CN117263851A

CN117263851A - Pyridine-naphthyl urea-piperazine derivative, and preparation method and application thereof

Info

Publication number: CN117263851A
Application number: CN202311227366.8A
Authority: CN
Inventors: 徐学军; 傅凯; 马建国; 徐春萍; 杨玉坡; 杨争艳; 段超群
Original assignee: Henan Radiomedical Science And Technology Co ltd
Current assignee: Henan Radiomedical Science And Technology Co ltd
Priority date: 2023-09-22
Filing date: 2023-09-22
Publication date: 2023-12-22

Abstract

The invention discloses a pyridine-naphthyl urea-piperazine derivative, a preparation method and application thereof, wherein the structural formula is shown in a general formula I: i, wherein R is ₁ Selected from the group consisting of、、、、、、、、、Or (b)

Description

Pyridine-naphthyl urea-piperazine derivative, and preparation method and application thereof

Technical Field

The invention belongs to the field of tumor targeted therapy, and particularly relates to a pyridine-naphthyl urea-piperazine derivative, and a preparation method and application thereof.

Background

There have been extensive studies demonstrating that overexpression and aberrant activation of signal transduction and transcriptional activator 3 (Signal transducer and activators of transcriptions, STAT 3) is closely related to the development and poor prognosis of a variety of solid and hematological tumors. Under normal conditions STAT3 exists in the cytosol in an inactive monomeric form and has a strict negative feedback regulatory mechanism. Abnormal negative feedback regulation mechanisms or genetic mutations of STAT3 can lead to sustained increases in phosphorylation levels at the STAT3 tyrosine 705 and serine 727 sites. Activated STAT3 monomers are capable of forming homodimers or heterodimers through the SH2 domain into the nucleus, binding to specific gene promoter sequences through DNA binding domains, initiating transcription and protein expression of downstream genes, including BCL-2 and BCL-XL of the BCL-2 protein family associated with mitochondrial apoptosis, and expression of a range of anti-apoptotic factors, such as C-myc, associated with cell cycle regulation. In animal transplanted tumor models with STAT3 continuously activated or in-vitro cultured tumor cell lines, the STAT3 protein is knocked down by gene or a small molecular compound is applied to inhibit the activation of STAT3, so that the growth of tumor cells can be effectively inhibited, the apoptosis of the tumor cells can be induced, and the metastasis of tumors can be reduced. STAT3 has become a popular target for tumor treatment. Although some inhibitors for STAT3 such as BBI608, TTI101, WP1066, etc. have entered clinical tests for tumor patients at home and abroad at present, no inhibitors that directly target STAT3 have been successfully marketed.

In order to develop STAT3 targeted antitumor drugs, a class of naphthylurea-piperazine compounds with brand new structural formulas is recently synthesized. Through analysis of some biological technologies, the compounds are found to be capable of remarkably inhibiting the activation of STAT3 signals and inhibiting proliferation of various tumor cells, and good targeted anti-tumor activity is shown.

The invention aims to disclose the antitumor effect and the potential pharmacological mechanism of a novel pyridine-naphthylurea-piperazine derivative, and the potential application of the compound in clinical treatment of lymphoma, multiple myeloma, leukemia cancer, gastric cancer, lung cancer and pancreatic cancer.

Disclosure of Invention

The invention aims to provide a pyridine-naphthyl urea-piperazine derivative, and a preparation method and application thereof.

Based on the above purpose, the invention adopts the following technical scheme:

the structural formula of the pyridine-naphthalenyl urea-piperazine derivative is shown as a general formula I:

wherein R is ₁ Selected from the group consisting of

The pyridine-naphthalenyl urea-piperazine derivative is specifically a compound with the following structure:

a biologically acceptable salt of the above-described pyridine-naphthalenyl urea-piperazine derivative with at least one of acetic acid, dihydrofolate, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, sulfuric acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid, and ethylenediamine tetraacetic acid.

The preparation method of the pyridine-naphthyl urea-piperazine derivative comprises the following synthetic route:

the preparation process comprises the following steps:

(1) Dissolving the compound 1 and t-BuOK in tetrahydrofuran, uniformly stirring, then adding the compound 2, and completely reacting at room temperature under stirring; filtering the reaction solution by using diatomite, eluting by using ethyl acetate, and carrying out organic phase spin-drying column chromatography to obtain a compound 3;

(2) Dissolving a compound 3, a compound 4 and potassium carbonate in DMF, and stirring at room temperature to react completely; diluting the reaction solution with ethyl acetate, washing with saturated salt water, and performing organic phase drying spin-drying column chromatography to obtain a compound 5;

(3) Dissolving a compound 5 in a mixed solution of ethanol and saturated ammonium chloride aqueous solution, adding Fe powder at 45-55 ℃, and stirring at the temperature to react completely; filtering the reaction solution by using diatomite, leaching by using ethyl acetate, adding water into the filtrate to extract and separate liquid, collecting an organic phase, and performing spin-drying column chromatography to obtain a compound 6;

(4) Triphosgene is dissolved in methylene dichloride, compound 6 and DIEA are added at the temperature of minus 5-5 ℃, and after 1 hour of reaction, compound 7 is added, and then the reaction is completed at room temperature; and (3) directly spin-drying and mixing the reaction solution with a sample column for chromatography to obtain the compound shown in the formula I.

Preferably, in step (1), the molar ratio of compound 1, compound 2 and t-BuOK is 1:1:1; in the step (2), the molar ratio of the compound 3 to the compound 4 to the potassium carbonate is 1:1:1; in the step (3), the mol ratio of the compound 5 to the Fe powder is 1:5, and the volume ratio of the ethanol to the saturated ammonium chloride aqueous solution is 2:1; in step (4), the molar ratio of triphosgene, compound 6, DIEA, and compound 7 was 1:3:3:3.

The application of the pyridine-naphtyl urea-piperazine derivative and the biologically acceptable salt thereof in preparing medicaments for treating diseases related to STAT3 cell signaling abnormality.

Further, the medicine for treating diseases related to STAT3 cell signaling abnormality is a medicine for treating hematological tumors such as lymphoma, multiple myeloma, leukemia cancer and the like.

Further, the medicine for treating diseases related to STAT3 cell signaling abnormality is a medicine for treating solid tumors such as breast cancer, gastric cancer, colon cancer, lung cancer, liver cancer, pancreatic cancer, bladder cancer, cervical cancer, ovarian cancer and prostate cancer.

Further, the medicine for treating diseases related to STAT3 cell signaling abnormality is a medicine for treating central nervous system tumors such as retinoblastoma and glioma.

Further, the medicine for treating diseases related to STAT3 cell signaling abnormality is an autoimmune disease such as psoriasis, rheumatoid arthritis and pulmonary fibrosis.

It is another object of the present invention to provide a class of small molecule compounds with targeted antitumor activity.

The tumor may be specifically a STAT3 high-expression or constitutively activated tumor including, but not limited to, lymphoma, multiple myeloma, leukemia cancer, gastric cancer, lung cancer, pancreatic cancer, and the like.

Specifically, the invention synthesizes a class of naphthylurea-piperidine compounds IY230801A-1, IY230803A-1, IY230805A-1, IY230809A-1, IY230810A-1 and IY230811A-1 with brand new structures. The proliferation inhibition effect of the compounds on tumor cells is detected by an MTT method, and the inhibition effect of the compounds on STAT3 signal transduction is proved by an immunoblotting method.

The results show that the compounds IY230801A-1, IY230803A-1, IY230805A-1, IY230803A-1, IY230810A-1 and IY230811A-1 can effectively inhibit proliferation of lymphoma, multiple myeloma, leukemia cancer, gastric cancer, lung cancer and pancreatic cancer cells.

In summary, the present invention provides a novel naphthylurea-piperidine compound and its derivatives for use in tumor therapy and potential molecular mechanisms.

Drawings

FIG. 1 is a Western blot results of IY230801A-1 (0, 25, 50 and 100 nM) after 48h treatment of lymphoma cells OCI-LY 3.

Detailed Description

In order to make the technical purpose, technical scheme and beneficial effect of the present invention more clear, the technical scheme of the present invention is further described below with reference to the accompanying drawings and specific embodiments.

In the process according to the invention for the synthesis of the compounds of the formula I, the various starting materials used for the reaction are preparable by the person skilled in the art according to the prior art, or can be prepared by methods known from the literature, or can be obtained commercially. The intermediates, raw materials, reagents, reaction conditions and the like used in the above reaction schemes may be appropriately changed according to the knowledge already known to those skilled in the art.

In the present invention, unless otherwise specified, wherein: (i) The temperature is expressed in degrees centigrade (DEG C), and the operation is performed in a room temperature environment; more specifically, the room temperature is 20-30 ℃; (ii) Drying the organic solvent by a common drying method, evaporating the solvent by a rotary evaporator under reduced pressure, wherein the bath temperature is not higher than 50 ℃; the volume ratio of the developing agent to the eluent is equal; (iii) the reaction process is followed by Thin Layer Chromatography (TLC); (iv) The final product has satisfactory proton nuclear magnetic resonance ¹ H-NMR)。

EXAMPLE 1 Synthesis of IY230806A-1 Compound

The compound IY230808A-1 is named 1- (4- ((4- (2-phenylacrylyl) piperazin-1-yl) method) benzyl) oxy) napthalen-1-yl) -3- (pyridin-4-ylmethyl) urea,

the synthetic route is as follows:

step 1.1- ((4- (2-bromomethod) benzyl) oxy) -4-nitronapthlene (intermediate 3)

Raw material 1 (2 g,8.65mmol,1.0 eq) and t-BuOK (0.97 g,8.65mmol,1.0 eq) were dissolved in 20ml tetrahydrofuran and stirred for 10 minutes, then raw material 2 (1.65 g,8.65mmol,1.0 eq) was added and stirred at room temperature for 2 hours; TLC (PE/ea=4/1, rf/product=0.25) showed that the starting material was reacted completely, with a new spot; the reaction solution was filtered through celite, rinsed with ethyl acetate, and the organic phase was spin-dry stirred through the column and rinsed with (PE/ea=10/1 to 1/1) to give intermediate 3 (2.20 g, 63.2%) as a yellow solid.

Step 2.1- (4- (2- (4- (((4-nitrothiophen-1-yl) oxy) methyl) oxy) phenyl)

ethyl) piperazin-1-yl) -2-phenylethan-1-one (intermediate 5)

Intermediate 3 (1 g,2.49mmol,1.0 eq), starting material 4 (0.5 g,2.49mmol,1.0 eq) and potassium carbonate (0.34 g,2.49mmol,1.0 eq) were dissolved in 20ml DMF and reacted at room temperature for 12 hours with stirring; TLC (DCM/meoh=20/1, rf/product=0.35) showed that the starting material was reacted completely, with a new spot; the reaction was diluted with 100ml ethyl acetate and washed 3 times with saturated brine (100 ml x 3), the organic phase was dried, spin-dried and passed through the column and rinsed with (DCM/meoh=100/1-20/1) to give intermediate 5 (750 mg, 57.2%) as a yellow solid.

Step 3.1- (4- (2- (4- (((4-phosphoraphtalen-1-yl) oxy)) methyl)

phenyl) ethyl) piperazin-1-yl) -2-phenylethan-1-one (intermediate 6)

Intermediate 5 (630 mg,1.14mmol,1.0 eq) was dissolved in 20ml ethanol and 10ml saturated aqueous ammonium chloride, fe powder (0.32 g,5.71mmol,5.0 eq) was added at 50℃and reacted for 1 hour with stirring at 50 ℃. TLC (DCM/meoh=20/1, rf/product=0.25) showed that the starting material was reacted completely, a new spot was generated; the reaction was filtered through celite, rinsed with ethyl acetate, the filtrate was separated by water extraction, the organic phase was collected, dried and filtered through the column, and rinsed with (DCM/meoh=100/1 to 20/1) to give intermediate 6 (400 mg, 70.7%) as a yellow solid.

Step 4.1- (4- ((4- (2-phenylacrylyl) piperazin-1-yl) ethoxy)

benzyl)oxy)naphthalen-1-yl)-3-(pyridin-4-ylmethyl)urea(IY230808A-1)

Triphosgene (100 mg,0.37mmol,1.0 eq) was dissolved in 20ml dichloromethane, intermediate 6 (500 mg,1.01mmol,3.0 eq) and DIEA (130 mg,1.01mmol,3.0 eq) were added at 0deg.C, reacted for 1 hour with stirring, then starting material 7 (109 mg,1.01mmol,3.0 eq) was added and then reacted overnight with stirring at room temperature. TLC (DCM/meoh=10/1, rf/product=0.2) showed that the starting material was reacted completely, a new spot was generated; the reaction was directly spin-dried through the column and rinsed with (DCM/meoh=50/1 to 10/1) to give IY230808A-1 (215 mg, 33.8%) as a brown solid.

IY230808A-1 nuclear magnetic data: ¹ H NMR(DMSO-d6,300MHz)δ:8.31(s,1H),8.17(d,J＝8.0Hz,1H),8.03(d,J＝8.0Hz,2H),7.69(d,J＝8.0Hz,2H),7.59-7.27(m,8H),7.10-7.07(m,5H),7.06-6.99(m,3H),6.83(m,1H),5.21(s,2H),4.52(s,2H),4.33(d,J＝4.0Hz,2H),4.10(d,J＝4.0Hz,4H),2.53(m,2H),1.50(m,4H),1.43(m,2H)。

the synthetic methods of IY230801A-1, IY230805A-1, IY230803A-1, IY230805A-1, IY230803A-1, IY230809A-1 and IY230811A-1 are described with reference to example 1, except that in step 2, the raw material 4a is replaced with piperazine of the corresponding substituent.

The IY230801A-1 nuclear magnetic data are: ¹ H NMR(DMSO-d6,300MHz)δ:8.32(s,1H),8.19(d,J＝8.0Hz,1H),8.01(d,J＝8.0Hz,2H),7.68(d,J＝8.0Hz,2H),7.58-7.26(m,8H),7.11-7.08(m,5H),7.05-6.98(m,3H),6.82(m,1H),5.20(s,2H),4.34(d,J＝4.0Hz,2H),4.11(d,J＝4.0Hz,4H),2.52(m,2H),1.53(m,4H),1.40(m,2H)。

example 2: proliferation inhibition of cells such as IY230801A-1, IY230803A-1, IY230805A-1, IY230803A-1, IY230810A-1 and IY230811A-1 for lymphoma, multiple myeloma, leukemia, gastric cancer, lung cancer and pancreatic cancer

Respectively collecting tumor cells in logarithmic growth phase, and adjusting cell suspension concentration to 5×10 ⁴ Each mL was added to a 96-well cell culture plate at 100ul per well volume. The novel naphthylurea-piperidine compounds IY230801A-1, IY230803A-1, IY230805A-1, IY230809A-1, IY230810A-1 and IY230811A-1 are diluted with DMSO and then added into culture wells to make the final concentrations of the compounds in the system be 0.1, 0.3, 1, 3, 10, 30, 100 and 300 (mu mol/L), respectively. After further culturing for 48h, 10. Mu.L of MTT solvent (5 mg/ml) was added to each well, incubated for 4h at 37℃and the culture supernatant was aspirated off, 150. Mu.L of DMSO was added to each well, shaking and decolorizing was performed for 10min on a shaker, reading was performed on a microplate reader, the OD at an absorbance wavelength of 490nm was measured, the results were recorded, and the cell growth curve was drawn with the dose of the compound as the abscissa and the absorbance as the ordinate. The statistical results of half-number inhibition ratios (IC 50 values) of the tumor cells of IY230801A-1, IY230803A-1, IY230805A-1, IY230809A-1, IY230810A-1 and IY230811A-1 and the like are shown in Table 1.

Table 1:

the results in table 1 show that: IY230801A-1, IY230803A-1, IY230805A-1, IY230803A-1 and IY230811A-1 have good proliferation inhibition effect on tumor cells such as lymphoma, multiple myeloma, leukemia cancer, gastric cancer, lung cancer and pancreatic cancer, and especially the tumor inhibition effect of IY230801A-1 on lymphoma OCI-LY3 is strongest, and the antitumor effect of the compound is further studied.

Example 3: inhibition of STAT3 phosphorylation and C-myc expression in OCI-LY3 cells by IY230801a-1

1. Cell culture and drug addition A. Taking OCI-LY3 cells in logarithmic phase, adjusting to 4×10 density ⁵ individual/mL of single cell suspension was seeded into 6-well plates at 2mL of cell suspension per well. b.37 ℃ 5% CO ₂ Incubators were incubated overnight and different concentrations (0, 25, 50, 100 nM) of IY230801A-1 were added. c. After a further 48h of incubation, the cells were lysed with RIPA lysate and the proteins were collected.

2. Cell collection and lysis: a. the upper medium was discarded and the cells were washed twice with pre-chilled PBS. 100. Mu.L of precooled RIPA cell lysate (protease inhibitor and PMSF were added to the lysate at a ratio of 1:100) was added per well.

b. Lysing on ice for 3min, scraping off the cells with a cell scraper and collecting into a 1.5mL EP tube; the mixture was then placed on ice for 30min and vortexed once every 6 min. c.4℃and 12000g for 10min. d. Cell supernatants were transferred to new EP tubes. Cell supernatants are divided into two parts: 5 mu L of the sample is added into an EP tube of 1.5mL for BCA protein content measurement, and 45 mu L of 1 XPBS is added for even mixing; the remaining cell supernatants were quantified by taking 80. Mu.L, adding 5X SDS Loading Buffer. Mu.L, mixing well, boiling in boiling water for 10min, centrifuging, and loading or storing in a refrigerator at-20deg.C.

e. Protein concentration determination: (1) BCA working solution preparation: the total required amount of A and B mixed working fluid is calculated according to the number of the standard substance and the sample to be tested. The volume ratio of the solid agent A to the solid agent B is 50:1, preparing working solution, and uniformly mixing by vortex oscillation for standby.

(2) 1 XPBS diluted protein standard:

7 pipe number	1×PBS(μl)	BSA standard dosage	BSA standard (μg/ml)
				A	0	100	2000
B	200	200	1000
				C	200	200 (from tube B)	500
D	200	200 (taken from the C-tube)	250
				E	200	200 (taken from the D-tube)	125
F	400	100 (taken from E-tube)	25
				G	200	0	0 (blank)

(3) Protein standards and sample supernatants diluted with PBS (10-fold dilution) were each taken at 25 μl and added to a new 96-well plate. Then 200. Mu.L of BCA working solution prepared in advance was added respectively and mixed well. The bubbles are not generated by blowing, the cover of the 96-well plate is tightly covered, and the reaction is carried out for 30min in a constant temperature box at 37 ℃. (4) Taking out the 96-well plate, recovering to room temperature for 3-5 min, measuring the absorbance value of A562 on an enzyme label instrument, copying out the obtained value and storing the obtained value in an Excel table. A standard curve was made and the protein content of 1 μl per sample was calculated for protein loading.

3. SDS-PAGE: (1) The gel plate was fixed and 10% SDS-PAGE separating gel was prepared.

The release gel was prepared according to the following table: 10mL

(2) And (3) adding the mixed separating glue into 2 glue plates respectively, adding the glue plates to a position 1.0cm away from the top, filling the glue plates with absolute ethyl alcohol, and standing for 30-45 min. (3) After the gel is separated, the residual absolute ethyl alcohol is poured out, and the residual absolute ethyl alcohol is sucked clean by filter paper. (4) 5mL of 5% concentrated gel was prepared according to the following Table

Deionized water	2.77mL
		30％(m/v)Acrylamide	830μL
0.5M Tris-HCl (pH 6.8) buffer	1.26mL
		10％(m/v)SDS	50μL
10％(m/v)APS	50μL
		TEMED	5μL
Total	5mL

(5) Slowly adding the prepared concentrated glue into a glue plate to avoid generating bubbles, inserting a comb, and standing for 30-45 min.

(6) The protein sample was removed and heated in a water bath at 100deg.C for 5min at 10000rpm and centrifuged for 5min. (7) The gel plate was fixed in an electrophoresis tank, SDS-PAGE electrophoresis buffer was added, the comb was pulled out, and the treated protein samples were sequentially added to the sample tank, 50. Mu.g per well of protein. (8) 80V electrophoresis for 40min. (9) Changing the voltage to 120V for electrophoresis for about 1.5 hours until bromophenol blue goes out of the colloid;

4. western-blot: (1) And (3) placing the SDS-PAGE gel subjected to electrophoresis into TBST buffer solution for rinsing once, and placing the protein gel into transfer buffer solution for soaking. (2) Soaking a layer of cotton pad in a membrane transfer buffer solution, clamping onto a membrane transferring instrument by using forceps, placing a blackboard, the cotton pad, filter paper, albumin glue, PVDF membrane, filter paper, the cotton pad and a whiteboard in order, clamping, and placing into the membrane transferring instrument. If bubbles exist between each two layers, the bubbles are removed by lightly rolling the glass solid tube. And (3) opening a film transfer instrument, and performing constant-current transfer printing for 80 minutes at 300 mA. (4) The membranes were placed in TBST buffer and rinsed 3 times for 8min each. (5) blocking with 20mL of 5% BSA-TBST blocking solution at room temperature for 2h. (6) Primary antibody was added and incubated at 4℃at 60rpm overnight. (7) The membranes were washed three times with TBST at room temperature, 60rpm, 10min each. (8) adding a secondary antibody, and incubating for 1h at room temperature. (9) The membranes were washed three times with TBST at room temperature, 60rpm, 10min each. (10) 1ml of each of chemiluminescent substrate solid solution A and solution B is taken and developed for 2min at room temperature. (11) the liquid on the membrane is sucked by filter paper, and the membrane is subjected to machine aeration.

5. And (3) preparation of a reagent:

(1) 10% SDS: 1g of high purity (electrophoretic grade) SDS was weighed into a 10mL centrifuge tube, added with about 8mL deionized water, dissolved by heating, and stored at room temperature to a volume of 10 mL.

(2) 10% ammonium persulfate (Ammonium persulfate, AP): 1g of ammonium persulfate was weighed, dissolved by stirring after adding about 10mL of deionized water, and stored at 4 ℃.

(3) 5 Xrunning buffer: 15.1g of Tris, 94g of Glycine and 5.0g of SDS are weighed in a beaker, added with 1L of double distilled water for dissolution, stored at room temperature and diluted 5 times with time.

(4) Transfer buffer: 5.8g of Tris, 11.6g of glycine and 0.75g of SDS are weighed into a beaker, 700mL of double distilled water is added, the volume is fixed to 800mL after dissolution, and finally 200mL of methanol is added.

(5) Tris-HCl of 1.5mol/L, 100ml: then 18.15gtris is dissolved in 80ml water and adjusted to 8.8 by 4N HCl, and the volume is fixed to 100 ml.

(6) 0.5mol/L Tris-HCl,1000ml: 60.5 g of tris base was weighed, water was added to 850ml, concentrated hydrochloric acid was added and stirred until all dissolved, the pH was adjusted to 6.8, and water was added to 1L.

(7) TBS buffer: 8.8g of NaCl was weighed out in 800mL of distilled water, dissolved, 10mL of 1mol/LTris HCl (pH 7.5) was added, the volume was set to 1L, and the mixture was stored at room temperature.

(8) TBST buffer: to 1L TBS buffer, 500. Mu.L of 20% Tween20 was added to give a final concentration of 0.1% Tween20, and the mixture was prepared immediately.

(9) Blocking solution, antibody dilution: 5% skim milk powder or BSA was added to TBST buffer and ready-to-use.

As the results in FIG. 1 show, treatment with IY230801A-1 at 25. Mu.M, 50. Mu.M, and 100. Mu.M is effective to down-regulate the expression levels of p-STAT3 (Y705), p-STAT3 (S727), and the downstream target protein C-myc of STAT3 in OCI-LY3 cells.

In conclusion, the results show that the piperidine compound represented by IY230801A-1 can obviously inhibit the growth of lymphoma, multiple myeloma, leukemia cancer, gastric cancer, lung cancer and pancreatic cancer cells, has obvious inhibition effect on STAT3 and related proteins thereof, and shows good anticancer effect. According to the general way of drug development (conventional anti-tumor in-vitro screening is carried out firstly and then targeted research is carried out), the compound can be applied to cancer treatment drugs related to abnormal cell proliferation, and the anti-tumor drugs can be prepared by salifying with human bodies or mixing with a medicinal carrier.

Finally, what should be said is: the above embodiments are only for illustrating the technical solution of the present invention, but any equivalent replacement of the present invention and modification or partial replacement without departing from the spirit and scope of the present invention should be covered in the scope of the claims of the present invention.

Claims

1. The pyridine-naphthalenyl urea-piperazine derivatives are characterized by having a structural formula shown in a general formula I:

wherein R is ₁ Selected from the group consisting of

2. The pyridine-naphthalenyl urea-piperazine derivative according to claim 1, characterized in that it is in particular a compound of the following structure:

3. a biologically acceptable salt of the pyridine-naphthalenyl urea-piperazine derivative of claim 1 or 2 with at least one of acetic acid, dihydrofolate, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, sulfuric acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid, and ethylenediamine tetraacetic acid.

4. A process for the preparation of a pyridine-naphtyl urea-piperazine derivative according to claim 1 or 2, characterized in that the synthetic route is as follows:

the preparation process comprises the following steps:

5. The method for producing a pyridine-naphthylurea-piperazine derivative according to claim 4, wherein in the step (1), the molar ratio of the compound 1, the compound 2, and the t-BuOK is 1:1:1; in the step (2), the molar ratio of the compound 3 to the compound 4 to the potassium carbonate is 1:1:1; in the step (3), the mol ratio of the compound 5 to the Fe powder is 1:5, and the volume ratio of the ethanol to the saturated ammonium chloride aqueous solution is 2:1; in step (4), the molar ratio of triphosgene, compound 6, DIEA, and compound 7 was 1:3:3:3.

6. Use of a pyridine-naphthalenyl urea-piperazine derivative according to any one of claims 1 to 3, and its biologically acceptable salts, for the preparation of a medicament for the treatment of diseases associated with abnormal STAT3 cell signalling.

7. The use according to claim 6, wherein the medicament for treating diseases related to abnormal STAT3 cell signaling is a medicament for treating hematological neoplasms, such as lymphomas, multiple myeloma or leukemia.

8. The use according to claim 6, wherein the medicament for treating diseases related to abnormal STAT3 cell signaling is a medicament for treating solid tumors, which are breast cancer, gastric cancer, colon cancer, lung cancer, liver cancer, pancreatic cancer, bladder cancer, cervical cancer, ovarian cancer and prostate cancer.

9. The use according to claim 6, wherein the medicament for treating diseases related to abnormal STAT3 cell signaling is a medicament for treating central nervous system tumors, which are retinoblastoma and glioma.

10. The use according to claim 6, wherein the medicament for treating diseases related to abnormal STAT3 cell signaling is a medicament for treating autoimmune diseases, such as psoriasis, rheumatoid arthritis and pulmonary fibrosis.