.27 (d, J = 8.0 Hz), 142.54 (d, J = 234.7 Hz), 140.77, 135.48,126.73, 122.60, 122.48, 121.41, 117.45 (d, J = 18.1 Hz), 110.56, 107.88,100.72 (d, J = 20.8 Hz), 36.06. HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 13 F2N4O + 303.1052, found 303.1050.

[0235] Compound 80: N′-(perfluorophenyl)-1-methyl-1H-indazole-3-formylhydrazide

[0236] Yellow solid, melting point 201-202℃, yield 41%. 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s,1H), 8.27 (s, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.47(t, J = 7.7 Hz, 1H), 7.33 – 7.21 (m, 1H), 4.16 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 162.54, 155.64 (d, J = 22.1 Hz), 144.62, 141.13, 138.92 (d, J =23.7 Hz), 135.49, 127.13, 125.51, 123.08, 122.93, 121.75, 110.98, 36.49. HRMS(ESI) m / z: [M + H]⁺ calcd for C 15 H 10 F5N4O + 357.0769, found 357.0763.

[0237] Compound 81: 5-Bromo-N′-(4-Bromophenyl)-1H-Indazole-3-Formylhydrazide

[0238] Yellow solid, melting point 225-226℃, yield 52%. 1 H NMR (400 MHz, DMSO-d6) δ 13.97 (s,1H), 10.51 (s, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 162.13, 148.96, 139.76, 136.54, 131.41, 129.47,123.54, 115.03, 114.39, 113.07, 109.46, 103.49. HRMS (ESI) m / z: [M + H]⁺calcd for C 14 H 11 Br2N4O + 410.9283, found 410.9263.

[0239] Compound 82: 5-Bromo-N′-(3-Chlorophenyl)-1H-Indazole-3-Formylhydrazide

[0240] Yellow solid, melting point 215-216℃, yield 42%. 1H NMR (400 MHz, DMSO-d6) δ 13.94 (s,1H), 10.47 (d, J = 2.5 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J = 2.6 Hz, 1H), 7.66(d, J = 8.9 Hz, 1H), 7.55 (dd, J = 8.9, 1.9 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 162.00, 148.53,139.69, 136.47, 129.51, 128.55, 123.39, 121.76, 114.90, 113.74, 113.15. HRMS(ESI) m / z: [M + H]⁺ calcd for C 14 H 11 BrClN4O + 364.9799, found 364.9789.

[0241] Compound 83: 5-Bromo-N′-(3-Bromophenyl)-1H-Indazole-3-Formylhydrazide

[0242] Yellow solid, melting point 231-232℃, yield 56%. 1 H NMR (400 MHz, DMSO-d6) δ 13.96 (s,1H), 10.51 (d, J = 2.5 Hz, 1H), 8.26 (s, 2H), 7.66 (d, J = 8.9 Hz, 1H), 7.56(dd, J = 8.9, 1.9 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.90 (t, J = 2.1 Hz, 1H), 6.86 (dd, J = 7.7, 1.9 Hz, 1H), 6.77 (dd, J = 8.2, 2.2 Hz, 1H). 13C NMR(100 MHz, DMSO-d6) δ 162.13, 151.37, 139.83, 130.92, 129.70, 123.46, 123.44,122.21, 120.99, 115.11, 114.41, 113.29, 111.44, 108.93. HRMS (ESI) m / z: [M +H]⁺ calcd for C 14 H 11 Br2N4O + 410.9283, found 410.9271.

[0243] Compound 84: N′-(4-bromophenyl)-5-methyl-1H-indazole-3-formylhydrazide

[0244] Yellow solid, melting point 233-234℃, yield 46%. 1 H NMR (400 MHz, DMSO-d6) δ 13.62 (s,1H), 10.32 (s, 1H), 7.95 – 7.86 (m, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.31 –7.26 (m, 2H), 7.24 (dd, J = 8.7, 1.7 Hz, 1H), 6.75 (d, J = 8.9 Hz, 2H), 2.39(s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 162.77, 149.21, 139.87, 136.52, 131.63,131.54, 128.92, 122.39, 120.33, 114.47, 110.72, 109.45, 21.31. HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 14 BrN4O + 345.0345, found 345.0344.

[0245] Compound 85: N′-(4-bromophenyl)-6-chloro-1H-indazole-3-formylhydrazine

[0246] Yellow solid, melting point 228-229℃, yield 56%. 1H NMR (500 MHz, DMSO-d6) δ 10.45 (d, J= 2.0 Hz, 1H), 8.15 (d, J = 2.6 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.75 (d, J= 1.8 Hz, 1H), 7.34 – 7.23 (m, 3H), 6.73 (d, J = 8.9 Hz, 2H). 13 C NMR (125MHz, DMSO-d6) δ 161.98, 148.95, 141.30, 137.26, 131.76, 131.37, 123.13,122.86, 120.59, 114.23, 110.50, 109.22. HRMS (ESI) m / z: [M + H]⁺ calcd forC 14 H 11 BrClN4O + 365.9799, found 364.9792.

[0247] Example 3 Preparation of indazole-5-formylhydrazide compounds

[0248] The synthetic route for indazole-5-formylhydrazide compounds is as follows:

[0249]

[0250] R is selected from H, 4-F, 4-Cl, 4-Br, 4-CF3, 4-CF3O, 4-CN, 3-F, 3-Cl, 3-Br, 3-CF3O, 2-F, and 2-Cl.

[0251] The specific steps are as follows:

[0252] 1. Preparation of methyl 4-diazotetrafluoroborate-3-methylbenzoate (J): Methyl 4-amino-3-methylbenzoate (Maclean, CAS No.: 18595-14-7, I) (10 mmol) was added to an aqueous solution of tetrafluoroboric acid (40% by mass) under ice bath conditions and cooled to 0°C. Subsequently, an aqueous solution of sodium nitrite (2 mol / L, 10 mL) was added. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 15 minutes, resulting in a solid precipitate. After the reaction was completed, the solid was separated by filtration, washed with ice water, and dried to obtain a white solid, methyl 4-diazotetrafluoroborate-3-methylbenzoate (J).

[0253] 2. Preparation of methyl 5-indazolecarboxylate (K): At room temperature, methyl 4-diazotetrafluoroborate-3-methylbenzoate (J) (10 mmol), potassium acetate (25 mmol), and 18-crown-6 (Maclean, CAS No.: 17455-13-9, 1 mmol) were added to a three-necked flask containing 50 mL of chloroform. The reaction mixture was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was transferred to a mixed solvent of water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and then rinsed with anhydrous sodium sulfate. After concentrating the solvent, methyl 5-indazolecarboxylate (K) was obtained.

[0254] 3. Preparation of 5-Indazolecarboxylic Acid (L): At room temperature, methyl 5-indazolebenzoate (K) (10 mmol) was added to a three-necked flask containing 50 mL of methanol. Subsequently, an aqueous solution of sodium hydroxide (30 mmol) dissolved in 25 mL of water was added. The reaction mixture was heated to 40°C and reacted for 1 hour. After the reaction was complete, the methanol solvent was removed by vacuum distillation. The aqueous phase was extracted three times with ethyl acetate and then neutralized with 1 M hydrochloric acid solution to pH = 7, precipitating a yellow solid. The solid was separated by filtration and dried to obtain 5-indazolecarboxylic acid (L).

[0255] 4. Preparation of indazole-5-formylhydrazine derivatives: 1 mmol of 5-indazolecarboxylic acid (L) was weighed into a 50 mL round-bottom flask, and 1.2 mmol of substituted phenylhydrazine hydrochloride and 1.2 mmol of TBTU were added, along with 15 mL of acetonitrile as solvent. Subsequently, 0.5 mL of triethylamine was added as base, and the reaction was carried out at room temperature for 10 h. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the solvent was removed by rotary evaporation, and the target product was obtained by column chromatography. The substituent groups of each compound are shown in Table 3. The indazole-5-formylhydrazine compounds represented by Formula IV are shown in Table 3.

[0256] Table 3. Indazole-5-formylhydrazine compounds

[0257] The structural characterization data of the target compound, indazole carbamoyl hydrazide derivatives 86-98, are as follows:

[0258] Compound 86: N′-phenyl-1H-indazole-5-formylhydrazide

[0259] Yellow solid, melting point 193-194℃, yield 55%. 1H NMR (400 MHz, DMSO-d6) δ 13.37 (s,1H), 10.40 (d, J = 2.8 Hz, 1H), 8.46 (s, 1H), 8.26 (s, 1H), 7.93 (d, J = 7.3Hz, 2H), 7.64 (d, J = 8.7 Hz, 1H), 7.16 (t, J = 7.5 Hz, 2H), 6.84 (d, J = 7.8Hz, 2H), 6.72 (t, J = 7.1 Hz, 1H). 13 HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 13 N4O + 253.1084, found253.1084.

[0260] Compound 87: N′-(4-fluorophenyl)-1H-indazole-5-formylhydrazine

[0261] Yellow solid, melting point 210-211℃, yield 62%. 1 H NMR (400 MHz, DMSO-d6) δ 13.37 (s,1H), 10.41 (s, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 7.89 (dd, J = 8.8, 1.4 Hz,1H), 7.63 (d, J = 8.8 Hz, 1H), 7.00 (t, J = 8.8 Hz, 2H), 6.89 – 6.75 (m, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 167.14, 156.14 (d, J = 233.7 Hz), 146.39, 141.32,125.53, 125.45, 122.58, 121.16, 115.52, 115.31, 113.79 (d, J = 7.5 Hz),110.37. HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12FN4O⁺ 271.0990, found271.0987.

[0262] Compound 88: N′-(4-chlorophenyl)-1H-indazole-5-formylhydrazine

[0263] Yellow solid, melting point 227-228℃, yield 68%. 1 H NMR (400 MHz, DMSO-d6) δ 13.48 (s,1H), 10.46 (s, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.91 (d, J =8.7 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 8.3 Hz, 2H), 6.82 (d, J =8.4 Hz, 2H). 13 HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12 ClN4O + 287.0694, found 287.0693.

[0264] Compound 89: N′-(4-bromophenyl)-1H-indazole-5-formylhydrazine

[0265] Yellow solid, melting point 229-230℃, yield 59%. 1 H NMR (500 MHz, DMSO-d6) δ 10.41 (d, J= 2.5 Hz, 1H), 8.43 (d, J = 1.4 Hz, 1H), 8.24 (s, 1H), 8.14 (d, J = 2.6 Hz,1H), 7.89 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.31 (d, J = 8.7 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H). 13HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12 BrN4O + 331.0189, found331.0189.

[0266] Compound 90: N′-(4-trifluoromethylphenyl)-1H-indazole-5-formylhydrazide

[0267] Yellow solid, melting point 207-208℃, yield 55%. 1 H NMR (500 MHz, DMSO-d6) δ 10.50 (d, J= 2.3 Hz, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 7.91(dd, J = 8.7, 1.7 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 166.78, 152.90,141.17, 134.96, 126.27 (d, J = 3.5 Hz), 125.26, 125.06, 124.03, 122.42,121.09, 118.24 (q, J = 31.4 Hz), 111.64, 110.20. 19 F NMR (471 MHz, DMSO-d6) δ-59.14. HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 12 F3N4O + 321.0957, found 321.0956.

[0268] Compound 91: N′-(4-trifluoromethoxyphenyl)-1H-indazole-5-formylhydrazine:

[0269] Yellow solid, melting point 152-153℃, yield 65%.1 H NMR (400 MHz, DMSO-d6) δ 13.47 (s,1H), 10.49 (s, 1H), 8.46 (s, 1H), 8.22 (d, J = 14.4 Hz, 2H), 7.92 (d, J = 8.1Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.15 (d, J = 7.4 Hz, 2H), 6.87 (d, J = 7.8Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 167.34, 149.53, 141.60, 140.92, 135.49,125.73 (q, J = 4.6 Hz), 122.91, 122.53, 121.50, 120.85 (q, J = 252.3 Hz),113.48, 110.61, 100.69 (q, J = 625.4 Hz). HRMS (ESI) m / z: [M + H]⁺ calcd forC 15 H 12 F3N4O2 + 337.0906, found 337.0904.

[0270] Compound 92: N′-(4-cyanophenyl)-1H-indazole-5-formylhydrazide

[0271] Yellow solid, melting point 158-159℃, yield 56%. 1 H NMR (400 MHz, DMSO-d6) δ 13.38 (s,1H), 10.54 (s, 1H), 8.84 (s, 1H), 8.46 (s, 1H), 8.26 (s, 1H), 7.91 (dd, J =8.8, 1.6 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 6.87(d, J = 8.5 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 167.33, 153.66, 135.45,133.94, 125.73, 125.33, 122.84, 121.65, 120.60, 112.30, 110.64, 102.76,99.37. HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 12 N5O + 278.1036, found 278.1034.

[0272] Compound 93: N′-(3-fluorophenyl)-1H-indazole-5-formylhydrazide

[0273] White solid, melting point 208-209℃, yield 66%. 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s,1H), 8.48 (s, 1H), 8.27 (s, 1H), 7.94 (dd, J = 8.7, 1.6 Hz, 1H), 7.66 (d, J =8.8 Hz, 1H), 7.18 (q, J = 8.0 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.57 (dt, J= 11.6, 2.3 Hz, 1H), 6.50 (td, J = 8.5, 2.5 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 166.98, 164.54, 162.15, 152.08 (d, J = 10.3 Hz), 141.27, 135.02, 130.49(d, J = 9.9 Hz), 125.33 (d, J = 6.3 Hz), 122.52, 121.16, 110.28, 108.45,104.76 (d, J = 21.3 Hz), 98.90 (d, J = 25.4 Hz). HRMS (ESI) m / z: [M + H]⁺calcd for C 14 H 12 FN4O⁺ 271.0990, found 271.0987.

[0274] Compound 94: N′-(3-chlorophenyl)-1H-indazole-5-formylhydrazide

[0275] White solid, melting point 138-139℃, yield 71%. 1 H NMR (500 MHz, DMSO-d6) δ 10.42 (d, J= 2.6 Hz, 1H), 8.44 (d, J = 1.7 Hz, 1H), 8.26 (s, 1H), 8.24 (d, J = 2.8 Hz,1H), 7.90 (dd, J = 8.8, 1.7 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.17 (t, J =8.0 Hz, 1H), 6.81 – 6.71 (m, 3H). 13 C NMR (125 MHz, DMSO-d6) δ 166.78, 151.40,141.15, 134.98, 133.52, 130.50, 125.23, 125.12, 122.43, 121.04, 118.01,111.54, 110.98, 110.18. HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12 ClN4O + 287.0694, found 287.0693.

[0276] Compound 95: N′-(3-bromophenyl)-1H-indazole-5-formylhydrazine

[0277] Yellow solid, melting point 156-157℃, yield 62%. 1 H NMR (500 MHz, DMSO-d6) δ 10.43 (s,1H), 8.44 (s, 1H), 8.32 – 8.18 (m, 2H), 7.90 (d, J = 8.2 Hz, 1H), 7.64 (d, J= 7.6 Hz, 1H), 7.11 (td, J = 8.1, 2.6 Hz, 1H), 6.93 (s, 1H), 6.83 (dd, J =33.1, 8.0 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 166.79, 151.54, 141.15,135.04, 130.84, 125.24, 125.11, 122.44, 122.13, 121.05, 120.92, 114.44,111.35, 110.19. HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12 BrN4O + 331.0189, found 331.0188.

[0278] Compound 96: N′-(3-trifluoromethoxyphenyl)-1H-indazole-5-formylhydrazine

[0279] Yellow solid, melting point 154-153℃, yield 66%. 1 H NMR (400 MHz, DMSO-d6) δ 12.86 (s,1H), 10.72 (s, 1H), 8.65 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 168.26, 151.99, 137.79, 135.64, 133.83, 130.76, 124.79, 123.25,122.15 (q, J = 97.4 Hz), 120.98, 119.45, 113.37, 111.34. HRMS (ESI) m / z: [M +H]⁺ calcd for C 15 H 12 F3N4O2 + 337.0906, found 337.0903.

[0280] Compound 97: N′-(2-fluorophenyl)-1H-indazole-5-formylhydrazine

[0281] White solid, melting point 211-212℃, yield 78%. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s,1H), 8.25 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.83 (s, 1H), 7.64 (d, J = 8.7Hz, 1H), 7.16 – 7.06 (m, 2H), 6.99 (t, J = 7.7 Hz, 1H), 6.88 (t, J = 8.4 Hz, 1H), 6.73 (d, J = 6.4 Hz, 1H). 13 C NMR (125 MHz, DMSO-d6) δ 167.27 (d, J =118.8 Hz), 150.34 (d, J = 238.8 Hz), 141.41 (d, J = 63.4 Hz), 137.30 (d, J =10.5 Hz), 135.10 (d, J = 43.6 Hz), 126.64, 125.24 (d, J = 3.9 Hz), 124.62 (d, J = 2.7 Hz), 123.85, 122.84 (d, J = 54.1 Hz), 122.42, 121.04, 118.79 (d, J =6.6 Hz), 114.93 (d, J = 17.6 Hz), 113.76, 110.14 (d, J = 10.5 Hz). HRMS (ESI)m / z: [M + H]⁺ calcd for C 14 H 12 FN4O⁺ 271.0990, found 271.0987.

[0282] Compound 98: N′-(2-chlorophenyl)-1H-indazole-5-formylhydrazine

[0283] Yellow solid, melting point 201-202℃, yield 65%. 1H NMR (400 MHz, DMSO-d6) δ 13.49 (s,1H), 10.61 (s, 1H), 8.49 (s, 1H), 8.26 (s, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.62 (s, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.17 (t, J= 7.7 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H). 13 C NMR(100 MHz, DMSO-d6) δ 167.02, 145.20, 135.10, 129.37, 128.03, 125.45, 125.21,123.37, 122.55, 121.35, 119.89, 117.59, 113.31, 110.43. HRMS (ESI) m / z: [M +H]⁺ calcd for C 14 H 12 ClN4O + 287.0694, found 287.0694.

[0284] Example 4 Preparation of indazole-6-formylhydrazide compounds

[0285] The synthetic route for indazole-6-formylhydrazide compounds is as follows:

[0286]

[0287] R is selected from 4-F, 3-F, 2-F, 4-Cl, 3-Cl, 4-Br, 4-CF3, 4-CF3O, 3-Br, and 2-Cl.

[0288] The specific steps for preparing indazole-6-formylhydrazide compounds are as follows:

[0289] 1. Preparation of 3-diazotetrafluoroborate-4-methylbenzonitrile (N): 10 mmol of 3-amino-4-methylbenzonitrile (Maclean, CAS No.: 60710-80-7, M) was added to an aqueous solution of tetrafluoroboric acid (40% by mass) under ice bath conditions and cooled to 0°C. Subsequently, an aqueous solution of sodium nitrite (2 mol / L, 10 mL) was added. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 15 minutes, resulting in a solid precipitate. After the reaction was complete, the solid was separated by filtration, washed with ice water, and dried to obtain a white solid, 3-diazotetrafluoroborate-4-methylbenzonitrile (N).

[0290] 2. Preparation of 6-cyanoindazole (O): At room temperature, 10 mmol of 3-diazotetrafluoroborate-4-methylbenzonitrile (N), 25 mmol of potassium acetate, and 18-crown-6 (1 mmol) were added to a three-necked flask containing 50 mL of chloroform. The reaction mixture was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was transferred to a mixed solvent of water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and then rinsed with anhydrous sodium sulfate. After concentrating the solvent, 6-cyanoindazole (O) was obtained.

[0291] 3. Preparation of 6-Indazolecarboxylic Acid (P): At room temperature, 10 mmol of 6-cyanoindazole (O) was added to a three-necked flask containing 50 mL of ethanol. Subsequently, an aqueous solution of sodium hydroxide (40 mmol) dissolved in 25 mL of water was added. The reaction mixture was heated to 70°C and reacted for 1 hour. After the reaction was complete, the ethanol solvent was removed by vacuum distillation, and the mixture was neutralized with 1 M hydrochloric acid solution to pH = 7, precipitating a yellow solid. The solid was separated by filtration and dried to obtain 6-indazolecarboxylic acid (P).

[0292] 4. Preparation of indazole-6-carboxyhydrazide derivatives: 1 mmol of indazole-6-carboxylic acid (P) was weighed into a 50 mL round-bottom flask, and 1.2 mmol of substituted phenylhydrazine hydrochloride and 1.2 mmol of TBTU were added, along with 15 mL of acetonitrile as solvent. Subsequently, 0.5 mL of triethylamine was added as base, and the reaction was carried out at room temperature for 10 h. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the solvent was removed by rotary evaporation, and the target product was obtained by column chromatography. The substituent groups of each compound are shown in Table 4. The indazole-6-carboxyhydrazide compounds represented by Formula V are shown in Table 4.

[0293] Table 4 Indazole-6-formylhydrazide compounds

[0294]

[0295] The structural characterization data of the target compound, indazole carbamoyl hydrazide derivatives 99-109, are as follows:

[0296] Compound 99: N′-(4-fluorophenyl)-1H-indazole-6-formylhydrazine:

[0297] Yellow solid, melting point 209-210℃, yield 55%. 1 H NMR (400 MHz, DMSO-d6) δ 13.47 (s,1H), 10.56 (s, 1H), 8.18 (s, 2H), 7.98 (d, J = 2.5 Hz, 1H), 7.87 (d, J = 8.4Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.08 – 6.97 (m, 2H), 6.87 (d, J = 4.5 Hz, 1H), 6.85 (d, J = 4.8 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 167.00, 146.23,139.47, 133.78, 130.77, 124.68, 120.76, 119.38, 115.46, 115.24, 113.78,109.95. HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12 FN4O⁺ 271.0990, found271.0987.

[0298] Compound 100: N′-(4-chlorophenyl)-1H-indazole-6-formylhydrazide

[0299] White solid, melting point 207-208℃, yield 67%. 1 H NMR (400 MHz, DMSO-d6) δ 13.59 (s,1H), 10.61 (s, 1H), 8.19 (s, 3H), 7.87 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 7.9Hz, 1H), 7.20 (d, J = 7.9 Hz, 2H), 6.84 (d, J = 7.9 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 167.20, 148.70, 139.63, 133.80, 130.72, 128.80, 124.74, 122.23,120.95, 120.82, 119.44, 114.09. HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12 ClN4O + 287.0694, found 287.0696.

[0300] Compound 101: N′-(4-bromophenyl)-1H-indazole-6-formylhydrazide

[0301] White solid, melting point 210-211℃, yield 76%. 1 H NMR (400 MHz, DMSO-d6) δ 13.48 (s,1H), 10.58 (d, J = 2.2 Hz, 1H), 8.19 (s, 3H), 7.87 (d, J = 8.4 Hz, 1H), 7.69(d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.7 Hz, 2H), 6.86 – 6.78 (m, 2H). 13 C NMR(100 MHz, DMSO-d6) δ 167.23, 149.12, 139.67, 133.87, 131.69, 130.77, 124.82,121.01, 119.50, 114.65, 110.27, 109.87. HRMS (ESI) m / z: [M + H]⁺ calcd forC 14 H 12 BrN4O + 331.0189, found 331.0186.

[0302] Compound 102: N′-(4-trifluoromethylphenyl)-1H-indazole-6-formylhydrazide

[0303] White solid, melting point 200-201℃, yield 61%. 1H NMR (500 MHz, DMSO-d6) δ 10.61 (d, J= 2.1 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 19.3 Hz, 2H), 7.88 (d,J = 8.4 Hz, 1H), 7.65 (dd, J = 8.4, 1.4 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 167.29, 153.24, 139.82,134.21, 130.84, 126.82, 126.80, 125.14, 121.26, 119.75, 118.81 (q, J = 34.4),112.15, 110.41. HRMS (ESI) m / z: [M + H]⁺ calcd for C 15 H 12 F3N4O + 321.0957, found 321.0955.

[0304] Compound 103: N′-(4-trifluoromethoxyphenyl)-1H-indazole-6-formylhydrazine:

[0305] Yellow solid, yield 37%. 1 H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.17 (d, J= 7.5 Hz, 2H), 7.87 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.17 (d, J= 8.4 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.24,148.99, 140.79, 139.64, 133.83, 130.76, 124.79, 122.25, 121.33 (q, J = 97.4Hz), 120.98, 119.45, 113.27, 110.22. HRMS (ESI) m / z: [M + H]⁺ calcd forC 15 H 12 F3N4O2 +337.0906, found 337.0905.

[0306] Compound 104: N′-(4-cyanophenyl)-1H-indazole-6-formylhydrazide

[0307] Yellow solid, yield 57%. 1 H NMR (400 MHz, DMSO-d6) δ 13.53 (s, 1H), 10.69 (s,1H), 8.90 (s, 1H), 8.19 (s, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.5Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.16, 153.29, 139.59, 133.85, 133.72, 130.40, 124.85, 121.04,120.36, 119.47, 112.09, 110.35, 99.23. HRMS (ESI) m / z: [M + H]⁺ calcd forC 15 H 12 N5O + 278.1036, found 278.1058.

[0308] Compound 105: N′-(3-fluorophenyl)-1H-indazole-6-formylhydrazine:

[0309] Yellow solid, melting point 215-216℃, yield 61%. 1 H NMR (400 MHz, DMSO-d6) δ 13.45 (s,1H), 10.55 (d, J = 2.6 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 8.18 (d, J = 7.9Hz, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.18 (q, J = 8.0Hz, 1H), 6.66 (dd, J = 8.2, 2.1 Hz, 1H), 6.56 (dt, J = 11.7, 2.3 Hz, 1H), 6.51 (td, J = 8.5, 2.5 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 167.41, 164.87,152.21 (d, J = 10.1 Hz), 130.95, 130.86, 125.02, 121.23, 119.68, 110.43,108.81, 105.35, 105.14, 99.40, 99.14. HRMS (ESI) m / z: [M + H]⁺ calcd forC 14 H 12 FN4O⁺ 271.0990, found 271.0988.

[0310] Compound 106: N′-(3-chlorophenyl)-1H-indazole-6-formylhydrazide

[0311] Yellow solid, yield 67%. 1 H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 10.61 (s,1H), 8.31 (s, 1H), 8.18 (s, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.82 – 6.67 (m, 3H). 13 C NMR (125 MHz, DMSO-d6) δ 166.80, 151.24, 139.35, 133.71, 133.55, 130.55, 130.42, 124.61,120.77, 119.23, 118.11, 111.56, 111.00, 109.87. HRMS (ESI) m / z: [M + H]⁺calcd for C 14 H 12 ClN4O + 287.0694, found 287.0694.

[0312] Compound 107: N′-(3-bromophenyl)-1H-indazole-6-formylhydrazide

[0313] White solid, melting point 198-199℃, yield 59%. 1H NMR (400 MHz, DMSO-d6) δ 13.45 (s,1H), 10.56 (d, J = 2.6 Hz, 1H), 8.29 (d, J = 2.6 Hz, 1H), 8.18 (d, J = 9.0Hz, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 8.0Hz, 1H), 6.96 (t, J = 2.0 Hz, 1H), 6.88 (dd, J = 7.7, 1.9 Hz, 1H), 6.82 (dd,J = 8.1, 2.2 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 167.12, 151.46, 139.60,133.83, 131.05, 130.60, 124.79, 122.34, 121.28, 121.03, 119.40, 114.66,111.56, 110.18. HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12 BrN4O + 331.0189, found 331.0185.

[0314] Compound 108: N′-(2-fluorophenyl)-1H-indazole-6-formylhydrazine:

[0315] White solid, melting point 249-250℃, yield 58%. 1 H NMR (400 MHz, DMSO-d6) δ 13.44 (s,1H), 10.56 (d, J = 2.6 Hz, 1H), 8.17 (d, J = 11.0 Hz, 2H), 7.91 – 7.84 (m,2H), 7.66 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 12.1, 8.1 Hz, 1H), 7.00 (t, J =7.7 Hz, 1H), 6.88 (t, J = 8.4 Hz, 1H), 6.74 (q, J = 7.0 Hz, 1H). 13C NMR (100MHz, DMSO-d6) δ 167.05, 151.67, 149.30, 137.21 (d, J = 10.7 Hz), 130.66,124.77 (d, J = 2.9 Hz), 124.71, 120.90, 119.37, 119.09 (d, J = 6.2 Hz), 115.10 (d, J = 17.5 Hz), 113.89, 110.11. 19 F NMR (376 MHz, DMSO-d6) δ -133.06.HRMS (ESI) m / z: [M + H]⁺ calcd for C 14 H 12 FN4O⁺ 271.0990, found 271.0989.

[0316] Compound 109: N′-(2-chlorophenyl)-1H-indazole-6-formylhydrazide

[0317] White solid, melting point 245-246℃, yield 56%. 1 H NMR (400 MHz, DMSO-d6) δ 13.49 (s,1H), 10.69 (s, 1H), 8.21 (d, J = 5.6 Hz, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.71(d, J = 6.8 Hz, 2H), 7.32 (dd, J = 7.9, 1.4 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.77 (td, J = 7.6, 1.5 Hz, 1H). 13 C NMR (100MHz, DMSO-d6) δ 167.23, 145.12, 139.70, 133.99, 130.69, 129.52, 128.14,124.90, 121.11, 120.09, 119.55, 117.78, 113.35, 110.36. HRMS (ESI) m / z: [M +H]⁺ calcd for C 14 H 12 ClN4O + 287.0694, found 287.0694.

[0318] Example 5: Detection of the bactericidal activity of the target compound

[0319] This invention uses seven common pathogenic fungi affecting agricultural plants—*Botrytis cinerea* (strawberry), *Alternaria solani* (tomato early blight), *Rhizoctonia solani* (rice sheath blight), *Fusarium graminearum* (wheat scab), *Colletotrichum orbiculare* (cucumber anthracnose), *Valsamali* (apple rot), *Fusarium oxysporum* f. sp. lycopersici (tomato wilt), and *Magnaporthe oryzae* (rice blast fungus)—as experimental subjects. The mycelial growth rate method was used to preliminarily screen the fungicidal activity of the target compounds. Commonly used commercially available fungicides for controlling the corresponding crop diseases—carbendazim, cyazofamid, tebuconazole, and isoprothiolane—were selected as control agents.

[0320] The equipment used in the experiment included: petri dishes (Haimen Chuangxin Consumables Co., Ltd.), autoclave (TOMY SX-700), electric thermostatic biochemical incubator (Shanghai Jinghong Experimental Equipment Co., Ltd.), Eppendorf pipettes, double-sided clean bench for two people (Suzhou Purification Equipment Co., Ltd.), hole punch, alcohol lamp, etc.

[0321] Experimental methods:

[0322] (a) The mycelial growth rate method was used to preliminarily screen the antifungal activity of 111 target compounds.

[0323] Preparation of Potato Dextrose Agar (PDA) medium: Take 200 g of potatoes, peel and slice them, and boil them in 1000 mL of water for about 30 minutes, until the potatoes are soft but not mushy. Then, filter through two layers of gauze, pour the liquid into a graduated cylinder, remove the residue, and add water to 1000 mL. Add 18 g of agar to the filtrate, boil until completely dissolved, then add 20 g of glucose and stir well. Dispense into Erlenmeyer flasks and autoclave at 121°C for 21 minutes.

[0324] Preparation of drug-containing culture medium: Accurately weigh 25 mg of the test compounds (including 111 target compounds, commercially available drugs such as carbendazim (purchased from Maclean's, CAS No.: 10605-21-7), boscalid (purchased from Maclean's, CAS No.: 188425-85-6), cyazofamid (purchased from Maclean's, CAS No.: 39491-78-6), tebuconazole (purchased from Maclean's, CAS No.: 107534-96-3), and isoprothiolane (purchased from Sangon Biotech, CAS No.: 50512-35-1)), dissolve them in 1 mL of DMSO to prepare a drug solution with a concentration of 25 mg / mL. Take 0.1 mL of the drug solution and add it to 50 mL of sterile PDA medium (DMSO final concentration approximately 0.2%), shake thoroughly to prepare a drug-containing culture medium with a concentration of 20 μg / mL. Distribute it evenly into three sterile petri dishes with a diameter of 9 cm. The control group used a culture medium prepared with an equal volume of DMSO (0.1 mL).

[0325] EC 50 Toxicity assay: Based on the initial screening activity test data, a concentration gradient was set, and 10 mg of the test compound was weighed, dissolved in DMSO, and then diluted 2 / 3 times to obtain 5 concentrations (10 μg / mL, 5 μg / mL, 2.5 μg / mL, 1.25 μg / mL, and 0.625 μg / mL). Drug-containing culture media were prepared, and after inoculation and culture, the inhibition rate at each concentration was calculated. The linear equation and EC50 were obtained using the statistical software DPS. 50 Values ​​and confidence intervals.

[0326] Inoculation and activity assay: Preserved strains included: *Botrytis cinerea* (strawberry gray mold), *Alternaria solani* (tomato early blight), *Rhizoctonia solani* (rice sheath blight), *Fusarium graminearum* (wheat scab), *Colletotrichum orbiculare* (cucumber anthracnose), *Valsa mali* (apple rot), *Fusarium oxysporum f. sp. lycopersici* (tomato wilt), and *Magnaporthe oryzae* (rice blast fungus) (gifted by the College of Plant Protection, Nanjing Agricultural University, *Discovery of novel 3-phenylhydrazone coumarin derivatives as potential antifungal agents against phytopathogenic fungi*, *Food Chemistry 486 (2025) 144655*). After being removed from the 4°C freezer, each strain needed to be activated twice consecutively in fresh, sterile PDA medium before use. Use a punch (0.5 cm inner diameter) to make holes at the edge of normally growing colonies to prepare mycelial cakes, and use an inoculation needle to inoculate the mycelial cakes into the center of a drug-containing culture medium plate or a blank culture medium plate (mycelia facing up).

[0327] The culture was incubated at 25°C. When the colonies on the blank culture medium grew to approximately 2 / 3 of the plate diameter (i.e., a colony diameter of 6.5 cm), their diameter was measured. The diameter of each colony was measured twice using the cross-sectional method, and the average value was taken (unit: cm). Each treatment was performed in triplicate.

[0328] The growth inhibition rate after drug treatment is calculated using the following formula:

[0329] Inhibition rate (%) = (Coronavirus diameter in the control group - Coronavirus diameter in the treated group) / (Coronavirus diameter in the control group - 0.5) × 100%

[0330] Table 5. Preliminary screening results of antifungal activity of indazole-1-acetylhydrazine derivatives (compounds 1-51) [Inhibition rate η (%)] (test concentration 20 μg / mL)

[0331] Table 6. Preliminary screening results of antifungal activity of indazole carbamoyl hydrazide derivatives (compounds 52-109) [inhibition rate η (%)] (test concentration 20 μg / mL)

[0332] Table 7. EC50 of some indazole-1-acetylhydrazine derivatives against tested fungi 50 (μg / mL) Results

[0333] Table 8. EC50 of some indazole carbamoyl hydrazide derivatives against tested fungi 50 (μg / mL) Results

[0334] Tables 5-8 show the test results for common agricultural fungi, from which the following conclusions can be drawn:

[0335] 1. Indazole hydrazide compounds exhibit varying degrees of antifungal activity against a variety of common agricultural pathogenic fungi, with some compounds achieving 100% inhibition rates against specific pathogenic fungi. Furthermore, compared to commercially available pesticides such as carbendazim, cyproconazole, tebuconazole, and isoprothiolane, some compounds show significantly higher inhibitory activity against certain plant pathogenic fungi.

[0336] 2. The in vitro antibacterial activity of compounds 1–109 was determined using the mycelial growth rate method. The results showed that these compounds exhibited significant inhibitory activity against *Rhizoctonia solani*, *Sclerotinia serratifolia*, *Early blight*, *Anthracnose*, *Blastophytes oryzae*, *Fusarium wilt*, and *Botrytis cinerea*. Among them, most compounds showed an inhibition rate exceeding 80% against *Rhizoctonia solani* at a concentration of 20 μg / mL.

[0337] 3. From the analysis of the overall structure and activity relationship, when a halogen substituent is introduced onto the benzene ring of the hydrazine group, the compound exhibits superior antifungal activity against rice sheath blight, apple spot disease, tomato early blight, cucumber anthracnose, rice blast, tomato wilt, and strawberry gray mold, indicating that halogen substitution is beneficial to improving the antifungal properties of this type of compound.

[0338] 4. Comparative analysis of the antibacterial activity results of compounds shown in Formulas II, III, IV and V revealed that indazole acetylhydrazine compounds exhibited superior inhibitory activity against rice sheath blight pathogens; indazole carbamoylhydrazine compounds showed better inhibitory effects against wheat scab pathogens than indazole acetylhydrazine compounds; in addition, 3-indazole carbamoylhydrazine compounds showed a broader spectrum of antibacterial activity overall.

[0339] Overall, hydrazide compounds synthesized with indazole as the lead molecule exhibit excellent activity against plant pathogenic microorganisms, with broad-spectrum and highly effective control effects, and can be widely used in the prevention and control of plant diseases.

[0340] Example 6: In vivo antifungal activity of the target compound

[0341] To verify the efficacy of this invention in controlling plant pathogenic fungi, a field wheat variety (Fielder) in the heading and flowering stage was selected for in vivo efficacy evaluation. The formulation method was as follows: compounds 57, 70, and 79, along with the control agent 98% cyazofamid technical, were dissolved separately in a small amount of dimethyl sulfoxide (DMSO), and then diluted with an aqueous solution containing 0.1% Tween-80 to prepare a 100 μg / mL solution; simultaneously, a blank control (CK) was prepared using water containing an equal volume of solvent.

[0342] Preparation of spore suspension: *Fusarium graminearum*, the causal agent of wheat scab, was inoculated into mung bean soup medium and cultured with shaking at 25°C and 150 rpm for 3-5 days. After filtration through double-layer gauze, the conidial concentration was adjusted to 1×10⁻⁶ using sterile water. 5 The experiment used the single-flower drip inoculation method, with each treatment repeated 3-5 times, and 10-15 ears of wheat treated each time. In the protective effect experiment, the agent was sprayed evenly on the surface of the wheat ears at the early flowering stage. After the agent was allowed to air dry naturally for 24 hours, 10 μL of 1×10⁻⁶ solution was dripped into the florets in the middle of the wheat ears. 5 10 μL of 1×10⁶ spores / mL suspension was used as a single-flower inoculation method in the therapeutic experiment. 5 A spore suspension of 1 spore / mL was prepared and induced to cause infection for 24 hours under a high humidity environment (relative humidity greater than 95%) before being evenly sprayed with the agent. After inoculation, the spores were kept moist in a transparent plastic bag for 48 hours, and then cultured in a greenhouse at 25°C using standard methods. 7-14 days after inoculation, once the blank control group had fully developed disease, the disease incidence on the entire spike of florets was observed and recorded, and the final control efficacy for each group was calculated.

[0343] Table 9. In vivo control efficacy of compounds 57, 70, and 79 at 100 μg / mL against Fusarium graminearum, the causal agent of wheat blight.

[0344] To verify the efficacy of compounds 57, 70, and 79 in wheat plants, the commercially available fungicide cyazofamid was used as a positive control. At a concentration of 100 μg / mL, compound 70 showed a protective effect of 76% against Fusarium wilt of wheat, comparable to cyazofamid (76%), while compound 70 showed a curative effect of 50% against Fusarium wilt of wheat, superior to cyazofamid (44%).

Claims

1. An indolehydrazine compound, characterized in that, The structural formula of the indolehydrazine compound is shown in Formula I: in, Selected from , , or R1 is selected from 3-Br, 5-Br, 5-Cl, 5-CH3, 6-Cl, 6-Br, 1-CH3, or 6-NO2; R is selected from H, 4-F, 3-F, 2-F, 4-Cl, 3-Cl, 2-Cl, 4-Br, 3-Br, 2-Br, 4-Me, 4-CF3, 2-CF3, 4-CF3O, 3-CF3O, 4-CH3O, 2-CH3O, 4-CN, 4-BnO, 2,4-di-F, 2,5-di-F, 3,4-di-F, 3 The R1 is selected from one or more of 5-di-Cl, 2,4,6-tri-Cl, 1,2,3,4,5-F, and 3-Cl-4-F; preferably, the R1 is selected from 3-Br, 5-Br, 5-Cl, and 6-Br; preferably, the R is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 4-Br, 4-CF3, 2,4-di-F, 2,5-di-F, 3,4-di-F, or 2,4,6-tri-Cl.

2. The indolehydrazine compound according to claim 1, characterized in that, The structure of the compound is shown in Formula II: Wherein, R1 is selected from 3-Br, 5-Br, 5-Cl, 6-Br or 6-NO2; R is selected from one or more of H, 4-F, 3-F, 2-F, 4-Cl, 3-Cl, 4-Br, 4-Me, 4-CF3, 2-CF3, 4-CF3O, 3-CF3O, 4-CH3O, 2-CH3O, 2,4-di-F, 2,5-di-F, 3,5-di-Cl, 3-Cl-4-F. Preferably, R is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 4-Br, 4-CF3, 2,4-di-F, 2,5-di-F.

3. The indolehydrazine compound according to claim 1, characterized in that, The structure of the compound is shown in Formula III: Wherein, R1 is selected from 1-CH3, 5-Br, 6-CH3, 6-Cl; R is selected from H, 4-F, 3-F, 2-F, 4-Cl, 3-Cl, 2-Cl, 4-Br, 3-Br, 2-Br, 4-Me, 4-CF3, 2-CF3, 4-CF3O, 3-CF3O, 4-CH3O, 2-CH3O, 4-CN, 4-BnO, 2,4-di-F, 2,5-di-F, 3,4-di-F, 3,5 -di-Cl, 2,4,6-tri-Cl, 1,2,3,4,5-F, 3-Cl-4-F or more thereof; preferably, R1 is selected from H, 1-CH3, 5-Br, 6-Cl; preferably, R is selected from 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 4-Br, 4-CF3, 2,4-di-F, 2,5-di-F or 3,4-di-F or more thereof.

4. The indolehydrazine compound according to claim 1, characterized in that, The structure of the compound is shown in Formula IV: R is selected from one or more of H, 4-F, 4-Cl, 4-Br, 4-CF3, 3-F, 4-CF3O, 4-CN, 3-Cl, 3-Br, 3-CF3O, 2-F, and 2-Cl; preferably, R is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 4-Br, or 4-CF3.

5. The indolehydrazine compound according to claim 1, characterized in that, The structure of the compound is shown in Formula V: R is selected from one or more of 4-F, 4-Cl, 4-Br, 4-CF3, 3-F, 4-CF3O, 3-Cl, 3-Br, 2-F, and 2-Cl; preferably, R is selected from one or more of 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, or 4-Br.

6. The method for preparing the indolehydrazine compound according to claim 2, characterized in that, Includes the following steps: (1) Using o-methylaniline as raw material, acetic anhydride, potassium acetate, isoamyl nitrite, sodium hydroxide solution and tetrapropylammonium hydroxide were added in sequence to prepare substituted indazole; (2) The intermediate N-ethyl acetate indazole derivative was prepared by reacting substituted indazole with ethyl bromoacetate. (3) Add potassium hydroxide solution to N-ethyl acetate indazole derivative, dissolve and stir, then heat and stir to prepare intermediate 1-N-ethyl acetate indazole derivative; (4) The 1-N-acetic acid indazole derivative and the substituted phenylhydrazine were dissolved in acetonitrile solution, and then O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid was added. Triethylamine was then added dropwise. The reaction was stirred at room temperature and the reaction progress was monitored by TLC to prepare a series of target compounds indazole-1-acetylhydrazine.

7. The method for preparing the indolehydrazine compound according to claim 3, characterized in that, Includes the following steps: (1) Using substituted o-aminophenylacetic acid methyl ester as raw material, glacial acetic acid and tert-butyl nitrite were added to acetonitrile solvent and stirred at room temperature to prepare 1H-indazole-3-carboxylic acid methyl ester derivative. (2) The methyl ester derivative of 1H-indazole-3-carboxylic acid was placed in an aqueous sodium hydroxide solution and stirred at room temperature to completely hydrolyze it. Then, the pH of the system was adjusted to weak acidity with dilute hydrochloric acid to precipitate the product. After filtration, washing and drying, the 1H-indazole-3-carboxylic acid derivative was obtained. (3) Dissolve the 1H-indazole-3-carboxylic acid derivative and the substituted phenylhydrazine hydrochloride in acetonitrile, add TBTU, and then add triethylamine as a base, and stir the reaction at room temperature.

8. The method for preparing the indolehydrazine compound according to claim 4, characterized in that, Includes the following steps: (1) Using methyl 4-amino-3-methylbenzoate as raw material, add tetrafluoroboric acid aqueous solution, then add sodium nitrite aqueous solution, and stir the reaction at room temperature to obtain methyl 4-diazotetrafluoroborate-3-methylbenzoate; (2) 4-diazotetrafluoroborate-3-methylbenzoate methyl ester, potassium acetate and 18-crown-6 were added to chloroform solvent. After the reaction was completed, the reaction solution was introduced into a mixed solvent of water and ethyl acetate for extraction. The organic phases were combined, washed with saturated brine, dried and concentrated by rotary evaporation to obtain 5-indazolecarboxylate methyl ester. (3) Mix methyl 5-indazole carboxylate with sodium hydroxide solution, heat the reaction solution to 40-50°C and stir for 1-2 hours. After the reaction is completed, remove the methanol solvent by vacuum distillation, extract the aqueous phase three times with ethyl acetate, and then adjust the pH to 7 with hydrochloric acid solution to precipitate a yellow solid. 5-indazole carboxylic acid is obtained by filtration and drying. (4) 5-Indazole carboxylic acid, substituted phenylhydrazine hydrochloride, TBTU and triethylamine were dissolved in acetonitrile and reacted at room temperature. After the reaction was completed, the solvent was removed by rotary evaporation and the indazole-5-carboxyhydrazine derivative was obtained by column chromatography.

9. The method for preparing the indolehydrazine compound according to claim 5, characterized in that, Includes the following steps: (1) Using methyl 4-amino-3-methylbenzoate as raw material, add tetrafluoroboric acid aqueous solution, then add sodium nitrite aqueous solution, and stir the reaction at room temperature to obtain 3-diazotetrafluoroborate-4-methylbenzonitrile; (2) 3-diazotetrafluoroborate-4-methylbenzonitrile, potassium acetate, and 18-crown-6 were added to chloroform solvent and stirred at room temperature. After the reaction was completed, the reaction solution was extracted in a mixed solvent of water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and the solvent was concentrated by rotary evaporation to obtain 6-cyanoinazole; (3) Mix 6-cyanoindazole with sodium hydroxide solution, heat the reaction solution to 70-75°C and stir for 1-2 hours. After the reaction is completed, remove the ethanol solvent by vacuum distillation, and then adjust the pH to 7 with hydrochloric acid solution to precipitate a yellow solid. 6-indazole carboxylic acid is obtained by filtration and drying. (4) 6-Indazole carboxylic acid, substituted phenylhydrazine hydrochloride, TBTU and triethylamine were dissolved in acetonitrile and reacted at room temperature. After the reaction was completed, the solvent was removed by rotary evaporation and the indazole-6-carboxyhydrazide derivative was obtained by column chromatography.

10. The use of the indolehydrazine compound according to any one of claims 1 to 5 in the preparation of products that inhibit or kill pathogens, wherein, preferably, the pathogens include crop pathogenic fungi, and preferably, the crop pathogenic fungi include one or more of the following: *Botrytis cinerea* (strawberry gray mold), *Alternaria solani* (tomato early blight), *Rhizoctonia solani* (rice sheath blight), *Fusarium graminearum* (wheat scab), *Colletotrichum orbiculare* (cucumber anthracnose), *Valsa mali* (apple rot), *Fusarium oxysporum f. sp. lycopersici* (tomato wilt), and *Magnaporthe oryzae* (rice blast fungus).

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