CN102653526B

CN102653526B - 2, 3-diaryl thiazolinone compound and usage thereof in preparation of medicine for treating tumour

Info

Publication number: CN102653526B
Application number: CN201210139633.1A
Authority: CN
Inventors: 陈益华; 吴婧; 郁林羲; 翟东; 易正芳; 罗剑; 刘明耀
Original assignee: East China Normal University
Current assignee: Bioray Laboratories Inc
Priority date: 2012-05-08
Filing date: 2012-05-08
Publication date: 2015-04-08
Anticipated expiration: 2032-05-08
Also published as: CN102653526A

Abstract

The invention discloses a 2, 3-diaryl thiazolinone compound shown in a structural formula (I), or hydrate or pharmaceutically acceptable salt of the 2, 3-diaryl thiazolinone compound, a pharmaceutical composition containing the 2, 3-diaryl thiazolinone compound, and application of the 2, 3-diaryl thiazolinone compound in preparation of a medicine for treating various cancers and related diseases caused by tumor metastasis.

Description

2, 3-diaryl thiazolinone compound and application thereof in preparation of tumor treatment medicines

Technical Field

The invention relates to 2, 3-diaryl thiazolinone compounds and related analogs, and the compounds or pharmaceutical compositions containing the compounds can be used as medicaments for treating various malignant tumors and related diseases of tumor metastasis. The invention also relates to a preparation method of the thiazolinone compound.

Background

The problem of how tumors spread and ultimately cause death of the host has been troubling for humans, and for over a century biologists have generally accepted that tumor metastasis results from the interaction between free tumor cells and the target tissue. However, decades of research into the molecular mechanisms of cancer have focused primarily on the cause of cancer and in situ tumor formation. In contrast, studies of tumor metastasis (including changes in the microenvironment in which the orthotopic tumor resides, invasion of the circulatory system, and formation of new metastases on target tissue organs) are of less interest. However, over 90% of cancer patients die clinically from tumor metastasis, and this statistic has led to the growing recognition that tumors are not merely large masses of transformed malignant cells, and that tumor metastasis plays a very critical role in the development of tumors. Thereafter, the search for metastasis has been renewed (Gupta, g.p.et. al.j.cell2006, 127, 679-. Among them, the development of new drugs targeting tumor growth and metastasis simultaneously is an especially important aspect.

One of the main causes of death in patients with malignant tumors is metastasis of tumor cells, and the motility of cells plays a very important role in the proliferation and migration of cells. Actin polymerization to form actin skeleton is the structural basis of membranous processes at the cell front edge, and these membranous processes are the key factors of cell motility and are also essential for cell migration. As a actin nucleation factor which is deeply researched at present, the actin-related protein Arp2/3 complex plays a very key role in the actin polymerization process, and myofilament polymerization oriented by the Arp2/3 complex maintains many types of cell movement, such as cell-cell adhesion, membrane protrusion and formation of lamellipodia, participates in the formation of membrane-shaped protrusions at the cell front edge and is closely related to the migration movement of cells.

It is statistically more likely that heterocyclic compounds exhibit excellent biological activity, and thus play a very important role in the development of new drugs, and are often considered as the dominant structures in the development of new drugs (Wermuth, C.G.J. Med chem.2004, 47, 1303-. Thiazolinones possess a wide range of pharmacological effects and such heterocyclic compounds have affinity for many biological targets in the body and are considered to be one of the predominant structures in pharmaceutical chemistry. Studies have shown that thiazolinones as an important class of heterocyclic compounds have broad biological activities such as anti-HIV, anti-parasitic and antibacterial activities (Rawal, R.K. et al bioorg Med chem.2007, 15, 1725-1731; Barreca, M.L.et al.J Med chem.2002, 45, 5410-5413; Palekar, V.S.et al.Eur J Med chem.2009, 44, 5112-5116; Rao, A.et al.Farmaco 2004, 59, 33-39.CHOI, Ha-Soon.WOo 2008116274; Schulze, V.EP2141163; ZHenlu, S.CN10117; Matthew, O.F.20050113421; Mendoza, J.S.984084; Michell, WOerthG.WOerthQwo 618, WOr 0204197, WO 435427, WO 3597, WO 35310, WO97, WO 53, WO97, WO 3, WO97, WO 53, WO97, WO 3, WO 53, WO 97. Duane.D.M. et al have reported that thiazolinones or thiazolines have anti-tumor proliferation activity, but no study of such compounds on anti-tumor migration has been reported (Guduru, V.et al bioorg Med Chem Lett.2004, 14, 5289-. Peng-Cheng Lv et al also report that 2-hydrazinothiazolinone compounds have the activity of inhibiting EGFR and HER-2 kinase, and are potential anti-tumor growth inhibitors (Peng-Cheng Lv. et al. bioorg. Med. chem.2010, 18, 314-one 319), and the report that such compounds are used in anti-tumor migration is not available. The 2, 3-diaryl thiazolinone compounds and related analogs have the activity of inhibiting tumor growth and metastasis, and provide a good entry point for subsequent research of antitumor drugs.

Disclosure of Invention

The invention aims to provide 2, 3-diaryl thiazolinone compounds and related analogs which can be used as antitumor lead compounds, including available salts, solvent compounds (hydrates), esters and the like.

The invention also aims to provide application of the 2, 3-diaryl thiazolinone compounds and the related analogs in preparation of medicaments for treating related diseases caused by tumor angiogenesis.

The invention also aims to find the application of the compound or the pharmaceutical composition containing the compound in preparing medicaments for treating various malignant tumors, particularly breast cancer, lung cancer, liver cancer, prostatic cancer, skin cancer, colon cancer, pancreatic cancer, leukemia, ovarian cancer, gastric cancer, bladder cancer, kidney cancer, oral cancer and other diseases and related cancer metastasis and relapse processes.

The invention provides a 2, 3-diaryl thiazolinone micromolecule organic compound or hydrate or pharmaceutically acceptable salt thereof, which is represented by the following structural formula (I):

wherein:

x is S, O or NH;

n is 0, 1, 2 or 3;

Ar₁and Ar₂The substituent is selected from one of the following aryl or heterocyclic aryl, including monocyclic aryl, polycyclic aryl and polyheterocyclic aryl; the monocyclic aromatic group includes phenyl, azaaromatic group, thiaaromatic group, oxaaromatic group. The polycyclic aromatic group and the polyheterocyclic aromatic group refer to groups containing two or more monocyclic aromatic groups.

The R substituent is selected from any one of the following groups: hydrogen; an alkyl group; a substituted alkyl group; a hydroxyl group; a hydroxymethyl group; c₂-C₆An alkenyl group; substituted C₂-C₆An alkenyl group; c₂-C₆Alkynyl of (a); substituted C₂-C₆An alkynyl group; c₃-C₈Cycloalkyl groups of (a); a substituted cycloalkyl group; an aryl group; substituted aryl substituted with any one, two, three, four or five groups; a heterocyclic aryl group; one or more substituted heteroaryl groups; a benzyl group; a substituted benzyl group; a phenethyl group; a substituted phenethyl group; a phenylpropyl group; an alkanoyl group; aroyl; substituted alkanoyl and aroyl groups containing halogen atoms, alkoxy or hydroxy groups; c₂-C₆Alkenoyl of (a); c₃-C₈The cycloalkanoyl group of (a); any one, two or three groups including halogen atom, alkoxy group, alkylamino group and the likeSubstituted benzoyl; a furyl group; a thienyl group; an adamantyl group; a cycloalkoxy group; a cycloalkylamino group; an amine group; an amide group; an alkoxycarbonyl group; a cycloalkoxycarbonyl group; an alkylamide group; a cycloalkaneamide group; a carboxyl group.

In the present invention, the hydrate of the 2, 3-diaryl thiazolinone compound refers to a complex formed by the 2, 3-diaryl thiazolinone compound and water molecules.

In the present invention, the pharmaceutically acceptable salt of the 2, 3-diaryl thiazolinone compound means a salt form of the 2, 3-diaryl thiazolinone compound formed with a corresponding acid or base, which is generally accepted pharmaceutically.

The invention also provides a 2, 3-diaryl thiazolinone compound or a hydrate or a pharmaceutically acceptable salt thereof, wherein in the structural formula (I), when n is 0 and R is hydrogen, the compound is represented by the following structural formula (II):

wherein,

x is S, O or NH;

The invention also provides a 2, 3-diaryl thiazolinone compound or hydrate or pharmaceutically acceptable salt thereof, wherein in the structural formula (I), when n is 0, R is hydrogen, X is S, Ar₂Is Ar₃-R₁When represented by the following structural formula (III):

wherein:

Ar₁and Ar₃Any one of the following aromatic groups or heterocyclic aromatic groups, including monocyclic aromatic group, polycyclic aromatic group and polyheterocyclic aromatic group; the monocyclic aromatic group includes phenyl, azaaromatic group, thiaaromatic group, oxaaromatic group. The polycyclic aromatic group and the polyheterocyclic aromatic group refer to groups containing two or more monocyclic aromatic groups.

R₁Independently selected from one or more of the following groups: hydrogen, amino, cyano, hydroxy, nitro, halogen, carboxy, alkyl, alkoxy, amino, cycloalkoxy, cyclic amino, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, benzyl, alkylcarbonyl, C₂-C₁₂Alkenylcarbonyl group, C₃-C₁₂Cycloalkylcarbonyl, phenylcarbonyl, benzylcarbonyl, alkoxycarbonyl, ester, amide, sulfoxide, sulfone, sulfonamide; morpholinyl; a piperazinyl group.

The invention also provides a 2, 3-diaryl thiazolinone compound or hydrate or pharmaceutically acceptable salt thereof, wherein in the structural formula (III), when R is₁When the substitution is a chain substitution, the substitution is represented by the following structural formula (IV):

wherein,

m is 0, 1, 2,3, 4, 5, 6, 7, 8 or 9 CH₂；

X is O ═ S ═ NH, ═ N-NH2, -OH, or-H;

l is O, S, N or NH;

Ar₁、Ar₃and Ar₄The substituent is selected from any one of the following aryl or heterocyclic aryl, including monocyclic aryl, polycyclic aryl and polyheterocyclic aryl; the monocyclic aromatic group includes phenyl, azaaromatic group, thiaaromatic group, oxaaromatic group. The polycyclic aromatic group and the polyheterocyclic aromatic group refer to groups containing two or more monocyclic aromatic groups.

The invention also provides a 2, 3-diaryl thiazolinone compound or hydrate or pharmaceutically acceptable salt thereof, which is an acid addition salt formed by the 2, 3-diaryl thiazolinone compound and acid; wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, salicylic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, lactic acid, pyruvic acid, maleic acid, or succinic acid.

The invention also provides a 2, 3-diaryl thiazolinone compound or hydrate or pharmaceutically acceptable salt thereof, wherein the 2, 3-diaryl thiazolinone compound is combined with a radioactive group, a fluorescent group or biotin to form a marker.

The invention provides a 2, 3-diaryl thiazolinone compound or a hydrate or pharmaceutically acceptable salt thereof, which comprises the following components:

2- (3-bromophenyl) -3-phenyl-4-thiazolinone

2- (3-bromophenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (2-hydroxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone

2- (3-chlorophenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4-fluorophenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (2-thiazolyl) -4-thiazolinone

2-phenyl-3- (2-methoxyphenyl) -4-thiazolinone

2- (3-nitrophenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3-methoxyphenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (2-propionic acid methyl ester) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3- (1-Carboxylic acid methyl ester) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (1-Carboxylic acid methyl ester) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (2-acetic acid methyl ester) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3- (1-Carboxylic acid methyl ester) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (2-pyrimidinyl) -4-thiazolinone

2- (4-pyridyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (2-quinolyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (3-nitrophenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (2-methoxyphenyl) -1, 3-thiazin-4-one

2- (3-bromophenyl) -3- (2-hydroxyphenyl) -1, 3-thiazin-4-one

2- (3-bromophenyl) -3- (3-methoxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (4- (diethylamino) phenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (3-hydroxyphenyl) -4-thiazolinone

2- (4-bromophenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (2-bromophenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (4-ethoxyphenyl) -4-thiazolinone

2- (3-hydroxyphenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (4-hydroxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (2-aminophenyl) -4-thiazolinone

2- (2-furyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (2-thienyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (2-Propioniyl) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3-formyloxyphenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3-formyloxyphenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone

2- (4- (2-acetoxy) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (2- (N-phenylpropionamide)) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N, N-diethylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N, N-diallylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (pyridine benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N-benzylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N-phenylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N-phenethylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N-methylbenzamide) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone

2- (4- (N- (2-methoxyphenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (4-fluorophenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (4-chlorophenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (3-fluorophenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (4-trifluoromethylphenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (2-chlorophenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (4-hydroxybutyl) benzamide) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone

2- (4- (N, N-diethylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N-propylbenzamide) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone

2- (4- (N-Ethyl acetate benzamide) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone

2- (4- (N- (3-phenylpropyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (4-phenylbutyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (4-bromophenyl ethyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (4-hydroxybenzyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (4-chlorophenylethyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N-4-methoxyphenylethyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N-phenyl acetamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (4-fluorobenzoyl butyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (4-fluorophenethyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (2-bromophenyl ethyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (6-phenylhexyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (5-phenylpentyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (2, 4-dihydroxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (4-hydroxy-2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (2-phenylacetamide)) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (4- (N- (benzamide)) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3- (hydroxymethyl) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3- (bromomethyl) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (4-amino-2-methoxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (4- (benzylamino) -2-methoxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (2- (ethylamino) phenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (2- (methylamino) phenyl) -4-thiazolinone

2- (3- (3-pyridyl) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (2-methoxyphenyl) -4-oxazolinone

2- (3-bromophenyl) -3- (2, 4-dimethoxyphenyl) -4-oxazolinone

2- (3-bromophenyl) -3- (2- (dimethylamino) phenyl) -4-thiazolinone

2- (3-bromophenyl) -3- (2-phenylacetyl) thiazolin-4-one.

The invention provides a pharmaceutical composition, which contains the 2, 3-diaryl thiazolinone compound and related analogs or hydrates or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention are formulated as injectable fluids, aerosols, creams, gels, pills, capsules, syrups, transdermal patches or excipients.

The invention also provides application of the 2, 3-diaryl thiazolinone compound or hydrate or pharmaceutically acceptable salt thereof in inhibiting Actin polymerization.

The invention also provides application of the 2, 3-diaryl thiazolinone compound and related analogues or hydrates or pharmaceutically acceptable salts thereof in preparation of antitumor drugs. The invention provides application of the 2, 3-diaryl thiazolinone compound, hydrate or pharmaceutically acceptable salt in inhibiting proliferation, growth, migration and infiltration of tumor cells; wherein the tumor cells comprise lung cancer cells, breast cancer cells, epidermal cancer cells, colon cancer cells, liver cancer cells, stomach cancer cells and prostate cancer cells.

The invention also provides the application of the 2, 3-diaryl thiazolinone compound in preparing a medicament for treating malignant tumor; wherein the malignant tumor comprises liver cancer, lung cancer, prostate cancer, skin cancer, colon cancer, pancreatic cancer, breast cancer, leukemia, ovarian cancer, stomach cancer, bladder cancer, renal cancer, and oral cancer.

The invention also provides the application of the 2, 3-diaryl thiazolinone compound or the hydrate or the pharmaceutically acceptable salt thereof in preparing the medicine for treating the metastasis and the recurrence of the malignant tumor; wherein the malignant tumor comprises liver cancer, lung cancer, prostate cancer, skin cancer, colon cancer, pancreatic cancer, breast cancer, leukemia, ovarian cancer, stomach cancer, bladder cancer, renal cancer, and oral cancer.

In the present invention, the 2, 3-diaryl thiazolinone compound or its hydrate or pharmaceutically acceptable salt may be used alone or in combination with other drugs.

The 2, 3-diaryl thiazolinone compound is prepared by the following steps:

the method comprises the following steps:

aromatic amines, aromatic aldehydes and thioglycolic acid or related analogs from various sources are refluxed in a suitable solvent (such as toluene, dioxane, etc.) or subjected to Mannich reaction in the presence of a dehydrating agent (such as DCC) to obtain the target product.

The second method comprises the following steps:

the substituted phenylamine from various sources and glycollic acid are subjected to coupling reaction to generate the target product, and then the target product and the substituted benzaldehyde from various sources are subjected to reflux in a proper solvent (such as xylene) to carry out Mannich reaction.

Wherein R is₄And R₅Independently selected from one or more of the following groups: hydrogen, amino, cyano, hydroxy, nitro, halogen, carboxy, alkyl, alkoxy, amino, cycloalkoxy, cyclic amino, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl, benzyl, alkylcarbonyl, C₂-C₁₂Alkenylcarbonyl group, C₃-C₁₂Cycloalkylcarbonyl, phenylcarbonyl, benzylcarbonyl, alkoxycarbonyl, ester, amide, sulfoxide, sulfone, sulfonamide; morpholinyl; a piperazinyl group.

Drawings

FIG. 1 is a graph showing the inhibitory effect of the compound of the present invention on the proliferation of human lung cancer cells A549 at 5.0. mu. mol/L.

FIG. 2 is a graph showing the inhibitory effect of the compound of the present invention on the proliferation of human breast cancer cell MDA-MB-231 at 5.0. mu. mol/L.

FIG. 3 is a statistical chart showing the inhibitory effect of the compound of the present invention on the proliferation of various lung cancer cells and the proliferation of normal embryonic lung fibroblast MRC-5 cells at 5.0. mu. mol/L.

FIG. 4 is a graph showing the inhibitory effect of the compound of the present invention on Actin (Actin) polymerization at 20. mu. mol/L.

FIG. 5 is a graph showing the effect of the compounds of the present invention on the migration inhibition of Bcap37 and 4T1 in breast cancer cells at 20. mu. mol/L.

FIG. 6 is a graph showing the effect of the compounds of the present invention on the MDA-MB-231 migration inhibition in human breast cancer cells.

FIG. 7 is a graph showing the inhibitory effect of the compounds of the present invention on breast cancer growth in a xenograft model in nude mice. Wherein, FIG. 7A is the comparison of the tumor size in situ of the mice in the administration group and the control group 20 days after administration; FIG. 7B is a graph of tumor volume versus days of administration; fig. 7C is a graph comparing the body weights of mice in the administration group and the control group.

FIG. 8 is a graph showing the therapeutic effect of the compounds of the present invention on the in situ growth of breast cancer and non-specific organ metastasis in a spontaneous breast cancer metastasis model. Wherein, fig. 8A is a diagram of breast cancer chest metastasis and in vivo main organ metastasis after 25 days of administration of the compound of the present invention by an active imaging system and the effect of the compound on metastasis inhibition, fig. 8B is a diagram of in situ tumor volume versus administration days, and fig. 8C is a diagram of breast cancer chest metastasis rate in the administration group and the control group according to the statistics of in vivo imaging results.

Detailed Description

The present invention will be described in further detail with reference to the following specific examples and drawings, and the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.

¹H-NMR was measured using a Bruker 300 or Bruker 400 type apparatus; MS is measured by a VG ZAB-HS or VG-7070 type instrument, and is an ESI method except for indication; all solvents are redistilled before use, and the used anhydrous solvents are obtained by drying according to a standard method; all reactions were carried out under argon protection and followed by TLC except for the indication, and the post-treatment was carried out by washing with saturated saline and drying with anhydrous sodium sulfate; purification of the product except for the indication silica gel (200 and 300 mesh) column chromatography was used; the silica gel used comprises 200-300 mesh and GF₂₅₄Is Qingdao ocean chemical plant or tobacco terrace edge Bo silica gel companyAnd (4) production.

Example 1: preparation of the respective Compounds

Example 1-1, 2- (3-bromophenyl) -3-phenyl-4-thiazolinone

The compound 3-bromobenzaldehyde (185mg, 1.0mmol) and aniline (92 μ L, 1.0mmol) were put in toluene, stirred under nitrogen atmosphere and ice bath condition for 5min, then changed to oil bath and heated to reflux, and the device was connected with an oil-water separator. Cooling until no water is generated, adding mercaptoacetic acid (70 mu L, 1.0mmol) as a compound, continuously heating to reflux, obtaining a crude product after water separation is finished, and purifying by column chromatography to obtain TZL001(261mg, yield: 78%):¹H NMR(400MHz，DMSO)7.59(s，1H)，7.41-7.39(m，2H)，7.31-7.30(m，4H)，7.25-7.21(m，1H)，7.16-7.13(m，1H)，6.0(s，1H)4.07(d，J＝14.6Hz，1H)，3.87(d，J＝14.6Hz，1H).。

examples 1-2 to 1-80 preparation of TZL002-80 thiazolinones

TABLE 1

Example 2: inhibition experiment of the Compound of the present invention on the growth of tumor cells

The compound of the invention has the inhibition effect on the proliferation and migration activity of different tumor cells (human non-small cell lung cancer A549 and human breast cancer MDA-MB-231) and the inhibition effect on the formation of an Arp2/3 complex:

1. culture of cells

The cells used in this experiment were purchased from Shanghai cell bank of Chinese academy of sciences, and cultured in a constant temperature incubator (humidity 95%)，CO₂5%), DMEM high-glucose medium (Gibco) containing 10% fetal bovine serum (Front) was used as the culture medium for the tumor cells in this experiment.

Determination of cell growth by the SRB (sulforhodamine) method

Tumor cells were treated at 5x10³After 24 hours of routine incubation at a density of one well in a 96-well plate (Corning), the compounds of the present invention were added sequentially at different concentrations to give final concentrations of 0.01. mu. mol/L, 0.05. mu. mol/L, 0.10. mu. mol/L, 0.50. mu. mol/L, 1.0. mu. mol/L, 5.0. mu. mol/L, 10.0. mu. mol/L, and DMSO was added in equal amounts to the control groups, each group having 6 auxiliary wells. After further 48h of culture, add pre-cooled TCA (trichloroacetic acid, 50%, w/V), 25. mu.l/well and mix gently. Cells were fixed by incubation at 4 ℃ for 60 min. After fixation, washing for 5 times with running water, and air drying. Mu.l of SRB stain (4%, w/V) was added to each well and incubated at room temperature for 10min for staining. The dye solution was aspirated, and 100. mu.l of 1% acetic acid was added to each well and washed 5 times to remove unbound dye. After air drying, 100. mu.l of Tris solution with a concentration of 10mmol/L was added to each well, and the bound SRB dye was dissolved by shaking. The 96-well plate was placed in a microplate reader (SPECTRAMAX190) and OD was measured at a wavelength of 515 nm. The cell viability was calculated according to the following formula and the effect of the drug on cell growth was statistically analyzed.

The results of the experiment are shown in FIGS. 1-3, in which:

(1) the compound of the invention has very strong inhibition effect on the growth of human lung cancer cell A549 at 5.0 mu mol/L, which is shown in figure 1. It can be seen from the figure that most compounds have very obvious effect of inhibiting the growth of the lung cancer cells of the strain, and among the listed compounds, the inhibition rates of compounds TZL002, TZL005, TZL041, TZL043, TZL055-TZL066, TZL077 and the like to the growth of the lung cancer cells A549 at the concentration of 5.0 mu mol/L are all more than 50%, and part of compounds reach more than 90% at the concentration, so that the compounds have very obvious effect of inhibiting the growth of the A549 cells.

(2) The compound of the invention has very strong inhibition effect on the growth of human breast cancer cell MDA-MB-231 at 5.0 mu mol/L, which is shown in figure 2. As can be seen from the figure, most compounds have very obvious inhibitory effect on the growth of the breast cancer cells. Among the listed compounds, TZL002, TZL004, TZL005, TZL008, TZL056-TZL063, TZL065, TZL066 and TZL077 and other compounds have the inhibition rate of more than 50% on the growth inhibition of breast cancer cell MDA-MB-231 at the concentration of 5.0 mu mol/L, and therefore, the compound also has obvious inhibition effect on the breast cancer cell.

(3) The compound of the invention has strong inhibition effect on the growth of cancer cells, and has no obvious inhibition effect on normal cells. Among the tested compounds, TZL002, TZL005, TZL008, TZL055, TZL058, TZL063, TZL077, etc. have strong inhibitory selectivity to the growth of various lung cancer cells, and have poor growth inhibitory activity to corresponding normal cells. From FIG. 3, it can be seen that the compound has IC for inhibiting the growth of lung small cell lung cancer H1299 and A549₅₀IC for H460 growth inhibition at around 1-5 μmol/L₅₀About 5-10 mu mol/L, but has poor effect of inhibiting normal lung fibroblast MRC5, IC₅₀At least 100. mu. mol/L. These results indicate that such compounds have excellent selectivity for tumor cells.

The compound of the invention has obvious inhibition effect on various tumor cells such as liver cancer, lung cancer, prostatic cancer, skin cancer, colon cancer, pancreatic cancer, breast cancer, leukemia, ovarian cancer, gastric cancer, bladder cancer, kidney cancer, oral cancer and the like, and simultaneously, the compound of the invention has no obvious inhibition effect on normal cells.

Example 3: inhibitory Effect of the Compounds of the present invention on Actin (Actin) polymerization

We used the actin polymerization kit (Cytoskeleton) to test the effect of the compounds of the present invention on the in vitro actin polymerization mediated by Arp 2/3.

(1) Thawing actin polymerization buffer solution and ATP at 37 deg.C, centrifuging for 5s after thawing, and placing on ice;

(2) adding 2 mu L ATP into 1mL General actin Buffer solution to prepare G-Buffer, and placing on ice;

(3) melting and freezing pyrene-actin on ice, adding 225 μ L of precooled G-Buffer into every 5 μ L of pyrene-actin to prepare G-actin stock, uniformly mixing, and standing on ice for 1 h;

(4) centrifuging at 14000rpm and 4 ℃ for 30min, placing the supernatant in a new tube, and placing on ice;

(5) thawing Arp2/3(5mg/ml) on ice, diluting Arp2/3 to 0.3mg/ml with G-Buffer, and placing on ice;

(6) thawing VCA (5mg/ml) on ice, diluting VCA to 1mg/ml with G-Buffer, and placing on ice;

(7) diluting the thawed polymerization buffer solution in the step 1 by 10 times, and adding ATP to make the final concentration of ATP be 0.3 mM;

(8) diluting the G-actin stock by 4.5 times by using G-Buffer, and placing the diluted G-actin stock on ice;

(9) arp2/3, VCA, polymerization buffer and test compound were mixed on ice and left for 15min, followed by addition of pyrene-actin, reading on a fluorometer (excitation 350nm, emission 410 nm).

Some of the results are shown in FIG. 4, where the actin monomer used in the experiment was pyrene-coupled actin. When it exists in the form of monomer, it does not emit fluorescence, and when it is polymerized to form chain actin, the fluorescence intensity is increased under the excitation light of 350nm and the emitted light of 410nm, so that the polymerization of actin can be reflected by monitoring the change of fluorescence intensity in the reaction system with time. The experimental results show that it is difficult to form the chain actin by only relying on the spontaneous polymerization of the monomer actin without the participation of the nucleation factor (Arp2/3) and the nucleation promoting factor (VCA domain of WASP protein). In contrast, the polymerization of monomeric actin can be significantly promoted when a nucleation factor (Arp2/3) and a nucleation promoter (VCA domain of WASP protein) are present. The results that both 20. mu.M 2 and Compound 10 were effective in inhibiting the in vitro actin polymerization mediated by Arp2/3 indicate that the compounds of the present invention significantly inhibit the actin polymerization activity of Arp 2/3.

Example 4: the compound of the invention has the function of inhibiting the migration capacity of tumor cells.

Cells move along the culture plane to a smaller portion of the cells during in vitro culture. By utilizing this phenomenon, if a "scar" is artificially "scratched" in a culture well which is already full of cells, the cells on both sides of the "scar" move to the "scar" area and eventually re-cover the area, which is called "scar healing". The movement ability of the cells can be judged according to the number of the cells moving to the scar area and the healing degree of the scar.

Tumor cells were inoculated into 12-well plates at 37 ℃ with 5% CO₂The cells are cultured in an incubator for 24h in a conventional way until the cells grow to be 100% full. The serum-free medium is replaced and the culture is continued for 12 h. The wells were scratched with 10. mu.l of sterile tip, and after scratching, the cells were washed twice with PBS, and the floating cells were washed away, and 1ml of complete medium was added to each well. Adding drugs with different concentrations into the cell culture holes respectively, and placing the culture plate into CO₂The incubator is used for further conventional culture at 37 ℃ for 24 hours. The cells were observed under a microscope with the movement of the desired streaked portion and photographed. The cell migration rate was calculated according to the following formula, and the number of cells migrating into the streaked area from the drug groups at different doses was statistically analyzed to determine the effect of the drug on the cell migration ability.

As shown in FIGS. 5 to 6, it was found from the graphs of the migration inhibitory effect that Bcap37 and 4T1 were observed in two breast cancer cellsIn the white Healing migration experiment model, the compound of the present invention substantially inhibits the migration of tumor cells at 20. mu.M. From the statistics of migration inhibition effect in FIG. 6, it can be seen that in the experimental model of cell migration of breast cancer cell MDA-MB-231, compounds TZL056 and TZL057 have half the effective inhibitory concentration IC on MDA-MB-231₅₀IC of Compounds TZL063 and TZL064 for MDA-MB-231 migration inhibition between 0.01-0.05. mu. mol/L₅₀IC of less than 0.01. mu. mol/L for MDA-MB-231 migration inhibition by Compound TZL065₅₀Much less than 0.01. mu. mol/L. Indicating that the compound can effectively inhibit the migration of tumor cells in the tumor cell migration model.

The compound of the invention is used for carrying out migration capacity experiments on malignant tumor cells of liver cancer, lung cancer, prostatic cancer, skin cancer, colon cancer, pancreatic cancer, breast cancer, leukemia, ovarian cancer, gastric cancer, bladder cancer, renal cancer, oral cancer and the like, and remarkable inhibition effects are obtained. Therefore, the compound is suitable for preparing the medicine for treating the metastasis and the relapse of the malignant tumor.

Example 5: inhibitory Effect of Compounds of the invention in mouse models of Breast cancer growth and metastasis

1. Inhibition of mouse breast cancer growth model by compounds of the invention

50 ten thousand of individual breast cancer cells Bcap37 were injected subcutaneously into the back of immunodeficient mice (nude mice) to treat subcutaneous tumors growing to 100mm³On the left and right, the mice were divided into two groups (average tumor volume was the same), the mice of the drug group were intraperitoneally injected with 20mg/kg of the compound of the present invention dissolved in DMSO every day, the mice of the control group were injected with DMSO only, the body weight of the mice and the length and width of the tumor were measured and recorded every day, the mice were sacrificed 20 days after the administration, the subcutaneous tumors were taken, and photographs were taken. Tumor volume was counted according to the formula volume-length x width 2 x 0.52.

The results are shown in fig. 7, in which compounds TZL002, TZL015, TZL027, TZL056 and TZL062 were continuously administered for 20 days, and as a result, it was found that such compounds had a very significant inhibitory effect on the in situ growth of breast cancer (including the size and volume of tumor) at a dose of 20mg/kg/day, relative to the control group. Moreover, the body weight of the mice of the administration group is not obviously different from that of the control group, which preliminarily shows that the toxic and side effects of the compound are possibly small.

2. Inhibition of mouse breast cancer metastasis model by compounds of the invention

This experiment simulates the onset and course of treatment of breast cancer metastasis clinically. Bal b/c female mice at 4-6 weeks, 5X10 injected in situ into the breast pad⁴Mouse mammary carcinoma cells 4T 1. After 7 days of tumor loading, the in situ tumors grew to a diameter of about 5mm, and were randomly and equally divided into 3 groups according to the sizes of the in situ tumors of mice, namely a control group, a 20mg/kg/day dose group and a 40mg/kg/day dose group. The drug administration groups were injected intraperitoneally with the drugs at the corresponding doses, and the control group was injected with the same amount of solvent (DMSO). Mice were weighed daily before compound injection and mice survival was recorded. The administration is continued for 24 days, and the integral transferring condition of the thoracic cavity and the transferring condition of main organs in the body are photographed on the 25 th day by adopting a mouse living body imaging technology (IVIS), and the transferring condition of tumor cells to the organs is observed.

Results as shown in fig. 8, fig. 8A is a graph of the effect of the treatment on the mouse breast carcinoma in situ 25 days after administration (a picture is taken by an animal living body imaging system, since the tumor cells have fluorescence, the location and intensity of the fluorescence can be used to determine the distribution and amount of the tumor cells, respectively, the shading in the picture represents a fluorescence signal, which indicates that the tumor cells are aggregated in the region and the aggregation degree of the cells is deepened from the outside to the inside. the result shows that the compounds TZL002, TZL007, TZL045, TZL056 and TZL063 at the dose of 20mg/kg/day significantly inhibit the growth of the breast carcinoma in situ, while the compounds at the dose of 40mg/kg/day more significantly inhibit the growth of the breast carcinoma in situ. the right side of fig. 8A is the main organs of the mouse which is stripped at the end of the experiment, the breast cancer in the control group of mice significantly metastasizes to organs such as lung, heart, leg bone and liver, and the 40mg/kg/day, the probability and extent of tumor metastasis is significantly reduced, from which it can be seen that the compounds of the present invention now inhibit tumor metastasis to other organs. FIG. 8B is a graph of the change in tumor volume after measuring the size of the breast pad in situ during continuous dosing. The result shows that after 25 days of administration, compared with a control group, the compound has obvious inhibition effect on in-situ tumor growth and is in a dose dependent relationship. Fig. 8C is the thoracic cavity metastasis rate of breast cancer cells counted 25 days after administration according to the in vivo imaging results, from which it can be found that the compounds have significant inhibitory effect on mouse tumor metastasis relative to the control group.

The following examples 1-2 to 1-80 provide the preparation methods and the product detection results of the compounds TZL002-80 of the present invention.

Example 1-2, 2- (3-bromophenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL002)

By a method similar to the method for preparing the compound TZL001, aniline is replaced by o-anisidine, and the compound TZL002 is obtained after column chromatography purification, with the yield being 85%:¹H NMR(400MHz，DMSO)7.52(s，1H)，7.34(d，J＝8.0Hz，1H)，7.19(dd，J＝8.0，8.0Hz，1H)，7.09(dd，J＝8.0，8.0Hz，1H)，6.92(d，J＝8.0Hz，1H)，6.87-6.80(m，2H)，6.02(s，1H)，3.94(AB，J＝15.6Hz，1H)，3.86(AB，J＝15.6Hz，1H)，3.81(s，3H).¹³C NMR(100MHz，CDCl₃)171.3，154.9，141.7，132.1，130.9，130.1，130.0，129.8，126.5，125.3，122.5，121.0，112.1，64.1，55.8，33.1.。

examples 1-3, 2- (3-bromophenyl) -3- (2-hydroxyphenyl) -4-thiazolinone (TZL003)

By a method similar to the preparation of TZL001, the aniline was replaced with o-aminophenol, and purification by column chromatography gave compound TZL003, yield: 68%:¹H NMR(400MHz，DMSO)9.93(br s，1H)，7.63(s，1H)，7.43-7.41(m，2H)，7.24-7.20(m，1H)，7.06-7.02(m，1H)，6.92(d，J＝7.8Hz，1H)，6.84(d，J＝7.8Hz，1H)，6.68-6.64(m，1H)，6.0(br s，1H)，4.01(d，J＝14.1Hz，1H)，3.79(d，J＝14.1Hz，1H).。

examples 1-4, 2- (3-bromophenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone

By a method similar to the preparation of TZL001, aniline was replaced with 2, 4-dimethoxyaniline, and purification by column chromatography gave TZL004, yield: 78%:¹H NMR(400MHz，DMSO)7.62(d，J＝1.6Hz，1H)，7.44(d，J＝8.0Hz，1H)，7.39(d，J＝8.0Hz，1H)，7.24(dd，J＝8.0，8.0Hz，1H)，6.90(d，J＝8.8Hz，1H)，6.56(d，J＝2.8Hz，1H)，6.40(dd，J＝2.4，8.0Hz，1H)，6.09(s，1H)，4.01(AB，J＝1.6，15.6Hz，1H)，3.80(AB，J＝15.6Hz，1H)，3.76(s，3H)，3.70(s，3H).。

examples 1-5, 2- (3-chlorophenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL005)

By a method similar to the preparation of the compound TZL001, 3-bromobenzaldehyde is replaced by 3-chlorobenzaldehyde, aniline is replaced by o-anisidine, and the compound TZL005 is obtained after column chromatography purification with the yield being 66%:¹H NMR(400MHz，CDCl₃)： 7.37(s，1H)，7.24-7.20(m，2H)，7.18-7.17(m，2H)，6.93(dd，J＝8.0，1.6Hz，1H)，6.88(dd，J＝8.0，0.8Hz，1H)，6.83(ddd，J＝7.6，7.6，0.8Hz，1H)，6.03(s，1H)，3.96(d，J＝15.6Hz，1H)，3.89(d，J＝15.6Hz，1H)，3.84(s，3H).。

examples 1-6, 2- (3-fluorophenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL006)

By a method similar to the method for preparing the compound TZL001, replacing 3-bromobenzaldehyde by 3-fluorobenzaldehyde, replacing aniline by o-anisidine, and purifying by column chromatography to obtain the compoundCompound TZL006, 66% yield:¹H NMR(300MHz，DMSO)：7.29-7.27(m，2H)，7.20-7.17(m，2H)，7.07-7.04(m，1H)，7.01(d，J＝7.8Hz，2H)，6.81(dd，J＝7.8，7.8Hz，1H)，6.18(s，1H)，4.02(d，J＝15.9Hz，1H)，3.80(d，J＝15.9Hz，1H)，3.76(s，3H).。

examples 1-7, 2- (3-bromophenyl) -3- (2-thiazolyl) -4-thiazolinone (TZL007)

By a method similar to the method for preparing compound TZL001, only aniline was replaced with 2-aminothiazole, and purification by column chromatography gave compound TZL007, with 48% yield:¹H NMR(300MHz，DMSO)：7.74(d，J＝8.7Hz，2H)，7.64(s，1H)，7.43-7.41(m，2H)，7.29(d，J＝8.4Hz，2H)，7.31-7.28(m，1H)，6.63(s，1H)，4.09(d，J＝15.9Hz，1H)，3.91(d，J＝15.9Hz，1H).。

examples 1-8, 2-phenyl-3- (2-methoxyphenyl) -4-thiazolinone (TZL008)

By a method similar to the preparation of the compound TZL001, the 3-bromobenzaldehyde is replaced by benzaldehyde, the aniline is replaced by o-anisidine, and the compound TZL008 is obtained after column chromatography purification, with the yield being 58%:¹H NMR(300MHz，CDCl₃)：7.34-7.31(m，2H)，7.26-7.23(m，3H)，7.21-7.15(m，1H)，6.91-6.85(m，2H)，6.81-6.76(m，1H)，6.08(s，1H)，3.99-3.86(m，2H)，3.83(s，3H).。

examples 1-9, 2- (3-Nitrophenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL009)

By a method similar to the method for preparing the compound TZL001, the 3-bromobenzaldehyde is replaced by 3-nitrobenzaldehyde, the aniline is replaced by o-anisidine, and the compound TZL009 is obtained after column chromatography purification with the yield being 51%:¹H NMR(300MHz，CDCl₃)：8.24(s，1H)，8.11-8.08(m，1H)，7.68-7.65(m，1H)，7.47-7.42(m，1H)，7.24-7.18(m，1H)，6.96-6.93(m，1H)，6.89-6.80(m，2H)，6.20(s，1H)，4.02-3.89(m，2H)，3.84(s，3H).。

examples 1-10, 2- (3-methoxyphenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL010)

By a method similar to the preparation of the compound TZL001, 3-bromobenzaldehyde is replaced by 3-methoxybenzaldehyde, aniline is replaced by o-anisidine, and the compound TZL010 is obtained after column chromatography purification with the yield of 52%:¹H NMR(300MHz，CDCl₃)：7.23-7.18(m，1H)，7.17-7.13(m，1H)，6.94-6.92(m，1H)，6.89-6.86(m，3H)，6.83-6.81(m，1H)，6.78-6.75(m，1H)，6.06(s，1H)，3.98-3.90(m，2H)，3.83(s，3H).3.75(s，3H).。

examples 1-11, 2- (4- (2-propionic acid methyl ester) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL011)

By a method similar to the method for preparing the compound TZL001, 3-bromobenzaldehyde is replaced by methyl 2- (4-formylphenyl) propionate, aniline is replaced by o-anisidine, and the compound TZL011 is obtained after column chromatography purification with the yield being 42%:¹H NMR(400MHz， CDCl₃)：7.27(d，J＝8.0Hz，2H)，7.21-7.19(m，1H)，7.18(d，J＝8.0Hz，2H)，6.91(d，J＝7.6Hz，1H)，6.87(d，J＝7.6Hz，1H)，6.80(dd，J＝7.6，7.6Hz，1H)，6.07(s，1H)，3.95(d，J＝15.6Hz，1H)，3.87(d，J＝15.6Hz，1H)，3.81(s，3H)，3.67(q，J＝7.2Hz，1H)，3.63(s，3H)，1.43(d，J＝7.2Hz，3H).。

examples 1-12, 2- (3- (1-Carboxylic acid methyl ester) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL012)

By a method similar to that for the preparation of TZL 001-Compound, 3-bromobenzaldehyde was replaced by 3-formylBenzoic acid ester, wherein aniline is replaced by o-anisidine, and the compound TZL012 is obtained after column chromatography purification, with a yield of 84%:¹H NMR(300MHz，CDCl₃)：8.02(s，1H)，7.91(d，J＝7.8Hz，1H)，7.52(d，J＝7.8Hz，1H)，7.34(dd，J＝7.8，7.8Hz，1H)，7.18(dd，J＝7.8，7.8Hz，1H)，6.92-6.84(m，2H)，6.82-6.77(m，1H)，6.14(s，1H)，3.95-3.93(m，2H)，3.90(s，3H)，3.83(s，3H).。

examples 1-13, 2- (4- (1-Carboxylic acid methyl ester) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL013)

By a method similar to the preparation of the compound TZL001, 3-bromobenzaldehyde is replaced by methyl 4-formylbenzoate, aniline is replaced by o-anisidine, and the compound TZL013 is obtained after column chromatography purification with the yield being 66%:¹H NMR(300MHz，CDCl₃)：7.93(d，J＝8.1Hz，2H)，7.40(d，J＝8.1Hz，2H)，7.19(dd，J＝8.1，7.8Hz，1H)，6.90(d，J＝7.8Hz，1H)，6.85(d，J＝8.1Hz，1H)，6.80(dd，J＝8.1，7.8Hz，1H)，6.13(s，1H)，3.95-3.93(m，2H)，3.88(s，3H)，3.83(s，3H).。

examples 1-14, 2- (4- (2-acetic acid methyl ester) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL014)

By a method similar to the method for producing compound TZL001, 3-bromobenzaldehyde was replaced with methyl 4-formylphenylacetate and aniline was replaced with o-anisidine, and purification was performed by column chromatography to give compound TZL014 with 66% yield:¹H NMR(300MHz，CDCl₃)：7.29-7.27(m，2H)，7.18-7.16(m，3H)，6.92-6.85(m，2H)，6.80(dd，J＝7.8，7.8Hz，1H)，6.07(s，1H)，3.92-3.90(m，2H)，3.82(s，3H)，3.66(s，3H)，3.55(s，2H).。

examples 1-15, 2- (3- (1-Carboxylic acid methyl ester) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone (TZL015)

By a method similar to the method for producing the compound TZL001, 3-bromobenzaldehyde is replaced by 3-formylbenzoate, aniline is replaced by 2, 4-dimethoxyaniline, and the compound TZL015 is obtained after column chromatography purification with a yield of 52%:¹H NMR(300MHz，CDCl₃)：8.01(s，1H)，7.92(d，J＝7.8Hz，1H)，7.51(d，J＝7.8Hz，1H)，7.35(dd，J＝7.8，7.8Hz，1H)，6.79-6.76(m，1H)，6.40(d，J＝2.4Hz，1H)，6.29(dd，J＝2.4，8.4Hz)，6.05(s，1H)，3.94-3.92(m，2H)，3.91(s，3H)，3.80(s，3H)，3.71(s，3H).。

examples 1-16, 2- (3-bromophenyl) -3- (2-pyrimidinyl) -4-thiazolinone (TZL016)

By a method similar to the method for preparing compound TZL001, only aniline was replaced with 2-aminopyrimidine, and column chromatography purification was performed to obtain compound TZL016, with a yield of 30%:¹H NMR(300MHz，CDCl₃)：8.63(d，J＝4.8Hz，2H)，7.50(s，1H)，7.36(d，J＝7.8Hz，1H)，7.29-7.26(m，1H)，7.14(dd，J＝7.8Hz，7.8Hz，1H)，7.05(dd，J＝4.8Hz，4.8Hz，1H)，6.63(s，1H)，4.02(d，J＝16.2Hz，1H)，3.83(d，J＝16.2Hz，1H).。

examples 1-17, 2- (4-pyridyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL0017)

By a method similar to the preparation of compound TZL001, 3-bromobenzaldehyde is replaced by 4-aminopyridine, aniline is replaced by o-anisidine, and the compound TZL0017 is obtained after column chromatography purification with the yield of 55%:¹H NMR(400MHz，CDCl₃)：8.52(dd，J＝6.0，1.6Hz，2H)，7.23(dd，J＝6.0，1.6Hz，2H)，7.22-7.20(m，1H)，6.97-6.95(m，1H)，6.89(dd，J＝8.0，1.2Hz，1H)，6.84(dd，J＝8.0，1.2Hz，1H)，6.04(d，J＝1.6Hz，1H)，3.97(dd，J＝15.6，1.6Hz，1H)，3.90(d，J＝15.6Hz，1H)，3.84(s，3H).。

examples 1-18, 2- (2-quinolyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL018)

By a method similar to the preparation of compound TZL001, 3-bromobenzaldehyde is replaced by 1-aminoquinoline, aniline is replaced by o-anisidine, and the compound TZL018 is obtained after column chromatography purification with a yield of 46%:¹H NMR(300MHz，CDCl₃)：8.16(d，J＝8.1Hz，1H)，7.97(d，J＝8.4Hz，1H)，7.76(d，J＝8.1Hz，1H)，7.68(dd，J＝7.2，7.2Hz，1H)，7.60(d，J＝8.4Hz，1H)，7.52(dd，J＝7.8，7.2Hz，1H)，7.18(dd，J＝8.4，7.8Hz，2H)，6.88(d，J＝8.4Hz，1H)，6.78(d，J＝7.8Hz，1H)，6.24(s，1H)，4.02(d，J＝15.6Hz，1H)，3.82(d，J＝15.6Hz，1H)，3.81(s，3H).。

examples 1-19, 2- (3-bromophenyl) -3- (3-nitrophenyl) -4-thiazolinone (TZL019)

3-bromobenzaldehyde (2.34ml, 20mmol) was dissolved in 50ml tetrahydrofuran, 3-nitroaniline (1.38g, 10mmol) was added and stirred, mercaptoacetic acid (2.27ml, 30mmol) was added after 5 minutes, DCC (2.48g, 12mmol) was added after 5 minutes, and after 10 minutes, the reaction was carried out overnight at room temperature. Suction filtration, extraction twice with ethyl acetate, washing of the organic phase with water and saturated saline solution, drying with anhydrous sodium sulfate, and vacuum concentration to obtain a crude product. Purification by column chromatography gave compound TZL019(740mg, 54%):¹H NMR(400MHz，CDCl₃)：8.14-8.13(m，1H)，8.06-8.03(m，1H)，7.61-7.58(m，1H)，7.52-7.48(m，1H)，7.46-7.45(m，1H)，7.43-7.40(m，1H)，7.25-7.23(m，1H)，7.21-7.17(m，1H)，6.15(s，1H)，4.01(d，J＝15.6Hz，1H)，3.90(d，J＝15.6Hz，1H).。

examples 1-20, 2- (3-bromophenyl) -3- (2-methoxyphenyl) -1, 3-thiazin-4-one (TZL020)

By adopting a method similar to the method for preparing the compound TZL019, 3-nitroaniline is replaced by o-methoxyaniline, thioglycolic acid is replaced by mercaptopropionic acid, and the compound TZL020 is obtained after column chromatography purification, wherein the yield is 54%:¹H NMR(400MHz，CDCl₃)：7.54-7.51(m，1H)，7.37(d，J＝8.0Hz，1H)，7.29(d，J＝7.6Hz，1H)，7.21(dd，J＝8.0，7.6Hz，1H)，7.16(dd，J＝8.0，7.6Hz，1H)，6.99-6.97(m，1H)，6.89(d，J＝7.6Hz，1H)，6.85-6.83(m，1H)，5.83(s，1H)，3.86(s，3H)，3.02-3.01(m，2H)，3.00-2.95(m，2H).。

examples 1-21, 2- (3-bromophenyl) -3- (2-hydroxyphenyl) -1, 3-thiazin-4-one (TZL021)

By adopting a method similar to the method for preparing the compound TZL019, 3-nitroanilide is replaced by o-hydroxyaniline, thioglycolic acid is replaced by mercaptopropionic acid, and the compound TZL021 is obtained after column chromatography purification, wherein the yield is 55 percent:¹H NMR(400MHz，DMSO)：9.78(br s，1H)，7.62(s，1H)，7.44(dd，J＝7.6，7.6Hz，2H)，7.25(dd，J＝7.6，7.6Hz，1H)，7.00(dd， J＝7.6，7.2Hz，1H)，6.82-6.80(m，2H)，6.63(dd，J＝7.6，7.2Hz，1H)，6.08(br s，1H)，2.96-2.87(m，2H)，2.83-2.73(m，2H).。

examples 1-22, 2- (3-bromophenyl) -3- (3-methoxyphenyl) -4-thiazolinone (TZL022)

By a method similar to the method for preparing the compound TZL019, 3-nitroaniline is replaced by m-methoxyaniline, and the compound TZL022 is obtained after column chromatography purification, wherein the yield is 74%:¹H NMR(400MHz，CDCl₃)：7.47(d，J＝1.6Hz，1H)，7.40(dd，J＝7.6，1.6Hz，1H)，7.24-7.23(m，1H)，7.21(d，J＝1.2Hz，1H)，7.17(ddd，J＝7.6，7.6，1.2Hz，1H)，6.76(d，J＝1.6Hz，2H)，6.74(d，J＝1.6Hz，1H)，6.02(s，1H)，4.00(d，J＝15.6Hz，1H)，3.87(d，J＝15.6Hz，1H)，3.73(s，3H).。

examples 1-23, 2- (3-bromophenyl) -3- (4- (diethylamino) phenyl) -4-thiazolinone (TZL023)

By adopting a method similar to the method for preparing the compound TZL019, replacing 3-nitroaniline with 4-diethylaminoaniline, and purifying by column chromatography to obtain a compound TZL023 with the yield of 63%:¹H NMR(300MHz，DMSO)：7.56-7.54(m，1H)，7.42(d，J＝7.8Hz，1H)，7.38(d，J＝7.8Hz，1H)，7.25(dd，J＝7.8，7.8Hz，1H)，6.98(d，J＝9.0Hz，2H)，6.51(d，J＝9.0Hz，2H)，6.27(s，1H)，4.02(d，J＝15.6Hz，1H)，3.79(d，J＝15.6Hz，1H)，3.24(q，J＝6.9Hz，4H)，1.00(t，J＝6.9Hz，6H).。

examples 1-24, 2- (3-bromophenyl) -3- (3-hydroxyphenyl) -4-thiazolinone (TZL024)

The 3-nitroaniline is replaced by m-aminophenol by adopting a method similar to the method for preparing the compound TZL019, and the compound TZL024 is obtained after column chromatography purification, wherein the yield is 39%:¹H NMR(400MHz，DMSO)：9.57(br s，1H)，7.57(s，1H)，7.43(d，J＝8.0Hz，1H)，7.38(d，J＝8.0Hz，1H)，7.26(dd，J＝8.0，8.0Hz，1H)，7.07(dd，J＝8.0，8.0Hz，1H)，6.74-6.71(m，2H)，6.57-6.54(m，1H)，6.45(s，1H)，4.05(d，J＝15.6Hz，1H)，3.84(d，J＝15.6Hz，1H).。

examples 1-25, 2- (4-bromophenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL025)

By adopting a method similar to the preparation method of the compound TZL019, 3-bromobenzaldehyde is replaced by 4-bromobenzaldehyde, 3-nitroaniline is replaced by o-anisidine, and the compound TZL025 is obtained after column chromatography purification, with the yield of 30%:¹H NMR(400MHz，DMSO)：7.45(d，J＝8.4Hz，2H)，7.35(d，J＝8.4Hz，2H)，7.23-7.18(m，1H)，7.00(dd，J＝8.0，8.0Hz，2H)，6.83-6.79(m，1H)，6.16(s，1H)，4.05(d，J＝16.4Hz，1H)，3.84(d，J＝16.4Hz，1H)，3.85(s，3H).。

examples 1-26, 2- (2-bromophenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL026)

By adopting a method similar to the method for preparing the compound TZL019, 3-bromobenzaldehyde is replaced by 2-bromobenzaldehyde, 3-nitroaniline is replaced by o-anisidine, and the compound TZL026 is obtained after column chromatography purification, wherein the yield is 28%:¹H NMR(400MHz，DMSO)：7.74(d，J＝7.2Hz，1H)，7.48(d，J＝7.6Hz，1H)，7.38(dd，J＝7.2，7.2Hz，1H)，7.23(dd，J＝7.6，7.6Hz，1H)，7.18-7.15(m，2H)，7.05(d，J＝8.0Hz，1H)，6.85(dd，J＝8.0，8.0Hz，1H)，6.59(s，1H)，5.08(d，J＝15.6Hz，1H)，4.49(d，J＝15.6Hz，1H)，3.71(s，3H).。

examples 1-27, 2- (3-bromophenyl) -3- (4-ethoxyphenyl) -4-thiazolinone (TZL027)

By a method similar to the method for preparing the compound TZL019, 3-nitroaniline is replaced by p-ethoxyaniline, and the compound TZL027 is obtained after column chromatography purification, with the yield being 31%:¹H NMR(400MHz，DMSO)：7.57(s，1H)，7.43-7.38(m，2H)，7.24(dd，J＝8.0，8.0Hz，1H)，7.16(d，J＝8.0Hz，2H)，6.82(d，J＝8.0Hz，2H)，6.39(s，1H)，4.05(d，J＝15.6Hz，1H)，3.92(q，J＝7.2Hz，2H)，3.84(d，J＝15.6Hz，1H)，1.25(t，J＝7.2Hz，3H).。

examples 1-28, 2- (3-hydroxyphenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL028)

By adopting a method similar to the method for preparing the compound TZL019, replacing 3-bromobenzaldehyde with m-hydroxybenzaldehyde, replacing 3-nitroaniline with o-methoxyaniline, and purifying by column chromatography to obtain a compound TZL028 with a yield of 39%:¹H NMR(300MHz，DMSO)：9.40(br s，1H)，7.19(dd，J＝7.2，7.2Hz，1H)，7.02-6.97(m，3H)，6.81(d，J＝7.2Hz，1H)，6.76-6.74(m，2H)，6.59(d，J＝7.5Hz，1H)，6.04(s，1H)，3.94(d，J＝15.3Hz，1H)，3.89(d，J＝15.3Hz，1H)，3.76(s，3H).。

examples 1-29, 2- (3-bromophenyl) -3- (4-hydroxyphenyl) -4-thiazolinone (TZL029)

The 3-nitroaniline is replaced by the p-hydroxyaniline by adopting a method similar to the method for preparing the compound TZL019, and the compound TZL029 is obtained after column chromatography purification, wherein the yield is 38%:¹H NMR(300MHz，DMSO)：9.49(br s，1H)，7.54(s，1H)，7.42-7.35(m，2H)，7.32(dd，J＝7.8，7.8Hz，1H)，7.02(d，J＝8.7Hz，2H)，6.65-6.62(m，2H)，6.30(s，1H)，4.03(d，J＝15.3Hz，1H)，3.80(d，J＝15.3Hz，1H).。

examples 1-30, 2- (3-bromophenyl) -3- (2-aminophenyl) -4-thiazolinone (TZL030)

By a method similar to the method for preparing the compound TZL019, 3-nitroaniline is replaced by o-phenylenediamine, and the compound TZL030 is obtained after column chromatography purification, wherein the yield is 32%:¹H NMR(300MHz，DMSO)：7.63-7.61(m，2H)，7.59-7.55(m，1H)，7.35-7.33(m，2H)，7.18(dd，J＝7.2Hz，7.2Hz，1H)，7.09(dd，J＝7.2Hz，7.2Hz，1H)，6.92-6.89(m，1H)，6.86(s，1H)，4.68(d，J＝14.7Hz，1H)，4.41(d，J＝14.7Hz，1H).。

examples 1-31, 2- (2-furyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL0031)

By adopting a method similar to the method for preparing the compound TZL019, 3-bromobenzaldehyde is replaced by furan-2-formaldehyde, 3-nitroaniline is replaced by o-anisidine, and the compound TZL031 is obtained after column chromatography purification, wherein the yield is 65%:¹H NMR(300MHz，CDCl₃)：7.40-7.37(m，1H)，7.29-7.24(m，1H)，6.94-6.91(m，2H)，6.86(dd，J＝7.2，7.2Hz，1H)，6.21(d，J＝6.9Hz，2H)，6.05(s，1H)，4.02(d，J＝15.6Hz，1H)，3.85(s，3H)，3.78(d，J＝15.6Hz，1H).。

examples 1-32, 2- (2-thienyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL032)

By adopting a method similar to the method for preparing the compound TZL019, 3-bromobenzaldehyde is replaced by thiophene-2-formaldehyde, 3-nitroaniline is replaced by o-anisidine, and the compound TZL032 is obtained after column chromatography purification, wherein the yield is 31%:¹H NMR(400MHz，DMSO)：7.47(d，J＝8.0Hz，1H)，7.24(dd，J＝8.0，8.0Hz，1H)，7.04(d，J＝8.0Hz，1H)，6.95-6.92(m，2H)，6.83(d，J＝7.2Hz，1H)，6.80-6.78(m，1H)，6.47(s，1H)，3.92(d，J＝15.6Hz， 1H)，3.84(d，J＝15.6Hz，1H)，3.77(s，3H).。

examples 1-33, 2- (4- (2-Propioniyl) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL033)

Compound TZL011 (011) (590mg, 1.59mmol) was dissolved in 16ml of methanol, and an aqueous solution (4ml) of lithium hydroxide (267mg, 6.35mmol) was added dropwise to the solution in an ice bath under a nitrogen atmosphere, followed by reaction at room temperature overnight. Adding 3M hydrochloric acid to adjust the solution to acidity, extracting with ethyl acetate twice, washing the organic phase with water and saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Purification by column chromatography gave compound TZL033(370mg, 65%):¹H NMR(400MHz，CDCl₃)：7.25-7.20(m，4H)，7.10(dd，J＝7.6，7.6Hz，1H)，7.01(d，J＝8.0Hz，1H)，6.82(d，J＝8.0Hz，1H)，6.81(dd，J＝7.6，7.6Hz，1H)，6.32(s，1H)，4.00-3.92(m，2H)，3.83(s，3H)，3.66(q，J＝7.2Hz，1H)，1.44(d，J＝7.2Hz，3H).。

examples 1-34, 2- (3-formylphenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL034)

By a method similar to the preparation of compound TZL033, only compound TZL011 was substituted with TZL012, and after column chromatography purification, compound TZL034 was obtained in 69% yield:¹H NMR(300MHz，CDCl₃)：8.07(s，1H)，7.97(d，J＝7.8Hz，1H)，7.59(d，J＝7.8Hz，1H)，7.38(dd，J＝7.8，7.8Hz，1H)，7.21-7.16(m，1H)，6.94-6.92(m，1H)，6.87-6.85(m，1H)，6.83-6.78(m，1H)，6.17(s，1H)，4.03-3.90(m，2H)，3.84(s，3H).。

examples 1-35, 2- (3-formylphenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone (TZL035)

By a method similar to the preparation of TZL033, only TZL011 was replaced by TZL015, and after column chromatography purification, compound TZL035 was obtained with 88% yield:¹H NMR(300MHz，DMSO)：7.94(s，1H)，7.81(d，J＝7.5Hz，1H)，7.64(d，J＝7.5Hz，1H)，7.41(dd，J＝7.5，7.5Hz，1H)，6.87(d，J＝8.7Hz，1H)，6.53(d，J＝2.4Hz，1H)，6.37(dd，J＝2.4，8.7Hz，1H)，6.17(s，1H)，4.01-3.96(m，1H)，3.86-3.81(m，1H)，3.73(s，3H)，3.68(s，3H).。

examples 1-36, 2- (4- (2-acetoxy) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL036)

By a method similar to the method for producing compound TZL033, only compound TZL011 was replaced with TZL014, and after column chromatography purification, compound TZL036 was obtained with 85% yield:¹H NMR(300MHz，CDCl₃)：7.30-7.28(m，2H)，7.22-7.16(m，3H)，6.91-6.85(m，2H)，6.79-6.76(m，1H)，6.08(m，1H)，3.98-3.85(m，2H)，3.82(s，3H)，3.58(s，2H).。

examples 1-37, 2- (4- (2- (N-phenylpropionamide)) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL037)

2- (4-formylphenyl) propionic acid (267mg, 1.5mmol), EDC (374mg, 1.95mmol) and HOBt (223mg, 1.65mmol) were taken in a flask, 5ml DMF was injected under nitrogen protection at 0 deg.C, aniline (0.18ml, 1.95mmol) was added dropwise after 5min, and after 15min the reaction was removed from the ice bath and allowed to react at room temperature for 3 h. Extracting with ethyl acetate, and concentrating under reduced pressure to obtain the corresponding amide crude product. This intermediate (152mg, 0.62mmol) and o-anisidine (0.07ml, 0.62mmol) were used to prepare compound TZL037(82mg, 30%) by the method of preparation TZL 001:¹H NMR(300MHz，CDCl₃)：7.35-7.31(m，4H)，7.27-7.24(m，3H)，7.18-7.06(m，3H)，6.92-6.69(m，3H)，6.12(s，1H)，3.93-3.91(m，2H)，3.81(s，3H)，3.63 (q，J＝6.9Hz，1H)，1.51(d，J＝6.9Hz，3H).。

examples 1-38, 2- (4- (N, N-diethylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL038)

By a method similar to the preparation of compound TZL037, 2- (4-formylphenyl) propionic acid was substituted for p-formylbenzoic acid, n-propylamine was substituted for diethylamine, and column chromatography purification was performed to give compound TZL038 with 56% yield:¹H NMR(300MHz，CDCl₃)：7.35(d，J＝8.1Hz，2H)，7.26(d，J＝8.1Hz，2H)，7.22-7.16(m，1H)，6.91-6.84(m，2H)，6.79(dd，J＝7.5，7.5Hz，1H)，6.11(s，1H)，3.93-3.90(m，2H)，3.83(s，3H)，3.49(br s，2H)，3.16(brs，2H)，1.21(br s，3H)，1.05(br s，3H).。

examples 1-39, 2- (4- (N, N-Diallylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL039)

By a method similar to the method for preparing the compound TZL037, 2- (4-formylphenyl) propionic acid is replaced by 3-carboxybenzaldehyde, aniline is replaced by diallylamine, and the compound TZL039 is obtained after column chromatography purificationThe rate is 66%:¹H NMR(300MHz，CDCl₃)：7.42-7.39(m，1H)，7.36(s，1H)，7.31-7.26(m，2H)，7.18(dd，J＝7.5Hz，7.5Hz，1H)，6.89-6.85(m，2H)，6.78(dd，J＝7.5，7.5Hz，1H)，6.09(s，1H)，5.94-5.75(m，1H)，5.71-5.52(m，1H)，5.24-5.14(m，4H)，4.20-4.00(m，2H)，3.92-3.91(m，2H)，3.83(s，3H)，3.71-3.58(m，2H).。

examples 1-40, 2- (4- (pyridine benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL040)

In a similar manner to that for the preparation of TZL037, 2- (4-formylphenyl) propionic acid was substituted with 3-carboxybenzaldehyde, aniline was substituted with pyridine, and column chromatography purification was carried out to give TZL 040% yield:¹H NMR(300MHz，CDCl₃)7.42-7.40(m，1H)，7.33-7.27(m，3H)，7.21-7.15(m，1H)，6.90-6.85(m，2H)，6.80-6.75(m，1H)，6.11(s，1H)，3.98-3.92(m，2H)，3.83(s，3H)，3.71-3.59(m，2H)，3.16-3.06(m，2H)，1.71-1.63(m，4H)，1.48-1.38(m，2H)。

examples 1-41, 2- (4- (N-benzylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL041)

By a method similar to the preparation of compound TZL037, 2- (4-formylphenyl) propionic acid was substituted with 3-carboxybenzaldehyde, aniline was substituted with benzylamine, and column chromatography purification was performed to give compound TZL041, yield 51%:¹H NMR(300MHz，CDCl₃)：7.76(s，1H)，7.65-7.63(m，1H)，7.50-7.47(m，1H)，7.35-7.32(m，5H)，7.18-7.13(m，1H)，6.91-6.88(m，1H)，6.84-6.81(m，1H)，6.79-6.74(m，1H)，6.51-6.42(m，1H)，6.13(s，1H)，4.60-4.58(m，2H)，3.96-3.83(m，2H)，3.78(s，3H).。

examples 1-42, 2- (4- (N-phenylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL042)

By a method similar to the method for producing compound TZL037, only 2- (4-formylphenyl) propionic acid was substituted with 3-carboxybenzaldehyde, and column chromatography purification was carried out to give compound TZL042 in 70% yield:¹H NMR(300MHz，CDCl₃)：7.96(s，1H)，7.85(s，1H)，7.74-7.71(m，1H)，7.61-7.58(m，1H)，7.53-7.51(m，1H)，7.39-7.33(m，3H)，7.21-7.12(m，2H)，6.93-6.90(m，1H)，6.86-6.84(m，1H)，6.81-6.76(m，1H)，6.17(s，1H)，3.99-3.86(m，2H)，3.81(s，3H).。

examples 1-43, 2- (4- (N-phenethylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL043)

By a method similar to the preparation of compound TZL037, 2- (4-formylphenyl) propionic acid was substituted with 3-carboxybenzaldehyde, aniline was substituted with phenethylamine, and column chromatography purification was performed to give compound TZL043 with a yield of 64%:¹H NMR(300MHz，CDCl₃)：7.66(s，1H)，7.54-7.51(m，1H)，7.47(m，1H)，7.36-7.28(m，4H)，7.24-7.15(m，2H)，6.88-6.83(m，2H)，6.80-6.75(m，1H)，6.11(s，1H)，3.98-3.86(m，2H)，3.80(s，3H)，3.72-3.66(m，2H)，2.94-2.90(m，2H).。

examples 1-44, 2- (4- (N-methylbenzamide) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone (TZL044)

In a similar manner to the preparation of TZL037, 2- (4-formylphenyl) propionic acid was substituted with 3-carboxybenzaldehyde, aniline was substituted with methylamine, o-anisidine was substituted with 2, 4-dimethoxyaniline, and column chromatography was performed to purify the resulting product to obtain TZL044 with a yield of 43%:¹H NMR(300MHz，CDCl₃)：7.75(s，1H)，7.63(d，J＝7.5Hz，1H)，7.45(d，J＝7.5Hz，1H)，7.32(dd，J＝7.5，7.5Hz，1H)，6.76(d，J＝8.7Hz，1H)，6.39(d，J＝2.4Hz，1H)，6.27(dd，J＝2.4，8.7Hz，1H)，6.03(s，1H)，3.97-3.84(m，2H)，3.78(s，3H)，3.70(s，3H)，2.96(d，J＝4.8Hz，3H).。

examples 1-45, 2- (4- (N- (2-methoxyphenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL045)

In a similar manner to the preparation of TZL037, 2- (4-formylphenyl) propionic acid was substituted with 3-carboxybenzaldehyde and aniline was substituted with o-methoxybenzylamine, and purification by column chromatography gave compound TZL045 in 57% yield:¹H NMR(300MHz，CDCl₃)：7.74(s，1H)，7.59(d，J＝7.5Hz，1H)，7.47(d，J＝7.5Hz，1H)，7.33-7.27(m，3H)，7.19-7.13(m，1H)，6.97-6.88(m，3H)，6.85-6.82(m，1H)，6.80-6.75(m，1H)，6.61-6.59(m，1H)，6.13(s，1H)，4.61(d，J＝5.7Hz，2H)，3.93-3.91(m，2H)，3.88(s，3H)，3.79(s，3H).。

examples 1-46, 2- (4- (N- (4-fluorophenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL046)

By a method similar to the preparation of compound TZL037, 2- (4-formylphenyl) propionic acid was substituted with 3-carboxybenzaldehyde, aniline was substituted with 4-fluorobenzylamine, and column chromatography purification was performed to give compound TZL046 with a yield of 70%:¹H NMR(300MHz，CDCl₃)：7.77(s，1H)，7.63(d，J＝7.5Hz，1H)，7.48(d，J＝7.5Hz，1H)，7.34-7.27(m，3H)，7.20-7.14(m，1H)，7.05-6.99(m，2H)，6.91-6.88(m，1H)，6.85-6.82(m，1H)，6.79-6.74(m，1H)，6.53-6.50(m，1H)，6.13(s，1H)，4.55(d，J＝5.7Hz，2H)，3.97-3.83(m，2H)，3.79(s，3H).。

examples 1-47, 2- (4- (N- (4-chlorophenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL047)

By using and preparing compoundsTZL037 in a similar manner to that described for 2- (4-formylphenyl) propionic acid instead of 3-carboxybenzaldehyde and aniline instead of 4-chlorobenzylamine, column chromatography purification gave compound TZL047 in 66% yield:¹H NMR(300MHz，CDCl₃)：7.77(s，1H)，7.64(d，J＝7.5Hz，1H)，7.48(d，J＝7.5Hz，1H)，7.35-7.23(m，6H)，7.20-7.14(m，1H)，6.91-6.88(m，1H)，6.85-6.82(m，1H)，6.80-6.74(m，1H)，6.55-6.51(m，1H)，6.13(s，1H)，4.54(d，J＝5.7Hz，2H)，3.97-3.83(m，2H)，3.79(s，3H).。

examples 1-48, 2- (4- (N- (3-fluorophenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL048)

By a method similar to the preparation of compound TZL037, 2- (4-formylphenyl) propionic acid was substituted with 3-carboxybenzaldehyde, aniline was substituted with 3-fluorobenzylamine, and column chromatography purification was performed to give compound TZL048 with 55% yield:¹H NMR(300MHz，CDCl₃)：7.78(s，1H)，7.65(d，J＝7.5Hz，1H)，7.48(d，J＝7.5Hz，1H)，7.34-7.29(m，2H)，7.19-7.13(m，1H)，7.10-7.07(m，1H)，7.02-6.94(m，2H)，6.91-6.88(m，1H)，6.85-6.82(m，1H)，6.79-6.74(m，1H)，6.66(t，J＝5.1Hz，1H)6.13(s，1H)，4.56(d，J＝5.7Hz，1H)，3.96-3.82(m，2H)，3.78(s，3H).。

examples 1-49, 2- (4- (N- (4-trifluoromethylphenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL049)

In a similar manner to the preparation of TZL037, 2- (4-formylphenyl) propionic acid was substituted with 3-carboxybenzaldehyde, aniline was substituted with 4-trifluoromethylbenzylamine, and column chromatography was performed to give compound TZL049 in 56% yield:¹H NMR(300MHz，CDCl₃)：7.79(s，1H)，7.67-7.64(m，1H)，7.61-7.58(m，2H)，7.51-7.48(m，1H)，7.45-7.42(m，2H)，7.36-7.31(m，1H)，7.20-7.15(m，1H)，6.92-6.89(m，1H)，6.86-6.83(m，1H)，6.80-6.75(m，1H)，6.61(t，J＝5.1Hz，1H)，6.13(s，1H)，4.64(d，J＝5.7Hz，1H)，3.98-3.84(m，2H)，3.79(s，3H).。

examples 1-50, 2- (4- (N- (2-chlorophenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL050)

By a method similar to the preparation of compound TZL037, 2- (4-formylphenyl) propionic acid was substituted with 3-carboxybenzaldehyde, aniline was substituted with 2-chlorobenzylamine, and column chromatography purification was performed to give compound TZL050, 45% yield:¹H NMR(300MHz，CDCl₃)：7.73(s，1H)，7.62(d，J＝7.5Hz，1H)，7.50(d，J＝7.5Hz，1H)，7.46-7.38(m，2H)，7.36-7.7.31(m，1H)，7.27-7.24(m，2H)，7.19-7.13(m，1H)，6.92-6.89(m，1H)，6，85-6.82(m，1H)，6.81-6.75(m，1H)，6.53(t，J＝5.1Hz，1H)，6.14(s，1H)，4.69(d，J＝5.7Hz，1H)，3.98-3.86(m，2H)，3.79(s，3H).。

examples 1-51, 2- (4- (N- (4-hydroxybutyl) benzamide) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone (TZL051)

By a method similar to the preparation of TZL037, substitution of 2- (4-formylphenyl) propionic acid for 3-carboxybenzaldehyde, substitution of aniline for 4-amino-1-butanol, substitution of o-anisidine for 2, 4-dimethoxyaniline, and purification by column chromatography gave compound TZL051 with a yield of 28%:¹H NMR(300MHz，CDCl₃)：7.77(s，1H)，7.67-7.65(m，1H)，7.44-7.41(m，1H)，7.34-7.29(m，1H)，6.77(d，J＝8.7Hz，1H)，6.41(d，J＝2.4Hz，1H)，6.29(dd，J＝2.4，8.7Hz，1H)，6.02(s，1H)，3.98-3.84(m，2H)，3.78(s，3H)，3.73-3.70(m，5H)，3.49-3.42(m，2H)，2.16(s，1H)，1.74-1.64(m，4H).。

examples 1-52, 2- (4- (N, N-diethylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL052)

Compound TZL034(100mg, 0.3mmol), EDC (76mg, 0.4mmol) and HOBt (45mg, 0.33mmol) were placed in a flask, 3ml DMF was injected under nitrogen protection in ice bath, diethylamine (0.04ml, 0.4mmol) was added dropwise after 5 minutes, and after 15 minutes reaction was carried out in a full-ice bath at room temperature for 3 hours. Adding water for inactivation, extracting twice with ethyl acetate, washing the organic phase with water and saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Purification by column chromatography gave compound TZL052(50mg, 32%):¹H NMR(300MHz，CDCl₃)：7.41-7.39(m，1H)，7.32-7.27(m，3H)，7.21-7.15(m，1H)， 6.90-6.85(m，2H)，6.81-6.76(m，1H)，6.10(s，1H)，3.98-3.87(m，2H)，3.83(s，3H)，3.56-3.44(m，2H)，3.11-3.01(m，2H)，1.25-1.16(m，3H)，1.06-0.94(m，3H).。

examples 1-53, 2- (4- (N-propylbenzamide) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone (TZL053)

By a method similar to the preparation of the compound TZL052, TZL034 was replaced with TZL035, diethylamine was replaced with n-propylamine, and column chromatography purification was performed to obtain the compound TZL053 with a yield of 79%:¹H NMR(300MHz，CDCl₃)：7.72(s，1H)，7.62(d，J＝7.5Hz，1H)，7.48(d，J＝7.5Hz，1H)，7.34(dd，J＝7.5，7.5Hz，1H)，6.78(d，J＝8.7Hz，1H)，6.41(d，J＝2.4Hz，1H)，6.29(dd，J＝2.4，8.7Hz，1H)，6.05(s，1H)，3.98-3.86(m，2H)，3.80(s，3H)，3.71(s，3H)，3.43-3.36(m，2H)，1.64-1.62(m，2H)，0.98(t，J＝7.2Hz，3H).。

examples 1-54, 2- (4- (N-Acetoxybenzamide) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone (TZL054)

Replacing TZL034 with TZL035, replacing diethylamine with glycine ethyl ester by a method similar to the method for preparing the compound TZL052, and purifying by column chromatography to obtain the compoundCompound TZL054, 42% yield:¹H NMR(300MHz，DMSO)：9.01-8.97(m，1H)，7.94(s，1H)，7.75(d，J＝7.5Hz，1H)，7.53(d，J＝7.5Hz，1H)，7.38(dd，J＝7.5，7.5Hz，1H)，6.90(d，J＝8.7Hz，1H)，6，54(d，J＝2.4Hz，1H)，6.37(dd，J＝2.4，8.7Hz，1H)，6.11(s，1H)，4.05-4.02(m，1H)，3.99(s，2H)，3.86-3.83(m，1H)，3.75(s，3H)，3.69(s，3H)，3.65(s，2H)，1.26-1.24(m，3H).。

examples 1-55, 2- (4- (N- (3-phenylpropyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL055)

By a method similar to the preparation of the compound TZL052, the diethylamine is only replaced by amphetamine, and the compound TZL055 is obtained after column chromatography purification, with the yield being 90%:¹H NMR(300MHz，CDCl₃)：7.64(s，1H)，7.50-7.47(m，2H)，7.33-7.27(m，2H)，7.21-7.15(m，4H)，6.91-6.88(m，1H)，6.86-6.84(m，1H)，6.80-6.75(m，1H)，6.12(s，1H)，6.08(t，J＝5.1Hz，1H)，3.99-3.87(m，2H)，3.82(s，3H)，3.49-3.42(m，2H)，2.73-2.68(m，2H)，1.99-1.89(m，2H).。

examples 1-56, 2- (4- (N- (4-phenylbutyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL056)

By a method similar to the preparation of the compound TZL052, the diethylamine is only replaced by phentermine, and the compound TZL056 is obtained after column chromatography purification, with the yield being 93%:¹H NMR(300MHz，CDCl₃)：7.69(s，1H)，7.58(d，J＝7.5Hz，1H)，7.49(d，J＝7.5Hz，1H)，7.35-7.29(m，3H)，7.21-7.15(m，4H)，6.91-6.88(m，1H)，6.86-6.84(m，1H)，6.81-6.76(m，1H)，6.13(s，1H)，6.03(t，J＝5.1Hz，1H)，3.99-3.88(m，2H)，3.82(s，3H)，3.47-3.40(m，2H)，2.69-2.64(m，2H)，1.75-1.1.64(m，4H).。

examples 1-57, 2- (4- (N- (4-bromophenyl ethyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL057)

By adopting a method similar to the method for preparing the compound TZL052, only the diethylamine is replaced by 4-bromophenylethylamine, and the compound TZL057 is obtained after column chromatography purification, wherein the yield is 88%:¹H NMR(300MHz，CDCl₃)：7.67(s，1H)，7.54-7.50(m，2H)，7.47-7.43(m，2H)，7.35-7.30(m，1H)，7.22-7.16(m，1H)，7.11-7.08(m，2H)，6.89-6.84(m，2H)，6.81-6.76(m，1H)，6.12(s，1H)，6.04(t，J＝5.1Hz，1H)，3.99-3.88(m，2H)，3.81(s，3H)，3.69-3.62 (m，2H)，2.90-2.85(m，2H).。

examples 1-58, 2- (4- (N- (4-hydroxyphenylethyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL058)

By a method similar to the method for preparing the compound TZL042, only diethylamine is replaced by 4-hydroxyphenylethylamine, and the compound TZL058 is obtained after column chromatography purification, with the yield being 90%:¹H NMR(300MHz，CDCl₃)：7.64-7.63(m，1H)，7.55(s，1H)，7.28-7.26(m，3H)，7.23-7.18(m，1H)，7.11-7.08(m，2H)，6.88-6.81(m，3H)，6.78-6.75(m，1H)，6.05(s，1H)，6.00(t，J＝5.1Hz，1H)，3.99-3.88(m，2H)，3.80(s，3H)，3.78-3.71(m，1H)，3.61-3.52(m，1H)，2.90-2.84(m，2H).。

examples 1-59, 2- (4- (N- (4-chlorophenylethyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL059)

By a method similar to the preparation of the compound TZL052, the diethylamine is replaced by 4-fluorophenylethylamine only, and the compound TZL059 is obtained after column chromatography purification with 88% yield:¹H NMR(300MHz，CDCl₃)：7.67(s，1H)，7.54-7.47(m，2H)，7.34-7.27(m，3H)，7.19-7.13(m，3H)，6.89-6.84(m，2H)，6.81-6.76(m，1H)，6.12(s，1H)，6.06(t，J＝5.1Hz，1H)，3.99-3.87(m，2H)，3.81(s，3H)，3.69-3.62(m，2H)，2.91-2.87(m，2H).。

examples 1-60, 2- (4- (N-4-methoxyphenylethyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL060)

By a method similar to the method for preparing the compound TZL052, only diethylamine is replaced by 4-methoxyphenethylamine, and the compound TZL060 is obtained after column chromatography purification, with the yield being 89%:¹H NMR(300MHz，CDCl₃)：7.67(s，1H)，7.53-7.45(m，2H)，7.33-7.28(m，1H)，7.18-7.13(m，3H)，6.89-6.83(m，4H)，6.80-6.75(m，1H)，6.12(s，1H)，6.05(t，J＝5.1Hz，1H)，3.99-3.85(m，2H)，3.80(s，3H)，3.68-3.62(m，2H)，2.88-2.83(m，2H).。

examples 1-61, 2- (4- (N-phenylacetamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL061)

By a method similar to the preparation of the compound TZL052, TZL034 was replaced with TZL036, diethylamine was replaced with aniline, and column chromatography purification was performed to obtain the compound TZL061 with 88% yield:¹H NMR(300MHz，CDCl₃)：7.38-7.35(m，2H)，7.32-7.30(m，2H)，7.28-7.24(m，2H)，7.22-7.17(m，2H)，7.11-7.06(m，1H)，6.93-6.85(m，3H)，6.82-6.77(m，1H)，6.14(s，1H)，3.40-3.89(m，2H)，3.84(s，3H)，3.66(s，2H).。

examples 1-62, 2- (4- (N- (4-fluorobenzoyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL062)

Compound TZL029(56mg, 0.17mmol), EDC (42mg, 0.22mmol) and HOBt (25mg, 0.19mmol) were placed in a flask, 3ml of DMF was injected under nitrogen protection and ice bath, 4-fluorobenzylamine (37mg, 0.22mmol) was added after 5 minutes, and after 15 minutes, the mixture was subjected to a reaction in a full ice bath at room temperature for 3 hours. Adding water for inactivation, and adding acetic acidThe ethyl ester is extracted twice, and the organic phase is washed by water and saturated saline solution, dried by anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography gave compound TZL062(70mg, 86%):¹H NMR(300MHz，CDCl₃)：7.71(s，1H)，7.58(d，J＝7.5Hz，1H)，7.49(d，J＝7.5Hz，1H)，7.35-7.30(m，1H)，7.21-7.10(m，3H)，6.99-6.93(m，2H)，6.92-6.84(m，2H)，6.81-6.76(m，1H)，6.13(s，1H)，6.00(t，J＝5.1Hz，1H)，3.99-3.87(m，2H)，3.83(s，3H)，3.47-3.41(m，2H)，2.66-2.61(m，2H)，1.71-1.56(m，4H).。

examples 1-63, 2- (4- (N- (4-fluorophenethyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL063)

By a method similar to the preparation of compound TZL062, only 4-fluorobenzylamine was substituted for 4-fluorobenzethylamine, and purification by column chromatography gave compound TZL063 in 89% yield:¹H NMR(300MHz，CDCl₃)：7.68(s，1H)，7.53-7.46(m，2H)，7.34-7.29(m，1H)，7.21-7.15(m，3H)，7.03-6.98(m，2H)，6.89-6.84(m，2H)，6.81-6.76(m，1H)，6.12(s，1H)，6.09(t，J＝5.1Hz，1H)，3.99-3.87(m，2H)，3.81(s，3H)，3.68-3.62(m，2H)，2.91-2.87(m，2H).。

examples 1-64, 2- (4- (N- (2-bromophenyl ethyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL064)

By a method similar to the preparation of compound TZL062, only 4-fluorobenzylamine was replaced with 2-bromobenzethylamine, and after column chromatography purification, compound TZL064 was obtained with 86% yield:¹H NMR(300MHz，CDCl₃)：7.69(s，1H)，7.5-7.56(m，2H)，7.48-7.45(m，1H)，7.34-7.29(m，1H)，7.26-7.25(m，2H)，7.21-7.11(m，2H)，6.88-6.84(m，2H)，6.80-6.75(m，1H)，6.17(t，J＝5.1Hz，1H)，6.12(s，1H)，3.99-3.88(m，2H)，3.81(s，3H)，3.74-3.68(m，2H)，3.11-3.06(m，2H).。

examples 1-65, 2- (4- (N- (6-phenylhexyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL065)

By a method similar to the method for preparing the compound TZL062, only 4-fluorobenzylamine is replaced by phenylhexylamine, and after column chromatography purification, the compound TZL065 is obtained with 74% yield:¹H NMR(300MHz，CDCl₃)：7.71(s，1H)，7.59(d，J＝7.5Hz，1H)，7.48(d，J＝7.5Hz，1H)，7.36-7.25(m，4H)，7.18-7.16(m，3H)，6.92-6.85(m，2H)，6.82-6.77(m，1H)，6.14(s，1H)，6.02(t，J＝5.1Hz，1H)，3.99-3.88(m，2H)，3.83(s，3H)，3.44-3.37(m，2H)，2.63-2.58(m，2H)，1.65-1.59(m，4H)，1.46-1.34(m，4H).。

examples 1-66, 2- (4- (N- (5-phenylpentyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL066)

By a method similar to the method for preparing the compound TZL062, only 4-fluorobenzylamine is replaced by 5-benzenepentylamine, and after column chromatography purification, the compound TZL066 is obtained with 93% yield:¹H NMR(300MHz，CDCl₃)：7.71(s，1H)，7.57(d，J＝7.5Hz，1H)，7.50(d，J＝7.5Hz，1H)，7.35-7.30(m，1H)，7.29-7.25(m，3H)，7.21-7.16(m，3H)，6.92-6.85(m，2H)，6.82-6.77(m，1H)，6.14(s，1H)，6.04(t，J＝5.1Hz，1H)，3.99-3.88(m，2H)，3.83(s，3H)，3.44-3.37(m，2H)，2.65-2.60(m，2H)，1.73-1.58(m，4H)，1.45-1.37(m，2H).。

examples 1-67, 2- (3-bromophenyl) -3- (2, 4-dihydroxyphenyl) -4-thiazolinone (TZL067)

Compound TZL004 (004 mg, 1mmol) and boron tribromide (0.3ml, 3mmol) were reacted in 5ml of dichloromethane at room temperature under a nitrogen atmosphere for 4 hours. Extracting with ethyl acetate twice, washing the organic phase with water and saturated saline solution, and removing waterDried over sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography gave compound TZL067(322mg, 88%):¹HNMR(300MHz，DMSO)：9.75(br s，1H)，9.37(br s，1H)，7.63-7.59(m，1H)，7.43-7.41(m，1H)，7.20(dd，J＝7.8，7.8Hz，2H)，7.24(dd，J＝7.8，7.8Hz，1H)，6.64(d，J＝8.7Hz，1H)，6.28(d，J＝2.4Hz，1H)，6.08(s，1H)，6.07-6.04(m，1H)，3.98(dd，J＝15.6，1.8Hz，1H)，3.76(d，J＝15.6Hz，1H).。

examples 1-68, 2- (3-bromophenyl) -3- (4-hydroxy-2-methoxyphenyl) -4-thiazolinone (TZL068)

Compound TZL004(1g, 2.54mmol 1) is taken and stirred evenly in 20m11, 2-dichloroethane in ice bath under nitrogen atmosphere, anhydrous aluminum chloride (338mg, 2.54mmol) is added, the ice bath is removed after 0.5 hour, the mixture is stirred for 0.5 hour at room temperature, then the temperature is raised to 70 ℃, the anhydrous aluminum chloride (2.54mg, 2.54mmol) is added after 4 hours, and the temperature is raised to 80 ℃ for overnight reaction. Extracting twice with ethyl acetate, washing the organic phase with water and saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Purification by column chromatography gave compound TZL068(340mg, 35%):¹H NMR(300MHz，DMSO)：9.59(br s，1H)，7.59-7.54(m，1H)，7.43-7.41(m，1H)，7.37-7.34(m，1H)，7.23(d，J＝7.8Hz，1H)，6.72(d，J＝8.7Hz，1H)，6.35(d，J＝2.4Hz，1H)，6.18(dd，J＝2.4，8.7Hz，1H)，6.04-6.01(m，1H)，3.99(d，J＝15.6Hz，1H)，3.76(d，J＝15.6Hz，1H)，3.76(s，3H).。

examples 1-69, 2- (4- (N- (2-phenylacetamide)) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL069)

Taking 2- (3-aminophenyl) -3- (2-methoxyphenyl) -4-thiazolinone (150mg, 0.5mmol), EDC (125mg, 0.65mmol) and HOBt (74mg, 0.55mmol) in a flask, injecting 5ml DMF under nitrogen protection ice bath, adding phenethylamine (0.08ml, 0.65mmol) after 5 minutes, carrying out 15 minutes, and carrying out full-ice bath at normal temperatureThe reaction was carried out for 3 hours. Adding water for inactivation, extracting twice with ethyl acetate, washing the organic phase with water and saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Purification on a column afforded product TZL069(110mg, 53%):¹H NMR(300MHz，CDCl₃)：7.86(s，1H)，7.35(s，1H)，7.23-7.20(m，3H)，7.16-7.11(m，3H)，7.04(dd，J＝6.6，6.6Hz，2H)，6.88(d，J＝7.5Hz，1H)，6.77(d，J＝7.8Hz，1H)，6.66-6.61(m，2H)，5.88(s，1H)，3.80(d，J＝15.6Hz，1H)，3.68(d，J＝15.6Hz，1H)，3.81(s，3H)，3.52(s，2H).。

examples 1-70, 2- (4- (N- (benzamide)) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL070)

By a method similar to the method for preparing the compound TZL069, phenethylamine was substituted with aniline, and column chromatography purification was performed to obtain the compound TZL070 with a yield of 76%:¹H NMR(300MHz，CDCl₃)：8.04(s，1H)，7.82(d，J＝7.8Hz，2H)，7.72(s，1H)，7.52(d，J＝7.8Hz，2H)，7.45(dd，J＝7.5，7.5Hz，2H)，7.22(d，J＝7.8Hz，1H)，7.15(d，J＝7.8Hz，1H)，7.07(d，J＝7.5Hz，1H)，6.94(d，J＝7.5Hz，1H)，6.85-6.74(m，2H)，6.08(s，1H)，3.95(d，J＝15.6Hz，1H)，3.86(d，J＝15.6Hz，1H)，3.81(s，3H).。

examples 1-71, 2- (3- (hydroxymethyl) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL071)

3-hydroxymethylbenzaldehyde (47mg, 0.35mmol) and o-anisidine (0.04ml, 0.35mmol) were dissolved in 5ml of toluene, stirred under nitrogen atmosphere in ice bath for 5 minutes, then heated to reflux by oil bath, and the apparatus was connected to an oil-water separator. Cooling after no water is generated, adding thioglycolic acid (0.05ml, 0.7mmol), continuously heating to reflux, concentrating under reduced pressure after water separation is finished to obtain a crude product, and purifying by column chromatography to obtain a compound TZL071(80mg, 73%):¹H NMR(300MHz，CDCl₃)：7.33(s，1H)，7.25-7.17(m，4H)，6.92-6.86(m，2H)，6.80(dd，J＝7.8Hz，7.8Hz，1H)，6.10(s，1H)，4.63(s，2H)，3.99-3.92(m，2H)，3.84(s，3H).。

examples 1-72, 2- (3- (bromomethyl) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL072)

Compound TZL071 was obtained according to the above procedure, compound TZL071(100mg, 0.32mmol) was dissolved in 5ml of dichloromethane, and boron tribromide (0.03ml, 0.32mmol) was added dropwise under a nitrogen atmosphere, and reacted at room temperature for 4 hours. Extracting twice with ethyl acetate, washing the organic phase with water and saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Purification by column chromatography gave product TZL072(94mg, 78%):¹H NMR(300MHz，CDCl₃)：7.38(s，1H)，7.25-7.23(m，3H)，7.20-7.17(m，1H)，6.93-6.86(m，2H)，6.83-6.78(m，1H)，6.08(s，1H)，4.42-4.41(m，2H)，3.94-3.93(m，2H)，3.84(s，3H).。

examples 1-73, 2- (3-bromophenyl) -3- (4-amino-2-methoxyphenyl) -4-thiazolinone (TZL073)

The corresponding thiazolinone intermediate was obtained from 2-methoxy-4-Boc amino-aniline (263mg, 1.1mmol) and 3-bromobenzaldehyde (0.13ml, 1.1mmol) by the method of preparation TZL 001. This intermediate (527mg, 1.1mmol) was dissolved in 10ml DCM and 2ml trifluoroacetic acid was added to the ice bath under nitrogen atmosphere and after 0.5 h the reaction was carried out for 3 h at RT. Adding 3M potassium hydroxide to adjust to alkalinity, extracting twice with ethyl acetate, washing the organic phase with water and saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Purification by column chromatography gave compound TZL073(363mg, 87%):¹H NMR(300MHz，CDCl₃)：7.52(s，1H)，7.38-7.35(m，1H)，7.21-7.19(m，1H)，7.11(dd，J＝7.8Hz，7.8Hz，1H)，6.63(d，J＝8.4Hz，1H)，6.16-6.15(m，1H)，6.10-6.07(m，1H)，5.89(s，1H)，3.96-3.90(m，1H)，3.87-3.82(m，1H)，3.75(s，3H)，3.70-3.67(m，2H).。

examples 1-74, 2- (3-bromophenyl) -3- (4- (benzylamino) -2-methoxyphenyl) -4-thiazolinone (TZL074)

Compound TZL073 was obtained according to the above method, TZL073(100mg, 0.26mmol) and potassium carbonate (36mg, 0.26mmol) were dissolved in 5ml DMF, stirred under nitrogen atmosphere for 0.5 h, added benzyl bromide (0.03ml, 0.26mmol) and reacted at room temperature overnight. Adding water for inactivation, extracting twice with ethyl acetate, washing the organic phase with water and saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Purification by column chromatography gave compound TZL074(60mg, 49%):¹H NMR(400MHz，CDCl₃)：7.52-7.51(m，1H)，7.38-7.35(m，1H)，7.33-7.31(m，3H)，7.28-7.25(m，2H)，7.23-7.21(m，1H)，7.13(dd，J＝7.6Hz，7.6Hz，1H)，6.66(d，J＝8.4Hz，1H)，6.10(d，J＝2.4Hz，1H)，6.06(dd，J＝2.4Hz，8.4Hz，1H)，5.88(s，1H)，4.24(s，1H)，4.15-4.10(m，2H)，3.95-3.91(m，1H)，3.87-3.83(m，1H)，3.73(s，3H).。

examples 1-75, 2- (3-bromophenyl) -3- (2- (ethylamino) phenyl) -4-thiazolinone (TZL075)

2-Boc-aminoethylaniline (1.22g, 5.2mmol) and 3-bromobenzaldehyde (0.6ml, 5.2mmol) were taken to obtain 2- (3-bromophenyl) -3- (2- (Boc-aminoethyl) phenyl) -4-thiazolinone by the method referred to preparation TZL001, and this intermediate (568mg, 1.2mmol) was dissolved in 5ml DCM, 0.8ml trifluoroacetic acid was added to the ice bath under nitrogen atmosphere, and after 0.5 hours, the reaction was carried out at room temperature for 4 hours. Adding 3M potassium hydroxide to adjust to alkalinity, extracting twice with ethyl acetate, washing the organic phase with water and saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Purification by column chromatography gave compound TZL075(92mg, 20%):¹H NMR(300MHz，CDCl₃)：7.70-7.37(m，3H)，7.19-7.11(m，3H)，6.72-6.54(m，2H)，5.97(s，1H)，4.06-3.84(m，2H)，3.70(br s，1H)，3.22-2.88(m，2H)，1.25-1.20(m，3H).。

examples 1-76, 2- (3-bromophenyl) -3- (2- (methylamino) phenyl) -4-thiazolinone (TZL076)

In a similar manner to that used for the preparation of TZL075, only bromoethane was replaced by iodomethane and column chromatography purification gave TZL076 in 23% yield:¹H NMR(300MHz，CDCl₃)：7.61-7.34(m，3H)，7.19-7.13(m，3H)，6.73-6.54(m，2H)，6.01(s，1H)，4.09-3.86(m，2H)，3.85-3.78(m，1H)，2.82-2.81(m，3H).。

examples 1-77, 2- (3- (3-pyridyl) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone (TZL077)

3-pyridine benzaldehyde (69mg, 0.38mmol) and o-anisidine (0.04ml, 0.38mmol) are dissolved in 5ml of toluene, stirred for 5 minutes under the condition of ice bath under the nitrogen atmosphere, replaced by an oil bath and heated to reflux, and an oil-water separator is connected on the device. Cooling after no water is generated, adding thioglycolic acid (0.05ml, 0.76mmol), continuously heating to reflux, concentrating under reduced pressure after water separation is finished to obtain a crude product, and purifying by column chromatography to obtain a compound TZL077(70mg, 51%):¹H NMR(300MHz，CDCl₃)：8.73(s，1H)，8.59-8.58(m，1H)，7.81-7.78(m，1H)，7.51(s，1H)，7.44-7.35(m，4H)，7.23-7.18(m，1H)，6.97-6.95(m，1H)，6.89-6.87(m，1H)，6.85-6.80(m，1H)，6.18(s，1H)，4.01-3.89(m，2H)，3.83(s，3H).。

examples 1-78, 2- (3-bromophenyl) -3- (2-methoxyphenyl) -4-oxazolinone (TZL078)

2-Hydroxyacetic acid (990mg, 13mmol), EDC (3.24g, 16.9mmol) and HOBt (1.94g, 14.3mmol) were taken in a flask, 20ml of DMF was injected in an ice bath under nitrogen atmosphere, and after 5 minutes, o-methoxy group was added dropwiseAniline (1.12ml, 10mmol) was reacted for 15 minutes in a ice bath at room temperature for 3 hours. Extracting with ethyl acetate and purifying by column chromatography to obtain the corresponding intermediate. This intermediate (544mg, 3mmol) and p-toluenesulfonic acid (112mg, 0.6mmol) were dissolved in xylene, stirred for a while at room temperature, then 3-bromobenzaldehyde (0.7ml, 6mmol) was added, and water was partitioned at 140 ℃ for 4 hours. Concentration under reduced pressure gave a crude product which was purified by column chromatography to give compound TZL078(762mg, 73%):¹H NMR(300MHz，CDCl₃)：7.54-7.50(m，1H)，7.45-7.43(m，1H)，7.23-7.13(m，3H)，6.98-6.95(m，1H)，6.90-6.83(m，2H)，6.41(s，1H)，4.67(dd，J＝14.1，1.2Hz，1H)，4.56(dd，J＝14.1，1.2Hz，1H)，3.84(s，3H)，3.83(d，J＝15.6Hz，1H).。

examples 1-79, 2- (3-bromophenyl) -3- (2, 4-dimethoxyphenyl) -4-oxazolinone (TZL079)

By a method similar to the method for preparing the compound TZL078, o-anisidine is replaced by 2, 4-dimethoxyaniline, and the compound TZL079 is obtained after column chromatography purification with a yield of 48%:¹H NMR(300MHz，CDCl₃)：7.55-7.53(m，1H)，7.47-7.43(m，1H)，7.22-7.14(m，2H)，6.81(d，J＝8.7Hz，1H)，6.44(d，J＝2.4Hz，1H)，6.35(dd，J＝8.7，2.4Hz，1H)，6.33-6.28(m，1H)，4.67(dd，J＝13.8，1.8Hz，1H)，4.55(dd，J＝13.8，1.8Hz，1H)，3.80(s，3H)，3.74(s，3H).。

examples 1-80, 2- (3-bromophenyl) -3- (2- (dimethylamino) phenyl) -4-thiazolinone (TZL080)

TZL030(150mg, 0.43mmol) and potassium carbonate (297mg, mmol) were taken in 5ml of DMF and stirred at room temperature for 0.5 hour under nitrogen atmosphere, and methyl iodide (0.1ml, 1.72mmol) was added and stirred at room temperature overnight. Adding water for inactivation, extracting twice with ethyl acetate, washing the organic phase with water and saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Purifying by column chromatography to obtain TZ productL080(20mg，15％)：¹H NMR(300MHz，DMSO)：7.52-7.51(m， 1H)，7.40-7.31(m，2H)，7.18(dd，J＝7.5Hz，7.5Hz，1H)，7.15-7.09(m，1H)，7.00-6.92(m，2H)，6.84(dd，J＝7.5Hz，7.5Hz，1H)，6.43(s，1H)，4.11(d，J＝15.9Hz，1H)，3.83(d，J＝15.9Hz，1H)，2.66(s，6H).。

Claims

1. A 2, 3-diaryl thiazolinone compound or a pharmaceutically acceptable salt thereof, which is represented by the following structural formula (IV):

wherein,

m is 0, 1, 2,3, 4 or 5;

x is O ═ O;

l is NH;

Ar₁a phenyl group;

Ar₃is phenyl;

Ar₄is phenyl.

2. A 2, 3-diaryl thiazolinone compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

2- (4- (2- (N-phenylpropionamide)) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N, N-diethylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N, N-diallylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N-benzylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N-phenylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N-phenethylbenzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N-methylbenzamide) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone,

2- (4- (N- (2-methoxyphenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (4-fluorophenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (4-chlorophenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (3-fluorophenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (4-trifluoromethylphenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (2-chlorophenyl) benzamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (4-hydroxybutyl) benzamide) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone,

2- (4- (N, N-diethylformamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N-propylbenzamide) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone,

2- (4- (N-ethyl acetate benzamide) phenyl) -3- (2, 4-dimethoxyphenyl) -4-thiazolinone,

2- (4- (N- (3-phenylpropyl) carboxamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (4-phenylbutyl) carboxamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (4-bromophenyl ethyl) formamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (4-hydroxybenzyl) formamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (4-chlorophenylethyl) formamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N-4-methoxyphenylethyl) carboxamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N-phenylacetamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (4-fluorobenzoyl butyl) formamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (4-fluorophenethyl) carboxamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (2-bromophenyl ethyl) formamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (6-phenylhexyl) carboxamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (5-phenylpentyl) carboxamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N- (2-phenylethyl) formamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone,

2- (4- (N-phenylcarboxamide) phenyl) -3- (2-methoxyphenyl) -4-thiazolinone.

3. A 2, 3-diaromatic thiazolinone compound or a pharmaceutically acceptable salt according to claim 1 or 2, which is an acid addition salt of the 2, 3-diaromatic thiazolinone compound with an acid; wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, salicylic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, lactic acid, pyruvic acid, maleic acid, or succinic acid.

4. A pharmaceutical composition comprising the 2, 3-diaromatic thiazolinone compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is formulated as an injectable fluid, aerosol, cream, gel, pill, capsule, syrup, transdermal patch, or excipient.

6. The use of a 2, 3-diaromatic thiazolinone compound or a pharmaceutically acceptable salt according to any one of claims 1 to 3 in inhibiting Actin polymerization.

7. Use of a 2, 3-diaromatic thiazolinone compound or a pharmaceutically acceptable salt according to any one of claims 1 to 3 to inhibit proliferation, growth, migration and infiltration of tumor cells; wherein the tumor cells are lung cancer cells, breast cancer cells, epidermal cancer cells, colon cancer cells, liver cancer cells, stomach cancer cells and prostate cancer cells.

8. Use of a 2, 3-diaryi thiazolinone compound according to any one of claims 1 to 3 in the preparation of a medicament for treating a malignant tumor; wherein the malignant tumor is liver cancer, lung cancer, prostatic cancer, skin cancer, colon cancer, pancreatic cancer, breast cancer, leukemia, ovarian cancer, gastric cancer, bladder cancer, renal cancer, and oral cancer.

9. Use of a 2, 3-diaromatic thiazolinone compound or a pharmaceutically acceptable salt according to any one of claims 1 to 3 in the preparation of a medicament for treating metastasis and recurrence of a malignant tumor; wherein the malignant tumor is liver cancer, lung cancer, prostatic cancer, skin cancer, colon cancer, pancreatic cancer, breast cancer, leukemia, ovarian cancer, gastric cancer, bladder cancer, renal cancer, and oral cancer.