3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compounds and their synthesis and application

Abstract

The present invention discloses a 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof, which belongs to a new structure compound. The present invention also discloses the use of the compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, which can be used to treat osteosarcoma and other related diseases, has good inhibitory properties, and has good selectivity for different cell lines. The present invention also discloses a method for preparing the thiazolinone compound, which has the advantages of being able to synthesize heterocyclic and aliphatic compounds at the 3rd position of thiazolinone that cannot be synthesized by traditional synthesis routes.

Description

Technical Field

[0001] The invention belongs to the field of synthetic medicine and biomedicine, and mainly relates to a 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compound and a synthesis method and application thereof. Background Art

[0002] Osteosarcoma, also known as osteosarcoma, is a common malignant bone tumor that occurs in adolescents or children under the age of 20 (Link MP: Osteosarcoma in adolescents and young adults: new developments and controversies. Commentary on the use of presurgical chemotherapy. Cancer Treat Res 62: 383-385, 1993.). According to epidemiological studies of osteosarcoma, it is the most common bone malignancy in children, accounting for about 5% of pediatric tumors. Osteosarcoma is still a disease with a high mortality rate among malignant tumors in children and adolescents, second only to lymphoma and brain cancer, but early detection and timely treatment have greatly improved the survival rate of the disease.

[0003] Treatment methods for different types of osteosarcoma usually use combined medication after surgery. It is worth noting that the cancer metastasis rate of osteosarcoma patients is as high as 80%. Among patients with metastasis, 90% are lung metastases. The recurrence rate is 20-30%, and recurrence is possible in situ or in situ tissues. In the past few decades, despite the adjustment of increasing the dose, changing the number of times, and combining multiple chemotherapy drugs, the survival rate has not improved.

[0004] At present, the research on therapeutic targets for osteosarcoma mainly focuses on the cell surface receptor tyrosine kinase family (PTKs) and intracellular signaling targets. For these targets, the main therapeutic drugs are divided into three categories: 1) immunomodulators; 2) receptor tyrosine kinase inhibitors; 3) intracellular signaling pathway inhibitors. In addition, new targets and treatment options for osteosarcoma include NK-kB ligands, folic acid inhibitors, etc., but they are all in the experimental research stage. Summary of the invention

[0005] The inventors have noticed that in previous literature reports, compounds with a thiazolinone skeleton structure have a variety of pharmacological activities, such as the compound represented by formula (V) having anti-inflammatory activity and the compound represented by formula (VI) having anti-AIDS activity:

[0006]

[0007] However, there is no report on the evaluation of osteosarcoma cell activity test for this type of skeleton in the prior art. The inventors have discovered and proposed that this skeleton compound may produce a series of new compound molecules with significant structure and activity, which may provide a new source of compounds for biological activity screening.

[0008] The present invention provides a 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof as shown in formula (I). The compound is a compound of a completely new structure and there is no related report.

[0009] The structure of formula (I) of the present invention is as follows:

[0010]

[0011] in,

[0012] Ar 1 is aryl, aromatic heterocycle, alkyl-substituted aryl, halogen-substituted aryl, alkyl-substituted heteroaryl, halogen-substituted heteroaryl, trifluoromethyl-substituted aryl, nitro-substituted aryl, naphthylmethyl, furanyl, allyl, propargyl, diphenylmethyl, di(4-bromophenyl)methyl, trifluoromethyl-substituted heteroaryl, nitro-substituted heteroaryl; wherein the aromatic heterocycle and heteroaryl are selected from indole, benzotriazole, thiophene, furan, pyrrole, bislactam, piperazine, imidazole, oxazole, pyrazine, etc.;

[0013] R 1 is alkyl, cycloalkyl, epoxyalkyl, hydrogen, etc.;

[0014] R 2 is halogen, alkoxy, alkyl, cycloalkyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen;

[0015] Het is a heterocycle selected from the group consisting of pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone, pyrimidine, halogen-substituted heteroaryl, trifluoromethyl-substituted aryl, nitro-substituted aryl, decalinyl, furanyl, alkenealkyl, alkynyl, diphenylalkyl, di(4-bromophenyl)alkyl, trifluoromethyl-substituted heteroaryl, nitro-substituted heteroaryl; wherein the heteroaryl is selected from the group consisting of indole, benzotriazole, thiophene, pyrrole, dilactam, piperazine, imidazole, oxazole, and pyrazine.

[0016] Preferably,

[0017] Ar 1is phenyl, aromatic heterocycle, C1-C6 alkyl substituted phenyl, halogen substituted phenyl, C1-C6 alkyl substituted heteroaryl, halogen substituted heteroaryl, trifluoromethyl substituted phenyl, nitro substituted phenyl, naphthylmethyl, furanyl, allyl, propargyl, diphenylmethyl, di(4-bromophenyl)methyl, trifluoromethyl substituted heteroaryl, nitro substituted heteroaryl; wherein the aromatic heterocycle and heteroaryl are selected from indole, benzotriazole, thiophene, furan, pyrrole, dilactam, piperazine, imidazole, oxazole, pyrazine, etc.;

[0018] R 1 C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 epoxyalkyl, hydrogen, etc.;

[0019] R 2 is halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen;

[0020] Het is a heterocycle selected from the group consisting of pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone, pyrimidine, halogen-substituted heteroaryl, trifluoromethyl-substituted aryl, nitro-substituted aryl, naphthalene C1-C6 alkyl, furan C1-C6 alkyl, alkene C1-C6 alkyl, alkyne C1-C6 alkyl, diphenyl C1-C6 alkyl, di(4-bromophenyl) C1-C6 alkyl, trifluoromethyl-substituted heteroaryl, nitro-substituted heteroaryl; wherein the heteroaryl is selected from the group consisting of indole, benzotriazole, thiophene, pyrrole, dilactam, piperazine, imidazole, oxazole, and pyrazine.

[0021] More preferably,

[0022] Ar 1 phenyl, aromatic heterocycle, methyl substituted phenyl, halogen substituted phenyl, methyl substituted heteroaryl, halogen substituted heteroaryl, trifluoromethyl substituted phenyl, nitro substituted phenyl, naphthylmethyl, furanmethyl, allyl, propargyl, diphenylmethyl, di(4-bromophenyl)methyl, trifluoromethyl substituted heteroaryl, nitro substituted heteroaryl, indole, benzotriazole, thiophene, furan, pyrrole, dilactam, piperazine, imidazole, oxazole, pyrazine, etc.;

[0023] R 1 Methyl, ethyl, isopropyl, cyclopropane, glycidyl, hydrogen, etc.

[0024] R 2 is F, methoxy, methyl, cyclopropane, nitro, cyano, trifluoromethyl, phenyl, hydrogen;

[0025] Het is a heterocycle selected from the group consisting of pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone, pyrimidine, halogen-substituted heteroaryl, trifluoromethyl-substituted aryl, nitro-substituted aryl, naphthylmethyl, furanmethyl, allyl, propargyl, diphenylmethyl, di(4-bromophenyl)methyl, trifluoromethyl-substituted heteroaryl, nitro-substituted heteroaryl; wherein the heteroaryl is selected from the group consisting of indole, benzotriazole, thiophene, pyrrole, dilactam, piperazine, imidazole, oxazole, and pyrazine.

[0026] The 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compounds or pharmaceutically acceptable salts of the present invention include but are not limited to the following:

[0027] 3-(3-(2-pyridinyl)-4-thiazolinone)-N-(4-pyrazolbutyl)benzamide;

[0028] 3-(3-(2-(4-bromo)pyridinyl)-4-thiazolinone)-N-(4-pyrazolbutyl)benzamide;

[0029] 3-(3-(2-(4-chloro)pyridinyl)-4-thiazolinonyl)-N-(4-pyrazolbutyl)benzamide;

[0030] 3-(3-(2-(4-fluoro)pyridinyl)-4-thiazolinone)-N-(4-pyrazolbutyl)benzamide;

[0031] 3-(3-(2-(4-methyl)pyridinyl)-4-thiazolinone)-N-(4-pyrazolbutyl)benzamide;

[0032] N-(4-(1H-pyrazolin-1-yl)butyl)-3-(3-(4-(3-ethyl-2,6-dioxopiperidin-3-yl)phenyl)-4-oxathiazolidin-2-yl)benzamide;

[0033] Ethyl 2-(2-(3-((4-(1H-pyrazolin-1-yl)butyl)carbamoyl)phenyl)-4-oxathiazolidin-3-yl)-4-methylthiazole-5-carboxylate;

[0034] 3-(3-(3-pyridinyl)-4-thiazolinone)-N-(4-pyrazolbutyl)benzamide;

[0035] 3-(3-(4-pyridinyl)-4-thiazolinone)-N-(4-pyrazolbutyl)benzamide;

[0036] 3-Fluoro-5-(4-oxo-3-(pyridin-2-yl)thiazolidin-2-yl)-N-(4-phenylbutyl)benzamide;

[0037] 3-(3-(2-pyridyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0038] 3-(3-(2-pyrazinyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0039] 3-(3-(2-pyrazinyl)-4-thiazolinone)-5-fluoro-N-(4-phenylbutyl)benzamide;

[0040] 3-(3-(2-pyridinyl)-4-thiazolinone)-5-methyl-N-(4-phenylbutyl)benzamide;

[0041] 3-(3-(2-thiazolyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0042] 3-(3-(3-tert-butyl 2-isoxazolyl)-4-thiazolinone)-N-(4-phenylbutyl)benzamide;

[0043] 3-(3-(2-pyrazinyl)-4-thiazolinone)-N-(4-1,2,4-triazolylbutyl)benzamide;

[0044] 3-(3-(2-pyridinyl)-4-thiazolinone)-N-(4-N-indolbutyl)benzamide;

[0045] 3-(3-(2-pyridyl)-4-thiazolinone)-N-(4-N-benzotriazolylbutyl)benzamide;

[0046] 3-(3-(2-pyridinyl)-4-thiazolinone)-N-(4-1N-pyrazolbutyl)benzamide;

[0047] 3-(3-(2-pyridinyl)-4-thiazolinone)-N-(4-Boc-piperazinebutyl)benzamide;

[0048] 3-(3-(2-pyridyl)-4-thiazolinone)-N-(4-maleimidobutyl)benzamide;

[0049] 3-(3-(2-pyridinyl)-4-thiazolinone)-N-(4-thienylbutyl)benzamide;

[0050] 3-(3-(4-(tert-butyl)isoxazol-3-yl)-4-oxathiazolidin-2-yl)-N-(4-phenylbutyl)benzamide;

[0051] 3-(3-([1,1'-biphenyl]-4-yl)-4-oxathiazolidin-2-yl)-N-(4-phenylbutyl)benzamide.

[0052] The present invention also provides the 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof, wherein the compound forms an acid addition salt with an acid; wherein the acid is hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, salicylic acid, tartaric acid, lactic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, pyruvic acid or succinic acid, etc.

[0053] The present invention also provides a pharmaceutical composition, which contains a 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof as shown in the above formula (I), and a pharmaceutically acceptable carrier.

[0054] In the present invention, the pharmaceutical composition is formulated into pills, capsules, creams, gels, excipients, injectable fluids, aerosols, syrups or transdermal patches, etc.

[0055] The present invention also provides the use of the 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compound or pharmaceutically acceptable salt or pharmaceutical composition represented by formula (I) in the preparation of anti-tumor drugs.

[0056] The tumor includes but is not limited to osteosarcoma, lung cancer, colorectal cancer, leukemia, etc., preferably osteosarcoma.

[0057] In the present invention, the compound or pharmaceutically acceptable salt or pharmaceutical composition is used to inhibit the proliferation, growth, migration and infiltration of tumor cells; wherein the tumor cells include but are not limited to osteosarcoma cells, lung cancer cells, colorectal cancer cells, leukemia cells, etc., preferably osteosarcoma cells.

[0058] The osteosarcoma cells include SJSA-1 osteosarcoma cells, MNNG / HOS osteosarcoma cells, U-2-OS osteosarcoma cells, MG63 osteosarcoma cells, HOS osteosarcoma cells, and 143B osteosarcoma cells.

[0059] The lung cancer cells include A549 lung cancer cells.

[0060] The leukemia includes Jurkat leukemia cells.

[0061] The colorectal cancer includes HCT116 colorectal cancer cells.

[0062] The present invention also provides the use of the 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compound or pharmaceutically acceptable salt or pharmaceutical composition represented by formula (I) in the preparation of anti-malignant tumor drugs.

[0063] Wherein, the malignant tumor is osteosarcoma but not limited to osteosarcoma, such as colorectal cancer, leukemia, etc.

[0064] In the present invention, the compound or pharmaceutically acceptable salt or pharmaceutical composition is used to inhibit / treat the metastasis and recurrence of malignant tumors.

[0065] The present invention also provides a method for synthesizing the 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compounds or pharmaceutically acceptable salts of the formula (I). The solvent used in the method of the present invention includes one or a combination of alkanes, halogenated alkanes, ethers, halogenated ethers, substituted benzenes, alcohols, esters, ketones, halogenated benzenes, heteroaromatic hydrocarbons, amides, sulfoxides, and water. The basic synthesis steps of the method are as follows:

[0066]

[0067] In the first step, compound 1 (5 mmol, 1.0 eq) and LiOH (5.25 mmol, 1.05 eq) were reacted in a solvent of methanol: water (4:1) at room temperature for 20 hours. The substrate was completely consumed as monitored by spot plate. After the reaction, the methanol in the solvent was removed by rotary evaporation, and the remaining reaction solution was poured into 50 mL of water. 3N HCl was added dropwise to acidify. A large amount of white solid precipitated. The pH was monitored by pH paper until pH = 1. The white solid was filtered out with a Buchner funnel, dissolved with ethyl acetate, dried over anhydrous sodium sulfate, and then rotary evaporated to obtain product 2.

[0068] In the second step, compound 2 (1.5mmol, 1.0eq) and 1-hydroxybenzotriazole (i.e., HOBt, 3.0mmol, 2.0eq) were dissolved in 20mL tetrahydrofuran, and N, N-diisopropylethylamine (DIPEA, 4.5mmol, 3.0eq) was added under ice bath conditions. After stirring for 20 minutes, the compound alkylamine was added and continued to stir for 10 minutes. Subsequently, the condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 3mmol, 2.0eq) was added in batches. After two hours of reaction, the plate was monitored and the raw materials were completely consumed. An appropriate amount of saturated sodium bicarbonate was added to the reaction solution in sequence, washed with saturated brine, and extracted three times with ethyl acetate. The crude product obtained by rotary evaporation was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1-1:1) to obtain compound 3.

[0069] In the third step, aminopyridine 4 (5 mmol, 1.0 eq) and thioglycolic acid 5 (5 mmol, 1.0 eq) were reacted under the reflux condition of toluene / 1,4-dioxane mixed solution for 30 minutes, at which time the corresponding amide compound was generated. Then, the mixture was cooled to room temperature, and 3 (10 mmol, 1.0 eq) was added to the reaction system and continued to reflux. After reacting for 5 hours, the mixture was cooled to room temperature, and the reaction was monitored by spot plate to complete. Then, the mixture was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1 to 1:1) to obtain a white foam solid 1.

[0070] The beneficial effect of the present invention is that the 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compounds or pharmaceutically acceptable salts proposed in the present invention are compounds of a new structure, which can be used to treat osteosarcoma and other related diseases, have good inhibitory properties, and have good selectivity for different cell lines.

[0071] The invention also provides a method for preparing the thiazolinone compound, which has the advantage of being able to synthesize thiazolinone compounds with heterocyclic rings and aliphatic compounds at the 3rd position that cannot be synthesized by traditional synthesis routes. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 The product III-1 obtained in Example 1 1 HNMR Figure 1 A) 13 C NMR ( Figure 1 B) and 19 F NMR ( Figure 1 C) Schematic diagram.

[0073] Figure 2 The product III-2 obtained in Example 2 1 HNMR Figure 2 A) and 13 C NMR ( Figure 2 B) Schematic diagram.

[0074] Figure 3 The product III-3 obtained in Example 3 1 HNMR Figure 3 A) and 13 C NMR ( Figure 3 B) Schematic diagram.

[0075] Figure 4 The product III-4 obtained in Example 4 1 HNMR Figure 4 A) and 13 C NMR ( Figure 4 B) Schematic diagram.

[0076] Figure 5The product III-5 obtained in Example 5 1 HNMR Figure 5 A) and 13 C NMR ( Figure 5 B) Schematic diagram and 19 F NMR ( Figure 5 C) Schematic diagram.

[0077] Figure 6 The product III-6 obtained in Example 6 1 HNMR Figure 6 A) and 13 C NMR ( Figure 6 B) Schematic diagram.

[0078] Figure 7 The product III-7 obtained in Example 7 1 HNMR Figure 7 A) and 13 C NMR ( Figure 7 B) Schematic diagram.

[0079] Figure 8 The product III-8 obtained in Example 8 1 H NMR ( Figure 8 A) and 13 C NMR ( Figure 8 B) Schematic diagram.

[0080] Fig. 9 The product III-9 obtained in Example 9 1 H NMR ( Fig. 9 A) and 13 C NMR ( Fig. 9 B) Schematic diagram.

[0081] Fig.10 The product III-10 obtained in Example 10 1 H NMR ( Fig.10 A) and 13 C NMR ( Fig.10 B) Schematic diagram.

[0082] Fig.11 The product III-11 obtained in Example 11 1 H NMR ( Fig.11 A) and 13 C NMR ( Fig.11 B) Schematic diagram.

[0083] Fig.12 The product III-12 obtained in Example 12 1 H NMR ( Fig.12 A) and 13 C NMR ( Fig.12 B) Schematic diagram.

[0084] Fig.13 The product III-13 obtained in Example 13 1 H NMR.

[0085] Fig.14 The product III-14 obtained in Example 14 1 H NMR ( Fig.14 A) and 13 C NMR ( Fig.14 B) Schematic diagram.

[0086] Fig.15 The product III-15 obtained in Example 15 1 H NMR ( Fig.15 A) and 13 C NMR ( Fig.15 B) Schematic diagram. DETAILED DESCRIPTION

[0087] The present invention is further described in detail in conjunction with the following specific embodiments and drawings, and the protection content of the present invention is not limited to the following embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention and are protected by the attached claims.

[0088] For the preparation of the compounds in the following examples of the present invention, please refer to the preparation of the compounds of formula (I) in the above text. Determination method: low-resolution mass spectrometry (molecular weight) and nuclear magnetic resonance instrument (hydrogen spectrum, carbon spectrum and fluorine spectrum).

[0089] Representative implementation examples:

[0090] Embodiment 1:

[0091]

[0092] III-1 is a foamy white solid with a yield of 92%.

[0093] 1H NMR(400MHz,Chloroform-d)δ8.20(s,1H),8.12(d,J=8.3Hz,1H),7.69(t,J=6.9 Hz,1H),7.48(s,1H),7.29(s,3H),7.18(d,J=7.1Hz,3H),7.10(d,J=8.6Hz,1H), 7.02(d,J=4.6Hz,1H),6.85(s,1H),6.05(s,1H),4.02(d,J=16.1Hz,1H),3.81(d ,J=16.1Hz,1H),3.43(d,J=5.7Hz,2H),2.65(d,J=7.2Hz,3H),1.79–1.50(m,6H).

[0094] 13 C NMR (101MHz, CDCl3) δ171.04,165.71,163.94,150.37,147.69,144.79,141.94,137.98,137.38,128.40,12 5.91,120.92,120.31,116.82,115.87,115.64,113.98,113.74,62.08,40.07,35.45,34.02,29.10,28.66.

[0095] 19 F NMR (376MHz,CDCl3)δ-110.94.

[0096] Embodiment 2:

[0097]

[0098] Yield=65%.

[0099] NMR spectrum:

[0100] 1 H NMR(400MHz,Chloroform-d)δ8.31(s,1H),7.90(s,1H),7.73(s,1H),7.67–7.55(m,3H),7.42(s,1H),7.31(s,2H),7.26–7.20(m,2H),7.05(s,2 H),6.74(s,1H),6.68(s,2H),6.17(s,1H),4.09(s,3H),3.93(d,J=16.1 Hz,1H),3.69(d,J=16.0Hz,1H),3.33(s,2H),1.85(s,2H),1.50(s,3H).

[0101] 13 C NMR (101MHz, CDCl3) δ171.35,167.05,158.46,151.16,148.06,145.39,141.66,139.12,135.15,133.89,129.35,128.8 9,128.55,126.77,125.02,124.01,119.56,116.59,112.65,105.54,62.57,51.27,39.58,33.97,30.32,27.98,26.08.

[0102] Embodiment 3:

[0103]

[0104] Yield = 81%.

[0105] NMR spectrum:

[0106] 1 HNMR(400MHz,Chloroform-d)δ8.16(s,1H),7.98(s,1H),7.73(s,1H),7.58(d,J=6.3Hz,1H),7.43(s,1H),7.36–7.16(m,4H),6.90(s,2 H),6.75(s,1H),6.17(s,1H),4.10(s,2H),3.93(d,J=16.2Hz,1H),3.70(d,J=16.2Hz,1H),3.35–3.24(m,3H),1.86(s,2H),1.50(s,2H).

[0107] 13 C NMR (101MHz, CDCl3) δ171.34,166.98,151.35,148.17,145.35,141.72,139.18,135.18,129.30,128. 51,126.70,125.01,121.10,116.63,105.54,62.58,51.26,39.59,33.98,30.32,29.69,28.01,26.05.

[0108] Embodiment 4:

[0109]

[0110] Yield = 81%.

[0111] NMR spectrum:

[0112] 1 H NMR(400MHz,Chloroform-d)δ8.05(s,1H),7.83(s,2H),7.59(d,J=45.3Hz,2H),7.35(d,J=41.1Hz,2H),6.84(d,J=2 0.1Hz,3H),6.27(s,1H),4.16(s,2H),4.00(s,1H),3.80(s,1H),3.41(s,2H),2.31(s,2H),1.93(s,2H),1.58(s,2H).

[0113] 13 C NMR (101MHz, CDCl3) δ171.20,167.09,150.53,149.32,147.28,141.83,135.04,128.87,1 26.75,125.14,122.18,117.95,105.70,62.79,51.31,39.53,34.17,27.94,26.15,21.27.

[0114] Embodiment 5:

[0115]

[0116] Yield=76%.

[0117] NMR spectrum:

[0118] 1 H NMR(400MHz,Chloroform-d)δ8.12(s,1H),8.01(d,J=10.7Hz,1H),7.80(s,1H),7.65(s,1H),7.51(s,1H),7.44–7.29(m,3H),6.86(s ,1H),6.74(s,1H),6.25(s,1H),4.18(s,2H),4.01(d,J=16.2Hz,1H),3.78(d,J=16.2Hz,1H),3.42(s,2H),1.94(s,2H),1.59(s,2H).

[0119] 13C NMR (101MHz, CDCl3) δ171.40,170.70,168.11,166.99,152.57,149.46,141.91,139.17,135.18,129.30,128.8 7,128.42,126.60,124.94,109.06,108.89,105.54,104.35,104.12,62.64,51.26,39.61,33.99,28.01,26.08.

[0120] 19 F NMR (376MHz,CDCl3)δ-99.62.

[0121] Embodiment 6:

[0122]

[0123] Yield = 83%.

[0124] NMR spectrum:

[0125] 1 H NMR(400MHz,Chloroform-d)δ8.19(s,1H),8.07(d,J=8.3Hz,1H),7.73(s,1H),7.64 (d,J=7.5Hz,1H),7.56(d,J=7.0Hz,1H),7.40(d,J=6.8Hz,1H),7.33–7.24(m,4H),7. 17(d,J=7.0Hz,3H),6.97(s,1H),6.88(s,1H),6.16(s,1H),4.01(d,J=16.0Hz,1H), 3.80(d,J=16.1Hz,1H),3.51–3.27(m,3H),2.64(d,J=7.1Hz,3H),1.74–1.41(m,6H).

[0126] 13 C NMR (101MHz, CDCl3) δ171.23,166.94,150.53,147.72,142.02,137.84,135.29,128.87,128.3 7,126.47,125.87,124.99,120.82,117.16,77.37,62.65,39.96,35.48,34.11,29.19,28.70.

[0127] Embodiment 7:

[0128]

[0129] Yield=70%.

[0130] NMR spectrum:

[0131] 1 H NMR(400MHz,Chloroform-d)δ8.41(d,J=30.1Hz,1H),7.83(s,1H),7.70(d,J=6.9 Hz,1H),7.63(d,J=7.4Hz,1H),7.51(s,1H),7.40(dt,J=16.7Hz,7.4Hz,2H),7.27 (s,0H),6.95(s,1H),6.27(s,1H),6.20(s,1H),4.20(s,1H),3.99(d,J=16.0Hz,1 H),3.90(d,J=15.9Hz,1H),3.52–3.33(m,2H),1.96(s,1H),1.59(d,J=6.0Hz,1H).

[0132] 13 C NMR (101MHz, CDCl3) δ171.21,166.58,147.50,145.88,139.25,135.50,132.99,129.6 5,129.40,127.69,126.19,123.84,105.62,64.60,51.24,39.70,33.29,28.12,25.93.

[0133] Embodiment 8:

[0134]

[0135] Yield=72%.

[0136] NMR spectrum:

[0137] 1 H NMR(400MHz,Chloroform-d)δ8.12(s,1H),7.99(d,J=8.3Hz,1H),7.73(s,1H),7 .66–7.51(m,2H),7.45(s,1H),7.33(s,2H),7.24(d,J=7.6Hz,1H),6.91(s,1H), 6.81(s,1H),6.71(s,1H),6.19(s,1H),4.11(s,2H),3.95(d,J=16.1Hz,1H),3.7 3(d,J=16.1Hz,1H),3.34(d,J=5.7Hz,2H),1.90–1.80(m,3H),1.58–1.42(m,3H).

[0138] 13 C NMR (101MHz, CDCl3) δ171.26,167.07,150.51,147.71,141.86,137.84,135.07,128.7 9,126.67,125.12,120.83,117.22,62.68,51.31,39.56,34.12,29.70,27.98,26.12.

[0139] Embodiment 9:

[0140]

[0141] NMR spectrum:

[0142] 1 H NMR(400MHz,Chloroform-d)δ8.39(s,1H),7.77(s,1H),7.63(s,1H),7.43(s,1H),7.31(d,J=12.0Hz,2H),7.20(s,1 H),6.88(s,1H),6.19(s,1H),4.13(s,1H),3.89(d,J=16.1Hz,1H),3.75(d,J=16.1Hz,1H),3.37(s,1H),1.90(s,2H).

[0143] 13 C NMR (101MHz, CDCl3) δ171.31,166.52,150.60,144.76,139.67,139.18,135.68,129.50,129.35,1 28.48,127.26,125.46,116.78,105.62,63.58,51.21,39.72,33.32,29.70,29.32,28.12,25.86.

[0144] Embodiment 10:

[0145]

[0146] NMR spectrum:

[0147] 11H NMR (400 MHz, Chloroform-d) δ 7.76 (s, 1H), 7.58 (d, J = 7.0 Hz, 1H), 7.46 (d, J = 6.8 Hz, 6H), 7.41–7.35 (m, 6H), 7.32 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 10.5 Hz, 6H), 7.16 (d, J = 6.8 Hz, 4H), 6.16 (d, J = 13.4 Hz, 2H), 4.01 (d, J = 15.7 Hz, 1H), 3.89 (d, J = 15.7 Hz, 1H), 3.52–3.36 (m, 3H), 2.63 (d, J = 6.5 Hz, 3H), 1.74–1.56 (m, 6H).

[0148] 13 13C NMR (101 MHz, CDCl3) δ 170.37, 165.69, 156.32, 153.80, 150.25, 138.39, 134.93, 133.80, 129.48, 127.86, 127.47, 126.69, 126.30, 125.61, 124.88, 124.78, 120.46, 120.01, 118.30, 116.28, 116.04, 115.03, 114.80, 111.76, 111.68, 108.32, 100.14, 63.10, 55.23, 44.81, 38.43, 32.07, 26.43, 26.04.

[0149] Example 11:

[0150]

[0151] Nuclear magnetic spectrum:

[0152] 1 1H NMR (400 MHz, Chloroform-d) δ 9.41 (d, J = 1.3 Hz, 1H), 8.19 (d, J = 2.5 Hz, 1H), 8.11–8.03 (m, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.21–7.17 (m, 2H), 7.14–7.05 (m, 4H), 6.66 (s, 1H), 6.16 (s, 1H), 3.98 (d, J = 17.4 Hz, 1H), 3.74 (d, J = 16.3 Hz, 1H), 3.36 (q, J = 6.8 Hz, 2H), 2.57 (t, J = 7.3 Hz, 2H), 1.72–1.37 (m, 5H).

[0153] 13 C NMR (101MHz, CDCl3) δ171.37,166.91,147.45,142.00,141.82,141.25,140.60,138.98,135.41,12 9.05,128.65,128.41,128.37,126.61,125.87,125.19,61.94,40.04,35.46,33.64,29.15,28.69.

[0154] Embodiment 12:

[0155]

[0156] NMR spectrum:

[0157] 1 H NMR (400MHz, DMSO-d6) δ8.52(t,J=5.5Hz,1H),7.74(t,2H),7.47(d,J=7.9Hz,1H),7.43–7.33(m,3H),7.27(t,J=7.4Hz,2H),7.17(dd,J=15.4Hz,7.2Hz ,3H),6.79(s,1H),4.28(d,J=16.5Hz,1H),4.00(d,J=16.5Hz,1H),3.26(q, J=7.6Hz,7.1Hz,2H),2.59(t,J=7.3Hz,2H),1.56(dt,J=24.8Hz,7.3Hz,4H).

[0158] 13 C NMR (101MHz, DMSO) δ170.68,165.52,156.16,142.08,141.74,137.63,135.05,128.67,128 .26,128.19,127.97,126.66,125.60,124.00,114.99,62.42,34.79,31.80,28.77,28.47.

[0159] Embodiment 13:

[0160]

[0161] NMR spectrum:

[0162] 1¹H NMR (400 MHz, Chloroform-d) δ 7.64 (s, 1H), 7.54 (d, J = 6.1 Hz, 1H), 7.29 (t, J = 7.8 Hz, 2H), 7.20 (t, J = 6.3 Hz, 3H), 7.09 (d, J = 7.2 Hz, 3H), 6.73 (s, 1H), 6.22 (s, 1H), 6.18 (s, 1H), 3.91 (d, J = 16.3 Hz, 1H), 3.62 (d, J = 16.3 Hz, 1H), 3.35 (d, J = 6.0 Hz, 2H), 2.57 (t, J = 6.9 Hz, 3H), 1.73–1.48 (m, 7H), 1.36 (s, 1H), 1.21 (s, 10H).

[0163] Example 14:

[0164]

[0165] Nuclear magnetic spectrum:

[0166] 1 ¹H NMR (400 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.64 (d, J = 7.0 Hz, 1H), 7.53 (d, J = 5.6 Hz, 1H), 7.40 (s, 2H), 7.38–7.31 (m, 1H), 7.26 (s, 2H), 7.18 (s, 3H), 6.73 (s, 1H), 6.26 (s, 1H), 6.15 (s, 1H), 4.22 (s, 2H), 3.98 (d, J = 16.1 Hz, 1H), 3.87 (d, J = 16.0 Hz, 1H), 3.49–3.32 (m, 3H), 2.58–2.46 (m, 1H), 2.20 (dq, J = 24.1, 12.4, 11.0 Hz, 4H), 1.97 (s, 4H), 1.88–1.76 (m, 1H), 1.64–1.56 (m, 3H), 0.80 (q, J = 6.8 Hz, 4H).

[0167] 13C NMR (101MHz, CDCl3) δ174.67,172.02,171.41,170.99,166.77,154.82,141.99,140.12,139.80,1 39.19,137.52,136.72,135.36,134.98,130.65,130.08,129.70,129.43,128.75,128.37,127.23 ,127.01,126.50,125.88,125.59,125.25,120.91,112.15,105.56,64.98,64.34,55.77,51.30,50.80,50.76,39.96,39.66,35.47,33.41,33.17,32.74,29.19,28.70,28.10,26.91,26.02,9.02.

[0168] Embodiment 15:

[0169]

[0170] NMR spectrum:

[0171] 1 H NMR(400MHz,Chloroform-d)δ7.74(s,1H),7.63(s,1H),7.44(s,1H),7.30(d,J=15.9Hz,4H),6.87(d,J=28.0Hz,1H),6.60(s,1H),6.18(s,1H),4.3 1–4.17(m,3H),4.13(s,2H),4.04(d,J=16.2Hz,1H),3.74(d,J=16.6Hz,1H ),3.37(s,2H),2.40(s,3H),1.89(s,3H),1.64–1.48(m,8H),1.36(s,2H).

[0172] 13 C NMR (101MHz, CDCl3) δ170.55,167.01,162.60,157.14,156.27,141.13,139.09,135.29,129.45,128.94,128.39,12 6.95,124.91,116.87,105.61,62.79,60.98,51.24,43.18,39.61,32.57,30.32,29.69,27.98,26.04,17.22,14.34.

[0173] Embodiment 16:

[0174] Determination of compound IC50:

[0175] Experimental content: IC50 of 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide series compounds was determined using CCK8 method.

[0176] Experimental steps:

[0177] 1. Seed board:

[0178] 1) A single cell suspension was prepared using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 SJSA-1 osteosarcoma cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0179] 2) A single cell suspension was prepared using DMEM culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 MNNG / HOS osteosarcoma cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0180] 3) A single cell suspension was prepared using McCoy'5A culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 U-2-OS osteosarcoma cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0181] 4) A single cell suspension was prepared using DMEM culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 MG63 osteosarcoma cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0182] 5) A single cell suspension was prepared using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 HOS osteosarcoma cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0183] 6) A single cell suspension was prepared using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 143B osteosarcoma cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0184] 7) A single cell suspension was prepared using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 A549 lung cancer cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0185] 8) A single cell suspension was prepared using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 Jurkat leukemia cells were inoculated into a 96-well cell culture plate in each well, with a volume of 100 μl per well.

[0186] 2. Administration: The initial concentration was 1 μM, and the drug was administered in three-fold gradient dilutions to 6 / 7 concentrations. The 96-well plate was placed in an incubator for 72 h.

[0187] 3. Use the CCK8 method (see the initial screening step for details) to determine the inhibition rate of different drug concentrations.

[0188] 4. Calculate the IC50 value and plot it using prism.

[0189] Table 1

[0190]

[0191] The present invention selects five compounds in Table 1 for the initial screening of cell viability. It can be seen from the data in Table 1 that compound III-6 of the present invention has a certain inhibitory effect on SJSA-1, U-2-OS, HOS, 143B, MNNG / HOS and MG63 osteosarcoma cells, A549 lung cancer cells and Jurkat leukemia cells, but the best inhibitory activity is for MNNG / HOS and MG63 osteosarcoma cells. Therefore, in subsequent experiments, the present invention only uses the compounds of the present invention to detect the cell IC50 of two subtypes of MNNG / HOS and MG63 in osteosarcoma cells.

[0192] Table 2

[0193]

[0194] As can be seen from Table 2, compounds III-1, III-2, III-3, III-4, III-5, III-6, III-8, III-11, and III-15 have excellent to moderate IC50 values ​​for MNNG / HOS cells, and compounds III-1, III-2, III-3, III-4, III-5, III-6, III-8, and III-11 have good IC50 values ​​for MG63 cells. It can be seen from the table that the compounds of the present invention have good selectivity for different cell lines.

[0195] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the essence of the content of the present invention are covered within the protection scope of the present invention.

Claims

1. A 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following:

2. The 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The pharmaceutically acceptable salt is selected from the acid addition salt formed by 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide and an acid; wherein the acid is hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, salicylic acid, tartaric acid, lactic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, pyruvic acid or succinic acid.

3. A pharmaceutical composition, characterized in that It contains the 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, characterized in that The pharmaceutical composition is formulated as a pill, capsule, cream, gel, injectable fluid, aerosol, syrup or transdermal patch.

5. Use of the 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide or a pharmaceutically acceptable salt thereof as claimed in claim 1, or the pharmaceutical composition as claimed in claim 3 or 4, in the preparation of an anti-tumor and / or tumor treating drug, wherein the tumor is osteosarcoma or leukemia.

6. The use according to claim 5, characterized in that The compound or pharmaceutically acceptable salt or pharmaceutical composition is used to inhibit tumor cell proliferation, growth, migration and infiltration, and promote apoptosis; wherein the tumor cell is an osteosarcoma cell or a leukemia cell.

7. The use according to claim 5, characterized in that The compound or pharmaceutically acceptable salt or pharmaceutical composition is used for inhibiting metastasis and recurrence of malignant tumors.

8. The use according to claim 6, characterized in that: The osteosarcoma cells are SJSA-1 osteosarcoma cells, MNNG / HOS osteosarcoma cells, U-2-OS osteosarcoma cells, MG63 osteosarcoma cells, HOS osteosarcoma cells, and 143B osteosarcoma cells; the leukemia cells are Jurkat leukemia cells.

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