A compound having antitumor activity, a preparation method and application thereof

Abstract

This invention discloses a compound with antitumor activity, its preparation method, and its applications. The structure of the compound is shown in formula ① or formula ②, wherein R1 is selected from Ar, -CH(COR2)2, -CH(COOR2)2, -CH2NHR3; R2 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl; R3 is selected from Ar; and R4 is selected from Ar. This invention has the following significant advantages: the compound exhibits high biological activity and inhibits pancreatic cancer PANC-1 cells, providing a new direction for the research of anticancer drugs.

Description

Technical Field

[0001] This invention relates to a compound with antitumor activity, its preparation method and application, belonging to the field of medicinal chemistry. Background Technology

[0002] Cancer is a serious threat to human health, becoming the "second leading cause of death" after cardiovascular disease, with its incidence and mortality rates increasing annually worldwide. Currently, cancer treatments mainly include chemotherapy, radiotherapy, surgery, and targeted therapy. Chemotherapy differs from surgery and radiotherapy in that it is administered systemically via oral or intravenous administration, effectively inhibiting tumor cell growth. Although chemotherapy is currently the recognized treatment method, its therapeutic index is low, and existing drugs have drawbacks such as toxicity and drug resistance, leading to serious consequences for patients. Therefore, developing more effective and safer novel anti-tumor drugs has significant application value in the field of cancer-related drug research and development.

[0003] Pancreatic cancer is one of the most common malignant tumors of the digestive tract, and is often referred to as the "king of cancers" in the field of oncology. According to The Lancet, the five-year survival rate after diagnosis for pancreatic cancer is about 10%, making it one of the malignant tumors with the worst prognosis.

[0004] Pancreatic cancer presents with insidious and atypical clinical symptoms, making it a challenging malignant tumor of the digestive tract to diagnose and treat. Approximately 90% of cases are ductal adenocarcinomas originating from glandular epithelium. Its incidence and mortality rates have increased significantly in recent years. Early diagnosis of pancreatic cancer is difficult, surgical mortality is high, and the cure rate is very low. The incidence rate is higher in men than women, with a male-to-female ratio of 1.5–2:1. Male patients are far more common than premenopausal women, while the incidence rate in postmenopausal women is similar to that in men. The difficulty in diagnosing and treating pancreatic cancer lies primarily in its insidious onset and rapid metastasis.

[0005] The fundamental treatment principles and methods can be broadly categorized as follows.

[0006] 1. Surgical treatment

[0007] Surgical procedures include pancreaticoduodenectomy, extended pancreaticoduodenectomy, pylorus-preserving pancreaticoduodenectomy, and total pancreatectomy. However, due to the difficulty in early diagnosis of pancreatic cancer, the surgical resection rate is low, and the five-year survival rate is also low.

[0008] For pancreatic cancer with obstructive jaundice that cannot be resected, cholecystojejunostomy or choledochojejunostomy can be performed to alleviate jaundice and improve the patient's quality of life. Endoscopic stent placement can also relieve the obstruction.

[0009] 2. Palliative care

[0010] For cases unsuitable for radical surgery, it is often necessary to relieve obstructive jaundice. This is usually achieved through cholecystojejunostomy. If this is not possible, an external fistula (cholecystostomy or external bile duct drainage) can be performed to reduce jaundice. Most patients can alleviate symptoms and improve their overall condition in a short period of time, and their survival time is generally around six months.

[0011] 3. Comprehensive treatment

[0012] Pancreatic cancer is highly malignant, has a low surgical resection rate, and a poor prognosis. Although surgery remains the primary treatment method, pancreatic cancer is often detected late, resulting in the loss of the opportunity for radical cure. Therefore, comprehensive treatment is necessary. To date, like most cancers, there is no highly effective and universally applicable comprehensive treatment plan. Current comprehensive treatment still primarily relies on surgery, supplemented by radiotherapy and chemotherapy, while new methods combining immunotherapy and molecular biological therapies are being explored.

[0013] (1) Radiotherapy is used for pancreatic cancer, which is a tumor with low radiosensitivity.

[0014] (2) Chemotherapy can be used for pancreatic cancer that cannot be surgically removed, or to prevent postoperative recurrence. The goal of chemotherapy for pancreatic cancer is to reduce the incidence of postoperative cancer recurrence and metastasis.

[0015] (3) Biotherapy includes immunotherapy and molecular therapy. With the rapid development of immunology and molecular biology research, this will be the most challenging area of ​​research because refractory tumors such as pancreatic cancer must be treated with entirely new methods: ① Gene therapy: Most of these are still in the preclinical stage, with few entering Phase I or Phase II clinical trials. ② Immunotherapy: This involves using immunomodulatory agents to enhance the body's immune function and is part of comprehensive treatment.

[0016] 4. Symptomatic and supportive treatment

[0017] In advanced pancreatic cancer, patients experiencing steatorrhea due to pancreatic exocrine insufficiency can take pancreatic enzyme preparations with meals to aid digestion. For intractable abdominal pain, analgesics, including opioids, should be administered; if necessary, 50%–75% ethanol can be used for celiac plexus injection or sympathectomy. Radiotherapy can relieve pain in some patients. Nutritional support should also be strengthened to improve nutritional status.

[0018] Compared to other treatments, chemotherapy research is relatively more in-depth, especially with the advent of small-molecule targeted therapies in recent years, which has brought a glimmer of hope to patients. Currently, many drugs used to treat pancreatic cancer face problems such as drug resistance and severe side effects that are difficult for patients to tolerate. Furthermore, the number of cancer patients is steadily increasing each year, making the search for new anti-cancer drugs extremely urgent. This study synthesized a series of compounds and evaluated their activity against pancreatic cancer, discovering that several compounds exhibited outstanding activity and could potentially serve as drugs or scaffolding cores for future anti-pancreatic cancer treatment. Summary of the Invention

[0019] Objectives of the Invention: The first objective of this invention is to provide a compound with antitumor activity. The second objective of this invention is to provide a method for preparing the above-mentioned compound. The third objective of this invention is to provide an application of the above-mentioned compound.

[0020] Technical solution: The present invention comprises a compound with antitumor activity or its stereoisomer, prodrug, pharmaceutically acceptable salt or solvate, wherein the structure of the compound is shown in formula ① or formula ②:

[0021]

[0022] Among them, R1 is selected from Ar, -CH(COR2)2, -CH(COOR2)2, and -CH2NHR3;

[0023] R2 is selected from methyl, ethyl, propyl, isopropyl, and tert-butyl.

[0024] R3 is selected from Ar;

[0025] R4 is selected from Ar.

[0026] Furthermore, when R1 is Ar, Ar is selected from benzene ring, substituted benzene ring, quinoline ring, and substituted quinoline ring;

[0027] When R3 is Ar, Ar is selected from benzene rings and substituted benzene rings;

[0028] When R4 is Ar, Ar is selected from benzene ring, substituted benzene ring, piperidine ring, and substituted piperidine ring.

[0029] Furthermore, the specific structure of the compound is as follows:

[0030]

[0031]

[0032] A method for preparing the above-mentioned compound, wherein the synthetic method of compound ① is as follows:

[0033] When R1 is Ar, its preparation method is as follows:

[0034]

[0035] Using 3-bromo-6-azaindole as the parent nucleus and 1,4-dioxane as the solvent, palladium catalyst, ligand, and R1-substituted arylboronic acid were added, and the mixture was obtained by Suzuki coupling at 100 °C.

[0036] When R1 is -CH(COR2)2 or -CH(COOR2)2, the preparation method is as follows:

[0037]

[0038] The product is obtained by Knoevenagel reaction at 60 °C using 3-aldehyde-6-azaindole as the parent core, methanol as the solvent, and piperidine, a substituted 1,4-dicarbonyl compound, as the base catalyst.

[0039] When R1 is -CH2NH R3, the preparation method is as follows:

[0040]

[0041] It is obtained by reductive amination reaction using 3-aldehyde-6-azaindole as the parent nucleus and ethanol as the solvent at 50°C.

[0042] Furthermore, the preparation method of compound ②:

[0043]

[0044] The product is obtained by Suzuki coupling at 100 °C using 3-bromo-6-azaindole as the parent nucleus, 1,4-dioxane as the solvent, palladium catalyst, ligand, and R4-substituted arylboronic acid.

[0045] The pharmaceutical composition of the present invention comprises a compound of formula ① or ② above, or a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt or solvate.

[0046] Furthermore, the pharmaceutical composition contains a pharmaceutically acceptable carrier.

[0047] The use of the compounds of the present invention in the preparation of medicaments for the prevention and / or treatment of tumors.

[0048] Furthermore, the tumor is pancreatic cancer.

[0049] Furthermore, the concentration of the compound is above 2.07 μM.

[0050] Beneficial effects: Compared with the prior art, the present invention has the following outstanding advantages: The compounds of the present invention have high biological activity and inhibit pancreatic cancer PANC-1 cells, providing a new direction for the research of anticancer drugs. Attached Figure Description

[0051] Figure 1 The results show the inhibition rate of the compounds of this invention against pancreatic cancer cells. Detailed Implementation

[0052] The technical solution of the present invention will be further described below with reference to the accompanying drawings.

[0053] Example 1: Synthesis of the compound (1)

[0055]

[0056] Dissolve A (1 eq 100 mg) in 2.4 mL of 1,4-dioxane solution, then add quinoline 3-borate (2.0 eq), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2) (10% eq), 2-bicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) (10% eq), and 0.76 mL of K3PO4 aqueous solution (1N). Replace with N2 three times, and react at 100 °C for 4 hours. The reaction is complete as determined by TLC, and the solution is extracted.

[0057] (EA / H2O), combined organic phases, dehydrated with anhydrous Na2SO4, evaporated the reaction solution to dryness, and obtained product I-1 by column chromatography.

[0058] I-1 is a white solid with a yield of 70%. 1 H NMR(500MHz,DMSO)δ:12.12(s,1H,-NH),9.35(d,J=2.3Hz,1H,ArH),8.86(s,1H,ArH),8.67(d,J=2.6Hz,1H,ArH),8.33(d,J=2.4Hz,1H, ArH),8.27(d,J=5.5Hz,1H,ArH),8.08(t,J=6.2Hz,2H,ArH),8.02(d,J=8.2Hz,1H,ArH),7.74–7.67(m,1H,ArH),7.65–7.58(m,1H,ArH). 13C NMR (125MHz, MeOD), δ: 150.60, 146.99, 139.14, 135.68, 135.48, 133.75, 131.76, 130.3 3,129.97,129.92,129.68,129.12,128.89,128.42,115.34,114.00.ESI-MS,m / Z:[M+H] + Theoretical value: 246.1026; Tested value: 246.1022. (2)

[0060]

[0061] B (1 eq) was dissolved in 5 mL of methanol solution, and then substituted 1,4-dicarbonyl compound (2.0 eq) and piperidine (10% eq) were added sequentially. The reaction was carried out at 60 °C for 3 hours. The reaction was stopped by TLC, the reaction solution was evaporated to dryness, and the product was obtained by column chromatography. The specific substituted 1,4-dicarbonyl compounds are shown in Table 1.

[0062] Table 1

[0063] Compound serial number 1,4-Dicarbonyl compounds II-1 Acetylacetone II-2 3,5-Diheptanone II-3 Dimethyl malonate II-4 Diethyl malonate II-5 Dipropyl malonate II-6 Diisopropyl malonate II-7 di-tert-butyl malonate

[0064] II-1 White solid; Yield: 58%. 1 H NMR (500MHz, DMSO) δ: 12.38 (s, 1H, -NH), 8.85 (d, J = 1.1Hz, 1H, ArH), 8.30 (d, J = 5.5Hz, 1H, -CH), 7.96 ( dd,J=5.5,1.2Hz,1H,ArH),7.90(s,1H,ArH),7.78(s,1H,ArH),2.50(s,3H,-CH3),2.34(s,3H,-CH3); 13 C NMR(125MHz, DMSO)δ:206.71,197.66,139.98,137.94,135.80,133.84,132.49,132.38,132.03,113.86,108.97,31.40,26.48.ESI-MS,m / Z:[M+H] + Theoretical value: 229.0972; Tested value: 229.0971.

[0065] II-2 White solid; Yield: 61%. 1H NMR(500MHz,DMSO)δ:12.27(s,1H,-NH),8.82(d,J=1.1Hz,1H,ArH),8.26(d,J=5.5Hz,1H,-CH),7.92(d,J=5.3Hz,2H ,ArH),7.60(s,1H,ArH),2.92(q,J=7.2Hz,2H,-CH2),2.58(q,J=7.2Hz,2H,-CH2),1.04(dt,J=9.0,7.2Hz,6H,-CH3); 13 C NMR(125MHz,DMSO)δ:209.21,199.56,139.43,136.89,135.33,133.32,131.78 ,131.33,130.25,113.37,108.64,35.99,30.21,8.38,7.70.ESI-MS,m / Z:[M+H] + Theoretical value: 257.1285; Tested value: 257.1291.

[0066] II-3 White solid; Yield: 70%. 1 H NMR(500MHz,DMSO)δ:12.41(s,1H,-NH),8.83(d,J=1.1Hz,1H,ArH),8.25(d,J=5.5Hz,1H,-CH),7.99( s,1H,ArH),7.94(s,1H,ArH),7.72(dd,J=5.5,1.1Hz,1H,ArH),3.84(s,3H,-CH3),3.77(s,3H,-CH3); 13 C NMR(125MHz, DMSO)δ:167.55,164.86,139.96,135.60,134.52,133.58,133.06,131.62,118.92,113.21,108.41,52.76,52.42.ESI-MS,m / Z:[M+H] + Theoretical value: 261.0870; Tested value: 261.0870.

[0067] II-4 White solid; Yield: 71%. 1H NMR (500MHz, MeOD,), δ: 8.73 (d, J = 1.1Hz, 1H), 8.21 (d, J = 5.6Hz, 1H), 8.04–7.95 (m, 2H), 7.73 (td, J = 5. 5,1.1Hz,1H),4.33(dq,J=38.7,7.1Hz,4H),3.86(dd,J=26.2,1.1Hz,1H),1.33(dt,J=8.6,7.1Hz,6H); 13 C NMR(125MHz,MeOD)δ:169.14,166.66,140.04,135.71,135.02,134.88,134.48, 134.22,122.20,114.68,110.64,62.90,62.59,14.71,14.52.ESI-MS,m / Z:[M+H] + Theoretical value: 289.1183; Tested value: 289.1186.

[0068] II-5 White solid; Yield: 52%. 1 H NMR (DMSO, 500MHz), δ: 12.38 (s, 1H, -NH), 8.83 (d, J = 1.1Hz, 1H, ArH), 8.25 (d, J = 5.6Hz, 1H, -CH), 7.95 (d, J = 1.1Hz, 2H, ArH), 7.72 (dd, J = 5.6, 1 .1Hz,1H,ArH),4.24(t,J=6.5Hz,2H,-CH2),4.14(t,J=6.5Hz,2H-CH2),1.65(hd,J=7.2,3.0Hz,4H,-CH2),0.90(dt,J=26.8,7.4Hz,6H,-CH3);. 13 C NMR(125MHz,DMSO)δ:167.09,164.30,139.69,135.39,133.70,133.37,132.66,131 .43,119.56,113.01,108.29,66.71,66.18,21.57,21.32,10.20.ESI-MS,m / Z:[M+H] + Theoretical value: 317.1496; Tested value: 317.1504.

[0069] II-6 White solid; Yield: 44%. 1H NMR(500MHz,MeOD)δ:8.73(d,J=1.1Hz,1H,ArH),8.21(d,J=5.6Hz,1H,-CH),7.98(dd,J=16.9,0.7Hz,2H,ArH),7.76(d d,J=5.6,1.1Hz,1H,ArH),5.24(hept,J=6.3Hz,1H,-CH),5.13(hept,J=6.2Hz,1H,-CH),1.31(d,J=6.3Hz,12H,-CH3); 13 C NMR(125MHz,MeOD)δ:168.83,166.19,139.99,135.70,135.00,134.46,134.17, 133.99,123.07,114.69,110.68,70.67,70.37,22.27,22.09.ESI-MS,m / Z:[M+H] + Theoretical value: 317.1496; Tested value: 317.1496.

[0070] II-7 White solid; Yield: 15%. 1 H NMR(500MHz,MeOD)δ:8.76(d,J=1.1Hz,1H,Ar),8.23(d,J=5.6Hz,1H,-CH),8.01(d,J=0.8Hz,1H, ArH),7.85(d,J=0.7Hz,1H,ArH),7.79(dd,J=5.6,1.1Hz,1H,ArH),1.58(d,J=11.5Hz,18H,-CH3); 13 C NMR(125MHz,MeOD)δ:168.90,165.97,139.87,135.64,134.93,134.58,133.20, 132.32,125.66,114.67,110.74,83.55,83.05,28.63,28.53.ESI-MS,m / Z:[M+H] + Theoretical value: 345.1809; Tested value: 345.1814. (3)

[0072]

[0073] Dissolve B (1 eq) in 5 mL of ethanol solution, then add substituted amines (2.0 eq) sequentially, and react at 60 °C for 5 hours. Add NaBH4 (10 eq) to the reaction system and continue the reaction for 2 hours. The reaction is then stopped by TLC. After TLC detection, the mixture is extracted (EA / H2O), the organic phases are combined, dehydrated with anhydrous Na2SO4, the reaction solution is evaporated to dryness, and the product is obtained by column chromatography. Specific substituted amines are shown in Table 2.

[0074] Table 2

[0075] Compound serial number Substituted amines III-1 aniline III-2 p-Chloroaniline III-3 p-Bromoaniline III-4 p-Toluidine III-5 p-Methoxyaniline III-6 p-Fluoroaniline

[0076] III-1 White solid; Yield: 84%. 1 H NMR (500MHz, MeOD) δ: 8.64 (d, J = 1.1 Hz, 1H, ArH), 8.04 (d, J = 5.6 Hz, 1H, ArH), 7.65 (dd, J = 5.6, 1.1 Hz, 1H, ArH), 7.50 (d, J = 0. 9Hz,1H,ArH),7.13–7.04(m,2H,ArH),6.75–6.68(m,2H,ArH),6.62(tt,J=7.3,1.1Hz,1H,ArH),4.45(d,J=0.9Hz,2H,-CH2); 13 C NMR(125MHz,MeOD)δ:150.41,137.75,135.42,134.75,133.51,130.14,129.74,118.38,115.31,115.00,114.52,40.44.ESI-MS,m / Z:[M+H] + Theoretical value: 224.1182; Tested value: 224.1190.

[0077] III-2 White solid; Yield: 77%. 1 H NMR(500MHz,MeOD)δ:8.64(s,1H,ArH),8.04(d,J=5.6Hz,1H,ArH),7.64(dd,J=5.6,1.1Hz,1H,ArH), 7.49(d,J=0.9Hz,1H,ArH),7.07–6.99(m,2H,ArH),6.68–6.62(m,2H,ArH),4.44–4.40(m,2H,-CH2); 13C NMR(125MHz,MeOD)δ:149.03,137.64,135.28,134.64,133.29,129.72,129.56,122.34,117.49,115.19,114.49,40.18.ESI-MS,m / Z:[M+H] + Theoretical value: 258.0793; Tested value: 258.0801.

[0078] III-3 White solid; Yield: 63%. 1 H NMR(500MHz,MeOD)δ:8.62–8.59(m,1H,ArH),8.00(d,J=5.6Hz,1H,ArH),7.60(dd,J=5.6, 1.1Hz,1H,ArH),7.16–7.08(m,2H,ArH),6.60–6.53(m,2H,ArH),4.43–4.36(m,2H,-CH2); 13 C NMR(125MHz,MeOD)δ:149.42,137.65,135.28,134.65,133.28,132.64,129.55,115.66,115.09,114.43,109.15,40.06.ESI-MS,m / Z:[M+H] + Theoretical value: 302.0287; Test value: 302.0290.

[0079] III-4 White solid; Yield: 89%. 1 H NMR(500MHz,DMSO)δ:8.72(s,1H,ArH),8.07(d,J=5.5Hz,1H,ArH),7.63(d,J=5.5Hz,1H,ArH),7.54(s, 1H, ArH), 6.85 (d, J = 8.0Hz, 2H, ArH), 6.58 (d, J = 8.1Hz, 2H, ArH), 4.34 (s, 2H, -CH2), 2.11 (s, 3H, -CH3); 13 C NMR(125MHz, DMSO)δ:146.74,137.34,134.41,133.62,131.14,129.44,127.82,124.40,113.94,113.16,112.79,38.66,20.24.ESI-MS,m / Z:[M+H] + Theoretical value: 238.1339; Tested value: 238.1347.

[0080] III-5 White solid; Yield: 84%. 1H NMR(500MHz,DMSO)δ:8.71(s,1H,ArH),8.07(d,J=5.5Hz,1H,ArH),7.63(d,J=5.5Hz,1H,ArH),7.54(s, 1H, ArH), 6.68 (d, J = 8.9Hz, 2H, ArH), 6.62 (d, J = 8.7Hz, 2H, ArH), 4.32 (s, 2H, -CH2), 3.60 (s, 3H, -CH3); 13 C NMR(125MHz, DMSO)δ:150.98,143.28,137.35,134.41,133.58,131.13,127.78,114.73,113.93,113.75,113.21,55.51,39.78.ESI-MS,m / Z:[M+H] + Theoretical value: 254.1288; Tested value: 254.1296.

[0081] III-6 White solid; Yield: 76%. 1 H NMR(500MHz,DMSO)δ:8.71(s,1H,ArH),8.07(d,J=5.5Hz,1H,ArH),7.63(d,J=5.5Hz,1H,ArH),7 .55(s,1H,ArH),6.87(t,J=8.7Hz,2H,ArH),6.64(dd,J=8.9,4.6Hz,2H,ArH),4.34(s,2H,-CH2); 13 C NMR (125MHz, DMSO) δ: 155.43, 153.59, 145.68, 137.40, 134.45, 133.60, 131.11, 127. 88,115.40,115.23,113.91,113.30(d,J=7.2Hz),112.77,38.86.ESI-MS,m / Z:[M+H] + Theoretical value: 242.1088; Tested value: 242.1091. (4)

[0083]

[0084] C (1 eq 100 mg) was dissolved in 2.4 mL of 1,4-dioxane solution, followed by the addition of substituted arylboronic acid (1.5 eq), XPhos Pd G2 (10% eq), XPhos (10% eq), and 0.76 mL of K3PO4 aqueous solution (1N). The reaction was carried out three times with N2 and at 100 °C for 4 hours. The reaction was stopped by TLC, extracted (EA / H2O), and the organic phases were combined. The mixture was dehydrated with anhydrous Na2SO4, evaporated to dryness, and then subjected to column chromatography to obtain the product. The specific substituted arylboronic acids are shown in Table 3.

[0085] Table 3

[0086] Compound serial number Substituted arylboronic acid IV-1 o-Methoxyphenylboronic acid IV-2 p-Mercaptomethylphenylboronic acid IV-3 p-Cyanobenzic acid IV-4 Furan-3-boronic acid IV-5 3-Thiopheneboronic acid IV-6 p-Methylphenylboronic acid IV-7 2-Fluoro-4-pyridineboronic acid

[0087] IV-1 White solid; Yield: 57%. 1 H NMR(500MHz,DMSO)δ:12.42(s,1H,-NH),8.17(s,1H,ArH),7.79(d,J=8.2Hz,1H,ArH),7.45–7.38(m,3 H,ArH),7.37–7.32(m,1H,ArH),7.17(d,J=7.2Hz,1H,ArH),7.11–7.04(m,1H,ArH),3.79(s,3H,-CH3); 13 C NMR(DMSO,125MHz)δ:156.65,155.47,151.82,141.06,132.05,131.52,130.84,13 0.20,128.99,128.68,125.16,121.42,116.54,112.50,56.11.ESI-MS,m / Z:[M+H] + Theoretical value: 253.0972; Tested value: 253.0957.

[0088] IV-2 Yellow solid; Yield: 18%. 1 H NMR(500MHz,DMSO)δ:12.46(s,1H,-NH),8.16(s,1H,ArH),7.84(d,J=8.4Hz,1H,ArH),7.68–7.63(m,2H,Ar H),7.61(dd,J=8.4,2.0Hz,1H,ArH),7.51(d,J=2.0Hz,1H,ArH),7.44–7.36(m,2H,ArH),2.54(s,3H,-CH3); 13C NMR(125MHz,DMSO)δ:154.97,151.25,141.71,138.92,135.14,132.34,131.38,129.28,127.28,126.36,121.69,112.72,14.48.ESI-MS,m / Z:[M+H] + Theoretical value: 269.0743; Tested value: 269.0742.

[0089] IV-3 White solid; Yield: 65%. 1 H NMR(500MHz,DMSO)δ:12.52(s,1H,-NH),8.20(s,1H,ArH),8.01–7.95(m,2H,ArH),7 .91–7.85(m,3H,ArH),7.65(dd,J=8.4,2.0Hz,1H,ArH),7.54(d,J=2.0Hz,1H,ArH); 13 C NMR(125MHz,DMSO)δ:155.07,152.42,143.54,140.51,133.23,132.52,132.24,129.68,128.04,122.40,118.83,114.09,111.05.ESI-MS,m / Z:[M+H] + Theoretical value: 248.0818; Tested value: 248.0823.

[0090] IV-4 White solid; Yield: 56%. 1 H NMR(500MHz,DMSO)δ:12.41(s,1H,-NH),8.30(t,J=1.2Hz,1H,ArH),8.13(s,1H,ArH),7.85–7.76 (m,2H,ArH),7.58(dd,J=8.4,1.9Hz,1H,ArH),7.42(d,J=1.9Hz,1H,ArH),6.95–6.91(m,1H,ArH); 13 C NMR(126MHz,DMSO)δ:154.97,150.82,144.85,140.57,134.31,132.42,131.15,129.25,124.93,121.11,111.64,108.56.ESI-MS,m / Z:[M+H] + Theoretical value: 213.0659; Tested value: 213.0647.

[0091] IV-5 Yellow solid; Yield: 50%. 1H NMR(500MHz,DMSO)δ:12.44(s,1H,-NH),8.15(s,1H,ArH),7.99(s,1H,ArH),7.81(d,J=8.4Hz, 1H, ArH), 7.73 (dd, J=5.0, 2.9Hz, 1H, ArH), 7.68 (dd, J=8.4, 2.0Hz, 1H, ArH), 7.54 (s, 2H, ArH); 13 C NMR(125MHz,DMSO)δ:155.01,151.00,140.13,137.19,132.41,131.26,129.28,127.83,126.03,122.96,121.63,112.31.ESI-MS,m / Z:[M+H] + Theoretical value: 229.0430; Tested value: 229.0430.

[0092] IV-6 White solid; Yield: 58%. 1 H NMR (CDCl3, 500MHz), δ: 8.34 (s, 1H, ArH), 7.93 (d, J = 8.4Hz, 1H, ArH), 7.63–7.55 (m, 3H, ArH), 7.48 (d, J=1.8Hz, 1H, ArH), 7.31 (d, J=7.8Hz, 2H, ArH), 2.43 (s, 3H, -CH3); 13 C NMR(125MHz,DMSO)δ:155.02,151.22,142.35,137.92,136.00,134.18,132.32,13 1.34,129.78,129.25,128.02,126.78,121.87,112.89,20.71.ESI-MS,m / Z:[M+H] + Theoretical value: 237.1022; Tested value: 237.1008.

[0093] IV-7 Yellow solid; Yield: 74%. 1 H NMR(500MHz,DMSO)δ:12.57(s,1H,-NH),8.39(d,J=5.2Hz,1H,ArH),8.25(s,1H,ArH),7.94(d,J=8.4Hz,1H,ArH) ,7.76(dd,J=8.4,2.0Hz,1H,ArH),7.69(dt,J=5.3,1.8Hz,1H,ArH),7.64(d,J=2.1Hz,1H,ArH),7.55(s,1H,ArH); 13C NMR (125MHz, DMSO) δ: 165.39, 163.52, 155.34, 153.30, 152.55 (d, J = 8.3Hz), 148.97 (d, J = 15.8Hz), 138.52 (d, J = 3.3 Hz),133.00(d,J=39.6Hz),130.10,122.65,120.44(d,J=3.7Hz),114.65,107.62(d,J=38.9Hz).ESI-MS,m / Z:[M+H] + Theoretical value: 242.0724; Tested value: 242.0713.

[0094] Example 2: Activity test of the compound

[0095] (1) Test of pancreatic cancer cell inhibition rate

[0096] The antitumor activity of the compounds was determined using the CCK8 assay. PANC-1 cells (human pancreatic cancer cells) were incubated at 10... 4 Cells were seeded at a density of 100 μL / mL in 96-well plates containing DMEM medium. After incubation at 37°C and 5% CO2 for 24 h, the old medium was discarded, and 100 μL of fresh medium containing 10 μM 5-FU (positive control) or the test compound was added to each well. The plates were incubated for another 24 h. Then, 10 μL of CCK8 solution was added to each well, and the plates were incubated for 4 h. The absorbance of each well was measured at 450 nm using a multi-mode microplate reader. Cytotoxicity was assessed compared to the solvent control group (DMSO), and the results were expressed as the percentage of cell viability in the treated group relative to the solvent control group.

[0097] Table 4. Results of activity tests on the compounds

[0098]

[0099]

[0100] (2) Testing of antitumor IC50

[0101] When calculating the IC50 of the compound, PANC-1 cells (human pancreatic cancer cells) showed an IC50 of 10. 4Cells were seeded at a density of 100 μL / mL in 96-well plates containing DMEM medium. After incubation at 37°C and 5% CO2 for 24 h, the old medium was discarded, and 100 μL of different concentrations of the drug (0-100 μM) dissolved in the medium was added to each well, followed by incubation for 24 h. Then, 10 μL of CCK8 solution was added to each well, and incubation was continued for 4 h. The absorbance of each well at 450 nm was measured using a multi-mode microplate reader. The concentration (IC50) at which the compound induced 50% cell growth inhibition was determined using a nonlinear regression algorithm in GraphPad Prism 9 software.

[0102] Table 5. Antitumor IC50 results of the compounds.

[0103] Compound numbering IC50 (μM) for pancreatic cancer 5-FU 16.03 I-1 7.15 II-6 2.14 II-7 2.07 .

Claims

1. A compound having antitumor activity or a pharmaceutically acceptable salt thereof, characterized in that, The compound is , or .

2. A pharmaceutical composition, characterized by comprising: A compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 2, wherein The pharmaceutical composition comprises a pharmaceutically acceptable carrier.

4. Use of a compound according to claim 1 for the manufacture of a medicament for the prevention and / or treatment of a tumor, characterized in that, The tumor is pancreatic cancer.

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