5-(1H-indol-6-yl)-1, 3, 4-oxadiazole-2-formylhydrazine derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of preparation of medical compounds, and particularly relates to a 5-(1H-indol-6-yl)-1, 3, 4-oxadiazole-2-formylhydrazine derivative as well as a preparation method and application thereof. The 5-(1H-indol-6-yl)-1, 3, 4-oxadiazole-2-formylhydrazine with a new structure is designed and synthesized by taking a quinoline compound and a hydrazide compound as a research basis and utilizing a molecular heterozygosis method and a bioisostere design thought, the derivative is low in reaction cost and high in yield, the reaction process is simple and easy to control, and the method is suitable for industrial production. And the derivatives have certain anti-prostatic cancer activity, and can be used for preparing anti-prostatic cancer drugs and researching the structure-function relationship of the compounds.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical compound preparation technology, specifically relating to a 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylhydrazine derivative, its preparation method, and its uses. Background Technology

[0002] Prostate cancer is one of the most common malignant tumors in men, with high incidence and mortality rates. In recent years, the number of prostate cancer cases has been steadily increasing, making it a significant type of common male malignant tumor. Prostate cancer typically has an insidious onset, with atypical early symptoms, and middle-aged and elderly men are the primary susceptible population. Current clinical treatments mainly involve surgery, radiotherapy, and endocrine therapy. However, the proportion of patients who can undergo radical surgery is limited, and androgen deprivation therapy eventually leads to drug resistance in most patients, progressing to castration-resistant prostate cancer. Traditional chemotherapy drugs also suffer from insufficient selectivity, high toxicity, and a tendency to induce drug resistance, limiting further improvements in treatment efficacy.

[0003] Nur77 is a product of the immediate early gene and can be induced by various stimuli, including growth factors, cellular stress, radiotherapy, chemotherapy, and pro-apoptotic drugs. Studies have shown that Nur77 expression is low in normal tissues but high in various solid tumors, including prostate cancer. Its expression level is closely related to the occurrence, progression, and treatment response of prostate cancer. Existing literature indicates that pyrimidine indole derivatives exert anti-tumor effects by regulating the expression or function of Nur77, thereby blocking tumor cell proliferation and inducing apoptosis. This suggests that Nur77 has potential important drug target value in prostate cancer. However, there are currently few drugs targeting Nur77 regulation, therefore, there is an urgent need to develop more safe, effective, and well-targeted prostate cancer treatment strategies and drugs to improve patient prognosis and survival rates. Summary of the Invention

[0004] To address the aforementioned problems, this invention provides a 5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-formylhydrazine derivative, its preparation method, and its uses. This invention employs molecular hybridization technology to splice together pharmacophore groups from different bioactive molecules, producing hybrid molecules with potentially high activity, low toxicity, and multiple mechanisms of action.

[0005] To achieve the above objectives, the technical solution of the present invention is as follows.

[0006] A 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carbamoylhydrazine derivative, characterized in that it has the structural formula shown in formula (1); Equation (1); R is any one of the following: 3-chlorobenzaldehyde substituent, 4-chlorobenzaldehyde substituent, and 4-fluorobenzaldehyde substituent.

[0007] A second aspect of the present invention provides a method for preparing the aforementioned 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-formylhydrazine derivative, comprising the following steps: Methyl indole-6-carboxylate was reacted with hydrazine hydrate in methanol at a mass ratio of 1:10~15 at 63℃~65℃, and purified to obtain 1-indole-6-carboxyhydrazide. 1-Indole-6-carboxylhydrazide, tetrahydrofuran, and oxaloyl chloride monoethyl ester were condensed in an alkaline environment at a mass ratio of 1:1.5~3:1.2~2 in an ice bath at 0~4℃, and purified to obtain ethyl 2-(2-(indole-6-carbonyl)hydrazino)-2-oxoacetic acid ester. Ethyl 2-(2-(1H-indole-6-carbonyl)hydrazino)-2-oxoacetate and p-toluenesulfonyl chloride were mixed in a mass ratio of 1:3 to 4 and mixed in an ice bath at 0°C to 4°C. The mixture was then reacted with a catalyst under an organic environment to obtain ethyl 5-(1H-indole-6-yl)-1,3,4-oxadiazole-2-carboxylic acid ester. Ethyl 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylic acid ester was reacted with hydrazine hydrate in an alcoholic environment at a mass ratio of 1:10~15 at 60℃~65℃ to give 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxyhydrazine. 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxyhydrazine was mixed with substituted benzaldehyde in a mass ratio of 1:1.2~2 and refluxed in an organic reagent with added catalyst to obtain a 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxyhydrazine derivative.

[0008] In another preferred embodiment, the purification process during the preparation of 1-indole-6-formylhydrazide is as follows: Filter to collect the precipitate, wash with water, dry, and recrystallize.

[0009] In another preferred embodiment, in the preparation of the ethyl 2-(2-(indole-6-carbonyl)hydrazino)-2-oxoacetic acid ester, the base is triethylamine; The purification was performed by column chromatography.

[0010] In another preferred embodiment, during the preparation of the ethyl 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylic acid ester, the reagents used in the organic environment are tetrahydrofuran and triethylamine; the catalyst is 4-dimethylaminopyridine (DMAP); and the mass ratio of 4-dimethylaminopyridine to p-toluene-5-ylsulfonyl chloride is 0.3~0.5:1.

[0011] In another preferred embodiment, in the preparation of the 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxyhydrazine derivative, the organic reagent is methanol, the catalyst is 4-dimethylaminopyridine, and the mass ratio of 4-dimethylaminopyridine to substituted benzaldehyde is equal.

[0012] A third aspect of the present invention provides the use of the 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylhydrazine derivative in the preparation of an anti-prostate cancer drug, characterized in that the concentration of the 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylhydrazine derivative in the drug is 0.78125M to 50M.

[0013] The fourth aspect of the present invention provides the use of the 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylhydrazine derivative in the preparation of Nur77 inhibitor, characterized in that the concentration of the 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylhydrazine derivative in the inhibitor is 0.75M to 3M.

[0014] Compared with the prior art, the present invention has the following beneficial effects.

[0015] This invention utilizes molecular hybridization methods and bioisosteric design to design and synthesize a class of novel 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-formylhydrazides. These derivatives exhibit low reaction cost, high yield, and a simple and easily controllable reaction process, making them suitable for industrial production. Furthermore, these derivatives possess anti-prostate cancer activity and can be used to prepare anti-prostate cancer drugs and study the structure-activity relationship of these compounds. The 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-formylhydrazide derivatives of this invention show excellent inhibitory effects on prostate cancer cells PC-3 and C4-2B, significantly inducing apoptosis in prostate cancer cells, while exhibiting relatively low toxicity to normal prostate epithelial cells. Moreover, the 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-formylhydrazide derivatives of this invention can downregulate the protein expression of Nur77.

[0016] The 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylhydrazine derivative of this invention exhibited low toxicity to normal human prostate epithelial cells RWPE-1 in in vitro toxicity evaluations, and the survival rate of RWPE-1 cells was significantly higher than that of prostate cancer cells PC-3 and C4-2B, indicating its good safety profile. Furthermore, the 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylhydrazine derivative, at a concentration of 1.5 M, significantly induced apoptosis in prostate cancer cells, demonstrating its highly effective anti-prostate cancer activity. Attached Figure Description

[0017] Figure 1 The figure shows the results of the analysis of the effect of YY-6 on PC-3 cells. Annexin V-FITC is a fluorescent labeling reagent used to detect cell apoptosis, and Propidium iodide represents propidium iodide.

[0018] Figure 2 The figure shows the results of the analysis of the regulatory effect of YY-6 on Nur77 expression; in the figure, DMSO represents dimethyl sulfoxide and serves as the control group.

[0019] Figure 3 The figure shows the effect of Nur77 overexpression on the effect of YY-6; in the figure, Nur77-OE represents Nur77 overexpression and YY-6-Nur77-OE represents Nur77-OE overexpression after adding YY-6. Detailed Implementation

[0020] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Furthermore, the technical features involved in the various embodiments of this invention described below can be combined with each other as long as they do not conflict with each other.

[0021] Quinoline compounds are a class of nitrogen-containing heterocyclic compounds with broad physiological activities, widely used in the pharmaceutical field, exhibiting various effects including bactericidal, antitumor, antiviral, anti-inflammatory, and immune-enhancing properties. Acylhydrazine compounds possess broad biological activities, including antiviral, antitumor, and anti-inflammatory effects.

[0022] Based on this, this invention utilizes molecular hybridization methods and bioisosteric design to design and synthesize a class of novel 5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-carboxylhydrazides. These derivatives have low reaction costs, high yields, and simple and easy-to-control reaction processes, making them suitable for industrial production. Furthermore, these derivatives exhibit certain anti-prostate cancer activity and can be used to prepare anti-prostate cancer drugs and study the structure-activity relationship of these compounds.

[0023] The following is a detailed description of a 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylhydrazine derivative, its preparation method, and its uses.

[0024] Example 1: Synthesis of intermediate 1-indole-6-carboxamide (2).

[0025] Take a clean and dried round-bottom flask, add 1.7 mmol, 0.3 g of methyl indole-6-carboxylate, and 3.5 mL of methanol. Stir at 65 °C until the solid is completely dissolved. Add 17 mmol and 824 μL of hydrazine hydrate dropwise. React for 4 h. The reaction is stopped when the endpoint is reached by TLC. After filtration, washing with water, drying, and recrystallization, 0.2572 g of the gray-brown product 1-indole-6-carboxamide is obtained, with a yield of 82.35%.

[0026] 1 H NMR (600MHz, DMSO-d6): 11.40(brs,1H), 9.68(s,1H), 7.95(s,1H), 7.59-7.54(m,1H), 7.54-7.47(m,2H), 6.48(brs.,1H), 4.48(brs,2H).

[0027] 13 C NMR (150MHz, DMSO-d6): 167.6, 135.7, 130.2, 128.3, 126.5, 119.9, 118.1, 111.4, 101.7, ESI-HRMS (+): m / zcalcd for C9H9N3O[M+H]+176.0824 found 176.0812.

[0028] Example 2: Synthesis of intermediate ethyl 2-(2-(1H-indole-6-carbonyl)hydrazino)-2-oxoacetate (3).

[0029] Take a clean and dried round-bottom flask, add 5.7 mmol and 1 g of 1-indole-5-carboxamide under ice bath conditions, add 25 mL of tetrahydrofuran, and dropwise add 8.55 mmol and 1.19 mL of triethylamine. Stir until the solid is completely dissolved, then dropwise add 6.84 mmol and 76 μL of oxaloyl chloride monoethyl ester. Stir at room temperature (23 °C) for 1 h. Detect the reaction at the endpoint by TLC, stop the reaction, extract with water-ethyl acetate, and then purify by column chromatography using ethyl acetate and petroleum ether in a volume ratio of 3:1 to obtain 0.8345 g of the white product ethyl 2-(2-(1H-indole-6-carbonyl)hydrazino)-2-oxoacetic acid ester, yield: 53.23%.

[0030] 1 H NMR(600MHz ,DMSO-d6): 11.48(brs,1H), 10.87(s,1H), 10.46(s,1H), 8.02(s,1H), 7.63(d,J=8.4H z,1H), 7.58-7.54(m,2H), 6.52(brs,1H), 4.32(q,J=7.0Hz,2H), 1.32(t,J=7.2Hz,3H).

[0031] 13 C NMR (150MHz, DMSO-d6): 166.8, 160.5, 157.1, 135.6, 130.9, 129.0, 125.2, 120.2, 118.5, 112.1, 101.9, 62.8, 14.3.

[0032] ESI-HRMS(+): m / z calcd for C 13 H 13 N3O4[M+H]+276.0984 found 276.0991.

[0033] Example 3: Synthesis of intermediate ethyl 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylic acid ester (4).

[0034] Take a clean and dried round-bottom flask, add 1.8 mmol and 0.4 g of ethyl 2-(2-(1H-indole-6-carbonyl)hydrazino)-2-oxoacetate, 25 mL of tetrahydrofuran, 0.54 mmol and 0.065 g of 4-dimethylaminopyridine, and dropwise add 5.4 mmol and 749 μL of triethylamine and 5.4 mmol and 1.0 g of p-toluenesulfonyl chloride. Stir until the solid is completely dissolved, heat to 65 °C and react for 3 h. Detect the reaction endpoint by TLC, stop the reaction, extract with water-ethyl acetate, and purify by column chromatography using petroleum ether-ethyl acetate (4:1 v / v) to obtain 0.2517 g of the purple-red product ethyl 5-(1H-indole-6-yl)-1,3,4-oxadiazole-2-carboxylic acid ester, yield: 65.58%.

[0035] 1 H NMR (600MHz, DMSO-d6): 11.59(brs,1H), 8.14(s,1H), 7.77(d,J=8.1Hz,1H), 7.70(d,J=8.1 Hz,1H), 7.64(t,J=2.8Hz,1H), 6.59(brs,1H), 4.46(q,J=7.1Hz,2H), 1.38(t,J=7.2Hz,3H).

[0036] 13 C NMR (150MHz, DMSO-d6): 167.4, 156.5, 154.6, 135.9, 131.5, 130.0, 121.6, 117.9, 115.1, 111.5, 102.4, 63.3, 14.4.

[0037] ESI-HRMS(+): m / z calcd for C 13 H 11 N3O3[M+H]+257.0800 found 258.0865.

[0038] Example 4: Synthesis of intermediate 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxyhydrazine (5).

[0039] Take a clean and dried round-bottom flask, add 0.389 mmol (0.1 g) of ethyl 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylic acid ester at room temperature, then add 2.5 mL of ethanol, stir, and wait until the solid is completely dissolved. Add 3.89 mmol (188 μL) of hydrazine hydrate dropwise, and react at 50 °C. Detect the reaction at the endpoint using TLC, and then stop the reaction. Place the flask in an ice-water bath to precipitate the solid, filter, and wash with ethanol to obtain 0.0651 g of white solid 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxyhydrazine, yield: 68.80%.

[0040] 1 H NMR (600MHz, DMSO-d6): 11.61(brs.,1H), 10.68(brs,1H), 8.16(s,1H), 7.79-7.71(m,2H), 7.62(t,J=2.6Hz,1H), 4.83(brs.,1H).

[0041] 13C NMR (150MHz, DMSO-d6): 166.6, 158.0, 152.8, 135.8, 131.3, 129.7, 121.5, 117.9, 115.4, 111.4, 102.4.

[0042] ESI-HRMS(+): m / z calcd for C11H9N5O2[M+H]+244.0834 found 244.0822.

[0043] Example 5: Synthesis of the product N'-(3-chlorobenzyl)-5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-formylhydrazine, wherein N'-(3-chlorobenzyl)-5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-formylhydrazine is designated as YY-6, and its structural formula is as follows: .

[0044] Take a clean and dried round-bottom flask, add 0.4 mmol and 0.1 g of 5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-carboxyhydrazine, add 5 mL of methanol at room temperature (23°C), and after the starting material dissolves, add 0.8 mmol and 93 μL of 3-chlorobenzaldehyde, followed by 0.8 mmol and 0.1 g of 4-dimethylaminopyridine. Reflux at 65°C for 3 h. Monitor the reaction until the endpoint by TLC. Filter and wash with methanol to obtain a pale yellow solid powder with a yield of 82.8% and a melting point of 280.3°C–281.6°C. Spectroscopy data: 1H NMR (600MHz, DMSO-d6): 12.91(brs.,1H), 11.62(brs,1H), 8.59(s,1H), 8.19(s,1H), 7.81(s,1H) ), 7.80-7.74(m,2H), 7.72(d,J=6.2Hz,1H), 7.65(brs,1H), 7.56-7.49(m,2H), 6.60(brs.,1H); 13 CNMR (150MHz, DMSO-d6): 167.3, 157.9, 150.5, 149.4, 136.4, 135.9, 134.2, 131.4, 131 .3, 130.8, 129.9, 127.1, 126.7, 121.6, 118.0, 115.2, 111.5, 102.4; ESI-HRMS(+): m / z calcdfor C 18 H 12 ClN5O2[M+H]+366.0758 found 366.0750.

[0045] Example 6: Synthesis of the product N'-(4-chlorobenzyl)-5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-formylhydrazide, wherein N'-(4-chlorobenzyl)-5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-formylhydrazide is designated as YY-8, and its structural formula is as follows: .

[0046] Take a clean and dried round-bottom flask, add 0.4 mmol and 0.1 g of 5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-carboxyhydrazine, and add 5 mL of methanol at room temperature (23°C). After the starting material dissolves, add 0.8 mmol and 93 μL of 4-chlorobenzaldehyde, followed by 0.8 mmol and 0.1 g of 4-dimethylaminopyridine. Reflux in an oil bath at 65°C for 3 h. Monitor the reaction until the endpoint by TLC. Filter and wash with methanol to obtain a white solid powder, yield: 78.9%, melting point 282°C~283°C.

[0047] Population data: 1 H NMR (600MHz, DMSO-d6): 12.85(s,1H), 11.61(brs.,1H), 8.60(s,1H), 8.19(s,1H), 7.81-7.74(m,4H), 7.65(t,J=2.8Hz,1H), 7.55(d,J=8.1Hz,2H); 13C NMR (150MHz, DMSO-d6): 167.3, 157.9, 150.4, 149.8, 135.9, 135.6, 133.2, 131 .4, 129.9, 129.6, 129.5, 121.5, 118.0, 115.2, 111.5, 102.4; ESI-HRMS(+): m / z calcd for C 18 H 12 ClN5O2[M+H]+366.0758 found 366.0748.

[0048] Example 7: Synthesis of the product N'-(4-fluorobenzyl)-5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-formylhydrazide, wherein N'-(4-fluorobenzyl)-5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-formylhydrazide is designated as YY-20, and its structural formula is as follows: .

[0049] Take a clean and dried round-bottom flask, add 0.4 mmol and 0.1 g of 5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-carboxyhydrazine, and add 5 mL of methanol at room temperature (23°C). After the starting material dissolves, add 0.8 mmol and 88 μL of 4-fluorobenzaldehyde, followed by 0.8 mmol and 0.1 g of 4-dimethylaminopyridine. Reflux in an oil bath at 65°C for 3 h. Monitor the reaction until the endpoint by TLC. Filter and wash with methanol to obtain a milky white powder with a yield of 75.4% and a melting point of 285.0°C–286.4°C.

[0050] Population data: 1 H NMR (600MHz, DMSO-d6): 11.62(brs.,1H), 8.60(s,1H), 7.83(dd,J=5.8,8.3Hz,2H), 7. 77(q,J=8.3Hz,2H), 7.64(t,J=2.6Hz,1H), 7.32(t,J=8.7Hz,2H), 6.60(brs.,1H); 13C NMR (150MHz, DMSO-d6): 167.3, 164.8, 163.1, 157.9, 150.4, 150.0, 135.9, 131.4, 130.8, 130.2, 130.2, 129.9, 121.5, 118.0, 116.6, 116.4, 115.3, 111.5, 102.4; ESI-HRMS(+): m / z calcd for C 18 H 12 FN5O2[M+H]+350.1053 found 350.1045.

[0051] The three compounds prepared above were subjected to anti-prostate cancer related experiments, as detailed below.

[0052] The in vitro anti-prostate cancer activity and toxicity of these compounds were evaluated using the CCK-8 assay. Seven concentrations (0.78125 M, 1.5625 M, 3.125 M, 6.25 M, 12.5 M, 25.0 M, and 50 M) were set up. The compounds were diluted to the corresponding concentrations with serum-free medium before administration. Cell viability was measured after 48 hours, and the IC50 was calculated. 50 The values ​​were calculated, with different cell types representing normal human prostate epithelial cells RWPE-1, prostate cancer cells PC-3, and C4-2B. The results are shown in Table 1. YY-6 exhibited significant inhibitory effects on prostate cancer cells PC-3 and C4-2B, while showing relatively low toxicity to normal prostate epithelial cells.

[0053] Table 1. CCK-8 assay for screening compounds for cytotoxicity. The results above show that YY-6 has the best effect. Next, we will use flow cytometry to detect apoptosis of YY-6, a compound with good anti-cancer activity and low toxicity to normal cells.

[0054] PC-3 cells were treated with 1.5M and 3M YY-6 for 24 h, respectively. Apoptosis was assessed by flow cytometry to evaluate the pro-apoptotic effect of YY-6. The flow cytometry results are as follows: Figure 1 As shown, YY-6 can significantly induce apoptosis in prostate cancer cells.

[0055] Studies have shown that Nur77 plays a crucial role in regulating the growth, survival, and apoptosis of prostate cancer cells, making it a potential therapeutic target for prostate cancer. To investigate whether YY-6 exerts its effects through Nur77, Western blotting was used to detect its influence on Nur77 expression. PC-3 cells were treated with 0.75M, 1.5M, and 3M YY-6 for 3 hours, with an equal amount of dimethyl sulfoxide added as a control. Nur77 protein expression levels were detected by Western blotting, with GAPDH used as an internal control to analyze the regulatory effect of YY-6 on Nur77 expression. The results are as follows: Figure 2 The results show that, compared with the control group, YY-6 can downregulate the protein expression of Nur77 in a concentration-dependent manner.

[0056] To further clarify the association between YY-6-induced Nur77 downregulation and apoptosis, a PC-3 cell line stably overexpressing Nur77 was constructed, with GAPDH used as an internal control. Subsequently, PC-3 and PC-3-Nur77-OE cells were treated with 2M YY-6 for 12 h, and the cleavage level of PARP protein was detected by Western blotting. Results are as follows: Figure 3 The results show that under Nur77 overexpression conditions, YY-6-induced PARP cleavage is significantly reduced. Figure 3 It can be seen that the upregulation of Nur77 can partially reverse the YY-6-mediated apoptosis effect.

[0057] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylhydrazine derivative, characterized in that, The structural formula is shown in equation (1); Equation (1); R is any one of the following: 3-chlorobenzaldehyde substituent, 4-chlorobenzaldehyde substituent, and 4-fluorobenzaldehyde substituent.

2. A method for preparing the 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-formylhydrazine derivative according to claim 1, characterized in that, Includes the following steps: Methyl indole-6-carboxylate was reacted with hydrazine hydrate in methanol at a mass ratio of 1:10~15 at 63℃~65℃, and purified to obtain 1-indole-6-carboxyhydrazide. 1-Indole-6-carboxylhydrazide, tetrahydrofuran, and oxaloyl chloride monoethyl ester were condensed in an alkaline environment at a mass ratio of 1:1.5~3:1.2~2 in an ice bath at 0~4℃, and purified to obtain ethyl 2-(2-(indole-6-carbonyl)hydrazino)-2-oxoacetic acid ester. Ethyl 2-(2-(1H-indole-6-carbonyl)hydrazino)-2-oxoacetate and p-toluenesulfonyl chloride were mixed in a mass ratio of 1:3 to 4 and mixed in an ice bath at 0°C to 4°C. The mixture was then reacted with a catalyst under an organic environment to obtain ethyl 5-(1H-indole-6-yl)-1,3,4-oxadiazole-2-carboxylic acid ester. Ethyl 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylic acid ester was reacted with hydrazine hydrate in an alcoholic environment at a mass ratio of 1:10~15 at 60℃~65℃ to give 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxyhydrazine. 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxyhydrazine was mixed with substituted benzaldehyde in a mass ratio of 1:1.2~2 and refluxed in an organic reagent with added catalyst to obtain a 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxyhydrazine derivative.

3. The preparation method according to claim 2, characterized in that, The specific purification process during the preparation of 1-indole-6-formylhydrazide is as follows: Filter to collect the precipitate, wash with water, dry, and recrystallize.

4. The preparation method according to claim 2, characterized in that, In the preparation of the ethyl 2-(2-(indole-6-carbonyl)hydrazino)-2-oxoacetic acid ester, the base is triethylamine; The purification was performed by column chromatography.

5. The preparation method according to claim 2, characterized in that, In the preparation of the ethyl 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylic acid ester, the reagents used in the organic environment are tetrahydrofuran and triethylamine; the catalyst is 4-dimethylaminopyridine; and the mass ratio of 4-dimethylaminopyridine to p-toluenesulfonyl chloride is 0.3~0.5:

1.

6. The preparation method according to claim 2, characterized in that, In the preparation of the 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxyhydrazine derivative, the organic reagent is methanol, the catalyst is 4-dimethylaminopyridine, and the 4-dimethylaminopyridine and the substituted benzaldehyde are in an equal mass ratio.

7. The use of the 5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-carboxylhydrazine derivative of claim 1 in the preparation of an anti-prostate cancer drug, characterized in that, In the drug, the concentration of the 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylhydrazine derivative is 0.78125M~50M.

8. The use of the 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylhydrazine derivative of claim 1 in the preparation of Nur77 inhibitors, characterized in that, The concentration of the 5-(1H-indol-6-yl)-1,3,4-oxadiazole-2-carboxylhydrazine derivative in the inhibitor is 0.75M~3M.

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