3-(thiazole-4-yl methyl alkene) indoline-2-ketone compound with triple negative breast cancer resisting activity, preparation method and application of 3-(thiazole-4-yl methyl alkene) indoline-2-ketone compound

Abstract

The invention discloses a 3-(thiazole-4-yl methyl ene) indoline-2-ketone compound with triple negative breast cancer resisting activity, a preparation method and application, and relates to the technical field of medicine synthesis. The compound has a structural general formula as shown in a formula (1): # imgabs0 #, wherein R1, R2, R3, R4 and R5 are defined in the specification. The compound shown in the formula (I) is designed and synthesized by taking an indolone derivative ZL170 with potential anti-tumor activity as a basic skeleton and adopting a bioisostere and skeleton transition strategy, and verification shows that the compound has a certain inhibition effect on proliferation and migration of triple-negative breast cancer cells including MDA-MB-231 and BT-549, and has a good application prospect. Some compounds can obtain a very good anti-tumor effect at a very low dosage.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a 3-(thiazol-4-ylmethylene)indolin-2-one compound having anti-triple-negative breast cancer activity, a preparation method and application thereof. Background Art

[0002] Breast cancer poses a major threat worldwide, affecting women around the world. Triple-negative breast cancer (TNBC) is one of four molecular subtypes of breast cancer, characterized by the lack of three hormone receptors commonly found in other types of breast cancer: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This means that TNBC will not respond to hormone therapy or conventional treatments.

[0003] Indole derivatives have played an important role in the development of a variety of anti-tumor drugs, including sunitinib, semaxanib and nintedanib. Thiazole derivatives are widely used in the design of anti-tumor drugs, such as dabrafenib, alpelisib, ixabepilone and dasatinib. The inventors previously isolated an indole derivative ZL170 with potential anti-tumor activity from the folk anti-tumor drug American cockroach. The structural formula is as follows:

[0004]

[0005] On this basis, it is of great significance to develop more drugs with anti-TNBC activity. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a compound with anti-triple-negative breast cancer activity, a preparation method and application.

[0007] In order to solve the above problems, the present invention proposes the following technical solutions:

[0008] In a first aspect, the present invention provides a 3-(thiazol-4-ylmethylene)indolin-2-one compound having anti-triple-negative breast cancer activity, wherein the compound has a general structural formula as shown in formula (1):

[0009]

[0010] In formula (1), R 1 is selected from hydrogen, methyl, ethyl, vinyl, cyclopropyl, cyclobutyl, unsubstituted or 4-substituted aromatic groups, wherein the substituents include any one of methyl, tert-butyl, methoxy, halogen, trifluoromethyl, cyano and methanesulfonyl;

[0011] R 2Selected from hydrogen, alkyl or cycloalkyl with carbon number C≤6;

[0012] R 3 is selected from hydrogen, methyl, methoxy, tert-butyl, hydroxy, trifluoromethoxy, halogen or trifluoromethyl;

[0013] R 4 is selected from hydrogen, methyl, methoxy, tert-butyl, hydroxy, trifluoromethoxy, halogen or trifluoromethyl;

[0014] R 5 is selected from hydrogen, methyl, methoxy, tert-butyl, hydroxy, trifluoromethoxy, halogen or trifluoromethyl.

[0015] Furthermore, the structural formula of the compound is at least one of Formulas LJ1-LJ27:

[0016]

[0017] In a second aspect, the present invention provides a method for preparing the 3-(thiazol-4-ylmethylene)indolin-2-one compound having anti-triple-negative breast cancer activity, and the synthetic route is as follows:

[0018]

[0019] Among them, III and VII have the following structures:

[0020]

[0021] In the above synthetic route, R 1 is selected from hydrogen, methyl, ethyl, vinyl, cyclopropyl, cyclobutyl, unsubstituted or 4-substituted aromatic groups, wherein the substituents include any one of methyl, tert-butyl, methoxy, halogen, trifluoromethyl, cyano and methanesulfonyl;

[0022] R 2 Selected from hydrogen, alkyl or cycloalkyl with carbon number C≤6;

[0023] R 3 is selected from hydrogen, methyl, methoxy, tert-butyl, hydroxy, trifluoromethoxy, halogen or trifluoromethyl;

[0024] R 4 is selected from hydrogen, methyl, methoxy, tert-butyl, hydroxy, trifluoromethoxy, halogen or trifluoromethyl;

[0025] R 5 is selected from hydrogen, methyl, methoxy, tert-butyl, hydroxy, trifluoromethoxy, halogen or trifluoromethyl.

[0026] Further, each step in the synthetic route is described in detail as follows:

[0027] Reacting 1,3-dichloro-2-alkylacetone and thioamide in solvent 1 to obtain a compound represented by formula (II);

[0028] The compound represented by formula (II) is dissolved in solvent 2, sodium benzoate is added, heated to reflux, and reacted for 8 to 12 hours to obtain the compound represented by formula (IV);

[0029] The compound represented by formula (IV) is dissolved in solvent 3, base 1 is added, and hydrolyzed at 25°C to the reflux temperature of the system for 2-6 hours to obtain the compound represented by formula (V);

[0030] The compound represented by formula (V) is dissolved in solvent 4, and reacted at 0°C to the reflux temperature of the system for 1-24 hours in the presence of an oxidant to obtain a compound represented by formula (VI);

[0031] In the presence of a base 2, the compound represented by formula (VI) and the compound represented by formula (VII) are refluxed in a solvent 5 to react to obtain a compound represented by formula (I).

[0032] Furthermore, the solvent 1 is at least one of methanol, ethanol, tetrahydrofuran, and toluene; the solvent 2 is at least one of tetrahydrofuran, DMF, acetone, acetonitrile, dioxane, and dimethyl sulfoxide; the solvent 3 is any one of water, a mixture of water and tetrahydrofuran, a mixture of water and dioxane, a mixture of water and ethanol, and a mixture of water and methanol; the solvent 4 is at least one of dichloromethane, dichloroethane, and acetonitrile; and the solvent 5 is at least one of water, methanol, ethanol, and acetonitrile.

[0033] In other embodiments, solvent 3 is any one of water, a mixture of water and tetrahydrofuran in a volume ratio of 1:1, a mixture of water and dioxane in a volume ratio of 1:1, a mixture of water and ethanol in a volume ratio of 1:1, and a mixture of water and methanol in a volume ratio of 1:1.

[0034] Furthermore, the base 1 is any one of lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, and triethanolamine; the base 2 is any one of piperidine, 4-methylpiperidine, morpholine, sodium hydroxide, and potassium fluoride.

[0035] Furthermore, the molar ratio of the base 1 to the compound represented by formula (IV) is 3 to 5:1;

[0036] The molar ratio of the base 2 to the compound represented by formula (VI) is 3-5:1.

[0037] Furthermore, the oxidant is any one of manganese dioxide, Dess-Martin reagent, and pyridinium chlorochromate.

[0038] Furthermore, in a specific embodiment of the present invention, the post-treatment of the compound represented by formula (II) includes: distilling the reacted material under reduced pressure to remove the solvent, extracting with ethyl acetate, washing the organic phase three times with saturated brine, drying the organic phase with anhydrous magnesium sulfate, and purifying the sample by silica gel column chromatography.

[0039] Furthermore, in a specific embodiment of the present invention, the post-treatment of obtaining the compound represented by formula (IV) comprises: pouring the reaction solution into an ice-water mixture to precipitate a solid, filtering and collecting the solid, and then performing column chromatography separation and purification.

[0040] Furthermore, in a specific embodiment of the present invention, the post-treatment of the compound represented by formula (V) includes: removing the solvent by distillation under reduced pressure, extracting and concentrating the material with ethyl acetate, then washing with saturated sodium bicarbonate, combining and collecting the organic phases, drying with anhydrous sodium sulfate, removing the solvent under reduced pressure, and then separating and purifying by column chromatography.

[0041] Furthermore, in a specific embodiment of the present invention, the post-treatment of the compound represented by formula (VI) comprises: pouring the reaction solution into an ice-water mixture, adding a saturated sodium sulfite solution and stirring for half an hour, extracting with dichloromethane, drying with anhydrous sodium sulfate, removing the solvent under reduced pressure, and then performing column chromatography separation and purification.

[0042] Furthermore, in a specific embodiment of the present invention, the post-treatment of the compound represented by formula (I) comprises: removing the solvent by distillation under reduced pressure, and separating and purifying by high performance liquid chromatography (mobile phase: methanol / water or acetonitrile / water).

[0043] It should be noted that the reaction time of each step above can be monitored by thin layer chromatography, and the reaction time is adjusted according to the reaction degree of the starting materials.

[0044] In other aspects, the present invention also provides the use of the 3-(thiazol-4-ylmethylene)indolin-2-one compounds with anti-triple-negative breast cancer activity, or the 3-(thiazol-4-ylmethylene)indolin-2-one compounds prepared by the preparation method in the preparation of anti-tumor drugs.

[0045] In other aspects, the present invention also provides the 3-(thiazol-4-ylmethylene)indolin-2-one compounds with anti-triple-negative breast cancer activity, or the 3-(thiazol-4-ylmethylene)indolin-2-one compounds prepared by the preparation method, and their use in the preparation of active drugs against triple-negative breast cancer.

[0046] Furthermore, the drug is a drug that inhibits the proliferation and migration of triple-negative breast cancer cells.

[0047] Furthermore, the triple-negative breast cancer cells include at least one of MDA-MB-231 and BT-549 cells.

[0048] In other aspects, the present invention provides a pharmaceutical composition for inhibiting the proliferation and migration of triple-negative breast cancer, wherein the pharmaceutical composition comprises the 3-(thiazol-4-ylmethylene)indolin-2-one compound or its pharmaceutically acceptable salt having anti-triple-negative breast cancer activity, or the 3-(thiazol-4-ylmethylene)indolin-2-one compound or its pharmaceutically acceptable salt prepared by the preparation method.

[0049] Furthermore, the pharmaceutical composition also includes a pharmaceutically acceptable carrier and / or adjuvant.

[0050] Compared with the prior art, the technical effects achieved by the present invention include:

[0051] The 3-(thiazol-4-ylmethylene)indolin-2-one compounds provided by the present invention are designed and synthesized based on the indolinone derivative ZL170 with potential anti-tumor activity as the basic skeleton, using the bioisosteric and skeleton transition strategies. It has been verified that the 3-(thiazol-4-ylmethylene)indolin-2-one compounds have a certain inhibitory effect on the proliferation and migration of triple-negative breast cancer cells including MDA-MB-231 and BT-549. Some compounds can obtain good anti-tumor effects at very low doses. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying any creative work.

[0053] Figure 1 This is the test result of the compound LJ23 in Example 5 for inhibiting TNBC migration activity. DETAILED DESCRIPTION

[0054] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments. Obviously, the embodiments described below are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0055] It should be understood that when used in this specification and the appended claims, the terms "include" and "comprises" indicate the presence of described features, integers, steps, operations and / or elements, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements and / or groups thereof.

[0056] It should also be understood that the terms used in this description of the embodiments of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the embodiments of the present invention. As used in the description of the embodiments of the present invention and the appended claims, unless the context clearly indicates otherwise, the singular forms of "a", "an" and "the" are intended to include plural forms.

[0057] All chemicals and reagents in the following examples were purchased from commercial suppliers and used directly without further purification; all temperatures are in degrees Celsius; and column chromatography used 200-300 mesh silica gel.

[0058] The compounds prepared in the embodiments of the present invention and conforming to the structure shown in the general formula (1) are as follows:

[0059] .

[0061] The physicochemical data of the above-mentioned compounds of formula LJ1-LJ27 are as follows:

[0062] LJ1: yellow solid, melting point 220-222°C; 1 H NMR (500MHz, Acetone-d6) δ9.53 (s, 1H), 9.17 (d, J = 7.6Hz, 1H), 8.07 (s, 1H), 7.53 (s, 1H), 7.24 (td,J=7.6,1.3Hz,1H),7.03(td,J=7.6,1.1Hz,1H),6.94(dd,J=15.0,7.7Hz,1H),2.88(s,3H). 13 CNMR(125MHz,Acetone-d6)δ166.8,166.2,151.6,143.0,129.6,128.3,127.4,126.0,125.6,122.2,121.3,109.3,18.6.HR-MS(ESI)m / z:calcd for C 13 H 10 N2OS[M+H] + 243.0587, found 243.0573.

[0063] LJ2: yellow solid, melting point 182°C; 1H NMR (400MHz, DMSO-d6) δ10.55(s,1H),9.08(d,J=7.8Hz,1H),8.32(s,1H),7.51(s,1H),7.24(td,J=7.6, 1.3Hz,1H),6.99(td,J=7.6,1.1Hz,1H),6.87(d,J=7.7Hz,1H),3.51-3.41(m,1H),1.46(d,J=6.9Hz,6H). 13 C NMR(100MHz,DMSO-d6)δ178.4,170.1,151.0,143.4,130.2,128.6,127.9,126.8,125.5,122.1,121.5,110.0,33.2,23.1.HR-MS(ESI)m / z:calcd for C 15 H 14 N2OS[M+H] + 271.0900, found 271.0886.

[0064] LJ3: yellow solid, melting point 211-212°C; 1 H NMR(500MHz, Acetone-d6)δ9.57(s,1H),9.24(d,J=7.7Hz,1H),8.11(s,1H),7.55(s,1H),7 .25(td,J=7.6,1.3Hz,1H),7.04(td,J=7.6,1.1Hz,1H),6.93(d,J=7.5Hz,1H),1.57(s,9H). 13 C NMR (125MHz, Acetone-d6) δ181.8,169.7,151.4,143.0,129.6,128.1,126.8,126.2,125.6,122.3,121.1,109.3,38.0,30.2.HR-MS(ESI)m / z:calcd for C 16 H 16 N2OS[M+H] + 285.1056, found 285.1043.

[0065] LJ4: yellow solid, melting point 262-263°C; 1H NMR (500MHz, DMSO-d6) δ10.60 (s, 1H), 9.12 (d, J = 7.7Hz, 1H), 8.51 (s, 1H), 8.10-8.08 (m, 2H), 7. 65-7.58(m,4H),7.29(td,J=7.6,1.4Hz,1H),7.09(td,J=7.7,1.1Hz,1H),6.90(d,J=7.7Hz,1H). 13 C NMR(150MHz,DMSO-d6)δ170.0,168.6,152.5,143.5,133.1,131.5,130.5,130.1 ,129.8,127.5,126.8,126.5,126.1,122.1,121.7,110.1.HR-MS(ESI)m / z:calcd for C 18 H 12 N2OS[M+H]+305.0743,found305.0741.

[0066] LJ5: yellow solid, melting point 277-278°C; 1 HNMR(500MHz,DMSO-d6)δ10.62(s,1H),9.05(d,J=7.7Hz,1H),8.60(s,1H),8.29(d,J=8.1Hz,2H),7.88(d, J=8.2Hz,2H),7.60(s,1H),7.30(td,J=7.6,1.3Hz,1H),7.11(td,J=7.7,1.1Hz,1H),6.90(d,J=7.6Hz,1H). 13 C NMR (125MHz, DMSO-d6) δ170.0,166.8,152.8,143.6,136.6,131.0(d,J=32.0Hz),130.7,130.6,127.6,127.4 ,127.1(q,J=3.8Hz),126.5,126.2,125.5(d,J=271.4Hz),122.0,121.8,110.2,93.4.HR-MS(ESI)m / z:calcd for C 19 H 11 F3N2OS[M+H] + 373.0617, found 373.0621.

[0067] LJ6: yellow solid, melting point 218℃; 1H NMR(500MHz,Acetone-d6)δ9.43(s,1H),9.05(s,1H),8.05(s,1H),7.50(s,1H) ,7.06(dd,J=7.8,0.9Hz,1H),6.81(d,J=7.8Hz,1H),2.89(s,3H),2.35(s,3H). 13 C NMR (125MHz, Acetone-d6) δ169.7,166.6,151.6,140.6,130.2,129.9,128.9,127.1,125.9,125.7,122.2,108.9,20.5,18.6.HR-MS(ESI)m / z:calcd forC 14 H 12 N2OS[M+H] + 257.0743, found 257.0737.

[0068] LJ7: yellow solid, melting point 194°C; 1 H NMR(500MHz,Acetone-d6)δ9.42(s,1H),9.12(s,1H),8.08(s,1H),7.51(s,1H),7.06(d,J =7.5Hz,1H),6.81(d,J=7.8Hz,1H),3.55-3.46(m,1H),2.35(s,3H),1.56(d,J=6.9Hz,6H). 13 C NMR (125MHz, Acetone-d6) δ183.6,177.9,151.5,140.7,130.2,129.9,129.2,128.7,126.6,125.9,122.4,109.0,33.3,22.3,20.4.HR-MS(ESI)m / z:calcd for C 16 H 16 N2OS[M+H] + 285.1056, found 285.1041.

[0069] LJ8: red solid 215-217℃; 1 H NMR (500MHz, Acetone-d6) δ9.13(s,1H),8.09(s,1H),7.51(s,1H),7.07(dd,J=7.8,0.9Hz,1H),6.81(d,J=7.9Hz,1H),2.35(s,3H),1.60(s,9H). 13C NMR (125MHz, Acetone-d6) δ181.7,169.8,151.4,140.7,130.1,129.9,128.6,126.7,125.9,125.8,122.4,108.9,38.1,30.3,20.3.HR-MS(ESI)m / z:calcd for C 17 H 18 N2OS[M+H] + 299.1213, found 261.1204.

[0070] LJ9: yellow solid, melting point 250-250℃; 1 H NMR(500MHz,DMSO-d6)δ10.49(s,1H),9.07(s,1H),8.48(s,1H),8.12(d,J=7.2Hz,2H),7 .62-7.60(m,3H),7.54(s,1H),7.11(d,J=7.8Hz,1H),6.78(d,J=7.8Hz,1H),2.36(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.1,168.4,152.5,141.2,133.2,131.5,130.7,130.1,13 0.0,129.5,128.4,126.8,126.4,126.1,122.2,109.7,21.4.HR-MS(ESI)m / z:calcd for C 19 H 14 N2OS[M+H] + 319.0900, found 319.0894.

[0071] LJ10: yellow solid, melting point 264°C; 1 H NMR (600MHz, Acetone-d6) δ9.23(s,1H),8.82(s,1H),8.04(s,1H),7.49(s,1H),6.76(s,1H),6.74(d,J=1.1Hz,1H),2.89(s,3H). 13 C NMR (125MHz, Acetone-d6) δ169.9,166.8,152.3,151.6,135.8,127.1,126.3,125.9,123.0,116.2,115.8,109.5,18.6.HR-MS(ESI)m / z:calcd for C 13 H 10 N2O2S[M+H]+ 259.0536, found 259.0533.

[0072] LJ11: red solid, melting point 228℃; 1 H NMR (600MHz, Acetone-d6) δ9.22 (s, 1H), 8.84 (d, J = 2.5Hz, 1H), 8.07 (s, 1H), 7.83 (s, 1H), 7.50 (s, 1H), 6.76(dd,J=8.2,2.5Hz,1H), 6.73(dd,J=8.3,0.6Hz,1H), 3.54(p,J=6.9Hz,1H), 1.52(d,J=6.9Hz,6H). 13 C NMR (125MHz, Acetone-d6) δ178.3,169.8,152.3,151.5,135.9,126.4,126.3,126.0,123.2,116.1,109.3,109.3,33.4,22.4.HR-MS(ESI)m / z:calcd for C 15 H 14 N2O2S[M+H] + 287.0849, found 287.0842.

[0073] LJ12: red solid, melting point 234°C; 1 H NMR (600MHz, Acetone-d6) δ9.22 (s, 1H), 8.83 (d, J = 2.5Hz, 1H), 8.08 (s, 1H), 7.77 (s, 1 H),7.50(s,1H),6.77(dd,J=8.2,2.6Hz,1H),6.72(dd,J=8.2,0.6Hz,1H),1.58(s,9H). 13 C NMR (125MHz, Acetone-d6) δ181.8,169.8,152.3,151.4,135.9,126.5,126.3,126.1,123.3,116.3,116.1,109.2,38.0,30.3.HR-MS(ESI)m / z:calcd for C 16 H 16 N2O2S[M+H] + 301.1005, found 301.0996.

[0074] LJ13: red solid, melting point 198℃; 1H NMR(500MHz,DMSO-d6)δ10.31(s,1H),8.97(s,1H),8.60(s,1H),8.47(s,1H),8.13-8.1 2(m,2H),7.60-7.59(m,3H),7.53(s,1H),6.75(d,J=8.2Hz,1H),6.69(d,J=8.2Hz,1H). 13 C NMR(125MHz,DMSO-d6))δ170.1,168.6,152.5,152.5,136.0,133.1,131.4,130.0 ,129.3,128.8,127.0,126.2,122.9,117.0,115.6,110.1.HR-MS(ESI)m / z:calcd for C 18 H 12 N2O2S[M+H]+321.0692,found 321.0690.

[0075] LJ14: red solid, melting point 293-294°C; 1 H NMR (500MHz, DMSO-d6) δ10.32(s,1H),8.96(s,1H),8.57(s,1H),8.50(d,J=2.5Hz,1H),8.31(d,J= 8.1Hz,2H),7.94(d,J=8.2Hz,2H),7.55(s,1H),6.76(dd,J=8.3,2.5Hz,1H),6.70(d,J=8.2Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ169.5,166.3,152.4,152.0,136.2,135.6,130.5(d,J=31.9Hz),129.8,127.3,127 .0,126.41(q,J=3.6Hz),125.5,123.9(d,J=272.3Hz),122.3,116.8,114.9,109.8.HR-MS(ESI)m / z:calcd for C 19 H 11 F3N2O2S[M+H] + 389.0566, found 389.0559.

[0076] LJ15: red solid, melting point 199-200℃; 1HNMR(500MHz,DMSO-d6)δ10.34(s,1H),8.89(d,J=2.7Hz,1H),8.29(s,1H),7.48(s ,1H),6.83(dd,J=8.4,2.7Hz,1H),6.76(d,J=8.4Hz,1H),3.80(s,3H),2.83(s,3H). 13 C NMR(100MHz,DMSO-d6)δ170.2,167.2,154.8,151.2,137.0,129.5,126.6,126.0,122.8,116.4,113.4,110.3,55.7,19.7.HR-MS(ESI)m / z:calcdfor C 14 H 12 N2O2S[M+H] + 273.0692, found 273.0691.

[0077] LJ16: red solid, melting point 171°C; 1 H NMR(500MHz,DMSO-d6)δ10.36(s,1H),8.80(d,J=2.7Hz,1H),8.33(s,1H),7.50(s,1H),6.85(dd, J=8.4,2.6Hz,1H),6.76(d,J=8.4Hz,1H),3.78(s,3H),3.49-3.41(m,1H),1.45(d,J=6.9Hz,6H). 13 C NMR (150MHz, DMSO-d6) δ178.7,170.2,154.9,151.2,137.1,128.8,126.9,125.9,122.9,115.6,114.4,110.1,56.1,33.4,23.2.HR-MS(ESI)m / z:calcd for C 16 H 16 N2O2S[M+H] + 301.1005, found 301.0997.

[0078] LJ17: yellow solid, melting point 218°C; 1 H NMR(500MHz,DMSO-d6)δ10.37(s,1H),8.72(d,J=2.6Hz,1H),8.34(s,1H),7.50(s, 1H), 6.86 (dd, J=8.5, 2.7Hz, 1H), 6.77 (d, J=8.4Hz, 1H), 3.77 (s, 3H), 1.51 (s, 9H).13 C NMR (100MHz, DMSO-d6) δ182.2,170.1,155.0,151.2,137.2,128.9,127.1,125.7,123.1,115.3,115.0,110.0,56.5,38.2,31.0.HR-MS(ESI)m / z:calcdfor C 17 H 18 N2O2S[M+H] + 315.1162, found 315.1144.

[0079] LJ18: red solid, melting point 227-228℃; 1 H NMR (500MHz, DMSO-d6) δ10.43(s,1H),8.82(d,J=2.6Hz,1H),8.54(s,1H),8.11(dd,J=6.6,2. 8Hz,2H),7.61-7.59(m,4H),6.89(dd,J=8.4,2.7Hz,1H),6.81(d,J=8.4Hz,1H),3.77(s,3H). 13 CNMR(150MHz,DMSO-d6)δ170.1,168.7,154.9,152.5,137.3,133.1,131.5,130.1,1 29.9,127.0,126.6,126.6,122.8,116.2,113.8,110.4,56.2.HR-MS(ESI)m / z:calcd for C 19 H 14 N2O2S[M+H]+335.0849,found335.0836.

[0080] LJ19: red solid, melting point 243-244°C; 1 H NMR(500MHz,DMSO-d6)δ10.42(s,1H),8.71(d,J=2.7Hz,1H),8.62(s,1H),8.30(d,J=8.1Hz,2H),7 .96(d,J=8.1Hz,2H),7.59(s,1H),6.88(dd,J=8.5,2.7Hz,1H),6.80(d,J=8.4Hz,1H),3.75(s,3H). 13C NMR (125MHz, DMSO-d6) δ169.5, 166.5, 154.5, 152.3, 136.9, 136.2, 130.7 (d, J = 31.8Hz), 130.6, 127.3, 126.5 ,126.4(q,J=3.9Hz),125.9,123.93(d,J=272.4Hz),122.2,115.9,113.1,110.0,55.7.HR-MS(ESI)m / z:calcd for C 20 H 13 F3N2O2S[M+H] + 403.0723, found 403.0726.

[0081] LJ20: yellow solid, melting point 239-241°C; 1 H NMR(500MHz,DMSO-d6)δ10.57(s,1H),8.94(dd,J=10.4,2.8Hz,1H),8.36(s,1H),7 .55(s,1H),7.09(td,J=8.9,2.8Hz,1H),6.84(dd,J=8.5,4.7Hz,1H),2.84(s,3H). 13 C NMR (125MHz, DMSO-d6) δ170.1,167.7,157.96(d,J=233.3Hz),150.9,139.65-139.58(m),130.6,128.0,125.00(d,J=2.8H z),123.17(d,J=10.2Hz),116.30(d,J=23.9Hz),115.00(d,J=27.5Hz),110.45(d,J=8.4Hz),19.7.HR-MS(ESI)m / z:calcd for C 13 H9FN2OS[M+H] + 261.0492, found 261.0480.

[0082] LJ21: yellow solid, melting point 203℃; 1 H NMR (600MHz, Acetone-d6) δ9.53 (s, 1H), 9.18 (dd, J = 10.5, 2.8Hz, 1H), 8.19 (s, 1H), 7.58 (s, 1H), 7. 03(td,J=8.8,2.8Hz,1H),6.91(dd,J=8.5,4.6Hz,1H),3.52(p,J=6.9Hz,1H),1.55(d,J=6.9Hz,6H). 13C NMR (125MHz, Acetone-d6) δ178.5,168.8,158.31(d,J=233.9Hz),151.2,139.16(d,J=1.9Hz),127.9,127.4,125.23(d,J=3.7H z),123.42(d,J=10.2Hz),115.57(d,J=24.2Hz),115.16(d,J=27.7Hz),109.74(d,J=8.2Hz),33.4,22.2.HR-MS(ESI)m / z:calcd for C 15 H 13 FN2OS[M+H] + 289.0805, found 289.0801.

[0083] LJ22: yellow solid, melting point 207-208°C; 1 H NMR (600MHz, Acetone-d6) δ9.51 (s, 1H), 9.2 (dd, J = 10.5, 2.8Hz, 1H), 8.20 (s, 1H), 7.58(s,1H),7.04(td,J=8.8,2.8Hz,1H),6.91(dd,J=8.5,4.6Hz,1H),1.59(s,9H). 13 C NMR (125MHz, Acetone-d6) δ182.2,169.7,158.32(d,J=233.7Hz),151.1,139.15(d,J=1.9Hz),128.0,127.5,125.16(d,J=2.7H z),123.43(d,J=10.4Hz),115.56(d,J=24.2Hz),115.12(d,J=27.7Hz),109.74(d,J=8.2Hz),38.1,30.2.HR-MS(ESI)m / z:calcd for C 16 H 15 FN2OS[M+H] + 303.0962, found 303.0952.

[0084] LJ23: yellow solid, melting point 291-292°C; 11H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.08 (dd, J = 10.4, 2.8 Hz, 1H), 8.59 (s, 1H), 8.08 (dd, J = 7.7, 1.8 Hz, 2H), 7.64 - 7.60 (m, 4H), 7.13 (td, J = 8.8, 2.8 Hz, 1H), 6.87 (dd, J = 8.5, 4.7 Hz, 1H). 13 13C NMR (125 MHz, DMSO-d6) δ 170.0, 168.9, 158.91 (d, J = 1.9 Hz), 152.2, 139.76 (d, J = 1.8 Hz), 133.0, 131.6, 131.0, 130.1, 127.7, 126.8, 125.71 (d, J = 2.9 Hz), 123.12 (d, J = 2.5 Hz), 116.59 (d, J = 24.0 Hz), 114.54 (d, J = 25.6 Hz), 110.65 (d, J = 8.4 Hz). HR-MS (ESI) m / z: calcd for C 18 H 11 FN2OS [M + H] + 323.0649, found 323.0640.

[0085] LJ24: Yellow solid, melting point 274 °C; 1 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.96 (dd, J = 10.3, 2.8 Hz, 1H), 8.67 (s, 1H), 8.26 (d, J = 8.1 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 7.65 (s, 1H), 7.14 (td, J = 8.8, 2.8 Hz, 1H), 6.88 (dd, J = 8.5, 4.6 Hz, 1H). 13 13C NMR (150 MHz, DMSO-d6) δ 169.5, 166.7, 158.3, 156.8, 152.1, 139.4, 136.2, 131.5, 130.18 (d, J = 146.7 Hz), 127.12 (d, J = 6.0 Hz), 126.62 (q, J = 38.1, 4.2 Hz), 125.66 (d, J = 4.0 Hz), 123.93 (d, J = 272.5 Hz), 122.59 (d, J = 10.0 Hz), 116.35 (d, J = 23.8 Hz), 1113.95 (d, J = 27.5 Hz), 110.32 (d, J = 8.0 Hz). HR-MS (ESI) m / z: calcd for C 19 H10 F4N2OS[M+H] + 391.0523, found 391.0518.

[0086] LJ25: yellow solid, melting point 258℃: 1 H NMR (500MHz, DMSO-d6) δ10.69(s,1H),9.20d,J=2.2Hz,1H),8.37(s,1H),7.55(s,1H),7.28(dd,J=8.3,2.3Hz,1H),6.86(d,J=8.3Hz,1H),2.84(s,3H). 13 C NMR(100MHz,DMSO-d6)δ169.9,167.6,150.8,142.0,130.7,129.5,128.1,127.8,125.6,124.4,123.7,111.2,19.7.HR-MS(ESI)m / z:calcd for C 13 H9ClN2OS[M+H] + 277.0197, found 277.0191.

[0087] LJ26: yellow solid, melting point 189°C; 1 H NMR(500MHz,DMSO-d6)δ10.68(s,1H),9.31(d,J=2.3Hz,1H),8.40(s,1H),7.56(s,1H),7. 28(dd,J=8.3,2.3Hz,1H),6.86(d,J=8.3Hz,1H),3.49-3.41(m,1H),1.49(d,J=6.9Hz,6H). 13 C NMR(100MHz,DMSO-d6)δ178.6,169.9,150.8,142.0,130.1,129.5,128.2,127.7,125.7,124.4,123.7,111.2,33.2,23.0.HR-MS(ESI)m / z:calcd for C 15 H 13 ClN2OS[M+H] + 305.0510, found 305.0504.

[0088] LJ27: yellow solid, melting point 205.9-206.8°C; 1HNMR (500MHz, DMSO-d6) δ10.69(s,1H),9.32(s,1H),8.41(s,1H),7.56(s,1H),7.28(d,J=8.3Hz,1H),6.87(d,J=8.3Hz,1H),1.52(s,9H). 13 C NMR (100MHz, DMSO-d6) δ182.4,169.8,150.7,142.0,130.0,129.5,128.3,127.6,125.7,124.5,123.7,111.2,38.3,31.0.HR-MS(ESI)m / z:calcd for C 16 H 15 ClN2OS[M+H] + 319.0666, found 319.0661.

[0089] The following examples introduce the synthesis methods of the compounds.

[0090] Example 1 Compound LJ1

[0091] The synthetic route is as follows:

[0092]

[0093] The specific methods are as follows:

[0094] Dissolve 50 mmol of thioacetamide and 50 mmol of 1,3-dichloroacetone in 100 mL of tetrahydrofuran, heat under reflux for more than 6 hours, and remove the solvent by distillation under reduced pressure after the raw material disappears by thin layer chromatography. Extract with ethyl acetate, wash three times with saturated brine, dry the organic phase with anhydrous magnesium sulfate, and purify the sample by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain 6.9 g of white solid, namely IIa. 11 HNMR (400MHz, CDCl3) δ7.15 (s, 1H), 4.66 (s, 2H), 2.74 (s, 3H).

[0095] 33 mmol of compound IIa and 36 mmol of sodium benzoate were dissolved in acetonitrile and refluxed for more than 6 hours. After the raw material disappeared after thin layer chromatography, the reaction solution was poured into ice water and extracted twice with dichloromethane. The organic phase was washed twice with a saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent. The obtained solid was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 7.06 g of a yellow oily liquid, namely IVa. 1HNMR (400MHz, CDCl3) δ 8.11-8.04 (m, 2H), 7.60-7.53 (m, 1H), 7.46-7.40 (m, 2H), 7.21 (s, 1H), 5.43 (d, J = 0.8Hz, 2H), 2.73 (s, 3H).

[0096] 30.3 mmol of compound IVa was dissolved in 100 mL of ethanol, and 45 mmol of lithium hydroxide was added. The reaction was carried out at room temperature. When the raw material disappeared after thin layer chromatography, the solution was adjusted to neutral with 10% dilute hydrochloric acid. The solvent was removed by vacuum distillation. The obtained solid was purified by column chromatography (petroleum ether: acetone = 1:1) to obtain 3.4 g of yellow oil, namely Va. yellow oil; 1 HNMR (400MHz, CDCl3) δ7.00 (t, J=0.9Hz, 1H), 4.68 (d, J=0.9Hz, 2H), 2.66 (s, 3H).

[0097] 10 mmol of compound Va was dissolved in 20 mL of anhydrous dichloromethane, and 20 mmol of Dess-Martin reagent and 40 mmol of pyridine were added. The reaction was stirred at room temperature for more than 2 hours. When the raw material disappeared after thin layer chromatography, the insoluble matter was removed by filtration. The mother liquor was washed twice with saturated sodium bicarbonate solution and saturated sodium sulfite solution. The organic phases were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent. The obtained solid was purified by column chromatography (petroleum ether: acetone = 3:1) to obtain 1.1 g of a white solid, namely VIa. 1 HNMR (400MHz, CDCl3) δ9.98(s,1H),8.04(s,1H),2.78(s,3H).

[0098] 0.1mmol VIa and indolin-2-one (VIIa) were dissolved in 3mL methanol, 0.4mmol piperidine was added, and the mixture was heated to reflux. After the raw material disappeared after TLC detection, the mixture was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. The obtained solid was purified by HPLC (chromatographic column YMC-Park-ODS, water / methanol=40 / 60, 0.05% trifluoroacetic acid, flow rate 3mL / min, retention time 23.3min) to obtain 21.8mg yellow solid, i.e. LJ1. Melting point 220-222°C; 1 H NMR (500MHz, Acetone-d6) δ9.53 (s, 1H), 9.17 (d, J = 7.6Hz, 1H), 8.07 (s, 1H), 7.53 (s, 1H), 7.24 (td,J=7.6,1.3Hz,1H),7.03(td,J=7.6,1.1Hz,1H),6.94(dd,J=15.0,7.7Hz,1H),2.88(s,3H).13 C NMR (125MHz, Acetone-d6) δ166.8,166.2,151.6,143.0,129.6,128.3,127.4,126.0,125.6,122.2,121.3,109.3,18.6.HR-MS(ESI)m / z:calcd for C 13 H 10 N2OS[M+H] + 243.0587, found 243.0573.

[0099] Example 2: Compound LJ23

[0100] The synthetic route is as follows:

[0101]

[0102] The specific methods are as follows:

[0103] 50 mmol of thiobenzamide and 50 mmol of 1,3-dichloroacetone were dissolved in 100 mL of ethanol and heated under reflux for more than 6 hours. After the raw material disappeared after thin layer chromatography, the solvent was removed by distillation under reduced pressure. The mixture was extracted with ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and the sample was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain 7.8 g of white solid IId. 1 HNMR (500MHz, CDCl3) δ7.92-7.90(m,2H),7.41-7.38(m,3H),7.24(s,1H),4.71(s,2H).

[0104] 20 mmol of compound IId and 22 mmol of sodium benzoate were dissolved in DMF and refluxed for more than 6 hours. After the raw material disappeared after thin layer chromatography, the reaction solution was poured into ice water and extracted twice with dichloromethane. The organic phase was washed twice with a saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent. The obtained solid was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 5.37 g of a yellow oily liquid, namely IVd. 1 HNMR (500MHz, CDCl3) δ8.13-8.07(m,2H),8.00-7.92(m,2H),7.55(d,J=7.5Hz,1H),7.50-7.39(m,5H),7.36(s,1H),5.53(s,2H).

[0105] 15 mmol of compound IVd was dissolved in 20 mL of tetrahydrofuran, 20 mL of sodium hydroxide aqueous solution (10%) was added, and the mixture was heated under reflux for 1 hour. After the raw material disappeared by thin layer chromatography, the mixture was cooled to room temperature, adjusted to neutral with 10% dilute hydrochloric acid, extracted twice with ethyl acetate, and the organic phase was washed twice with saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent. The obtained solid was purified by column chromatography (petroleum ether: acetone = 1:1) to obtain 2.4 g of a brown oily liquid, namely Vd. 1 HNMR (500MHz, CDCl3) δ7.97-7.86(m,2H),7.47-7.38(m,3H),7.16(s,1H),4.80(d,J=0.9Hz,2H),3.08(s,1H).

[0106] 10 mmol of compound Vd was dissolved in 20 mL of anhydrous dichloromethane, and 200 mmol of active manganese dioxide was added. The mixture was stirred at room temperature for more than 12 hours. After the raw material disappeared after thin layer chromatography, the insoluble matter was removed by filtration, and the solvent was removed by distillation under reduced pressure to obtain 1.7 g of a yellow oil, namely VId, which was used in the next step without purification. 1 H NMR (500MHz, CDCl3) δ10.10(s,1H),8.17(s,1H),8.08-7.97(s,2H),7.52-7.47(s,3H).

[0107] 0.1mmol VId and 5-fluoroindolin-2-one (VIIc) were dissolved in 3mL ethanol, 0.4mmol methylpiperidine was added, and the mixture was heated to reflux. After the raw material disappeared after TLC detection, the mixture was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. The obtained solid was purified by HPLC (chromatographic column YMC-Park-ODS, water / methanol = 20 / 80, 0.05% trifluoroacetic acid, flow rate 3mL / min, retention time 16.0min) to obtain 30.2mg yellow solid, i.e. LJ23. Melting point 291-292°C; 1 H NMR(500MHz,DMSO-d6)δ10.63(s,1H),9.08(dd,J=10.4,2.8Hz,1H),8.59(s,1H),8.08(dd,J= 7.7,1.8Hz,2H),7.64-7.60(m,4H),7.13(td,J=8.8,2.8Hz,1H),6.87(dd,J=8.5,4.7Hz,1H). 13C NMR (125MHz, DMSO-d6) δ170.0,168.9,158.91(d,J=1.9Hz),152.2,139.76(d,J=1.8Hz),133.0,131.6,131.0,130.1,127.7,126.8, 125.71 (d, J = 2.9Hz), 123.12 (d, J = 2.5Hz), 116.59 (d, J = 24.0Hz), 114.54 (d, J = 25.6Hz), 110.65 (d, J = 8.4Hz). HR-MS (ESI) m / z: calcd for C 18 H 11 FN2OS[M+H] + 323.0649, found 323.0640.

[0108] The preparation methods of other compounds can refer to compound LJ1 and compound LJ23, which will not be described in detail in the present invention.

[0109] Example 3

[0110] Compounds represented by general formula (I), such as LJ1-LJ27, were tested for their ability to inhibit TNBC proliferation.

[0111] Digest MDA-MB-231 cells and BT549 cells from the cell culture dish and evenly spread them in a 96-well plate with 4500 cells per well. Culture overnight. After adding a certain concentration of compound and incubating for 48 hours, remove the 96-well plate and remove the culture medium in the well. Dilute and mix the CCK8 detection solution and blank culture medium in the sample loading tank at a ratio of 9:1. Add 100μL CCK8 and culture medium mixture to each well for staining, incubate in a constant temperature CO2 incubator for 1-3h, then detect the OD value of each well in the enzyme-labeled imager, calculate the values ​​of the drug-added group and the control group, and obtain the cell survival rate in each well. Each sample was repeated three times at a concentration of 50uM, and the average value was calculated.

[0112] Compounds represented by general formula (I) such as LJ1-LJ27 were tested for TNBC proliferation inhibition activity, and the results are shown in Table 1 below:

[0113] Table 1 Results of the inhibition of TNBC proliferation activity by compounds LJ1-LJ27

[0114]

[0115]

[0116] *N stands for invalid.

[0117] From the experimental results in Table 1, it can be seen that at a mass concentration of 50uM, most of the 3-(thiazol-4-ylmethylene)indolin-2-one compounds provided by the present invention have a certain inhibitory effect on the selected cell lines. Preferably, the proliferation inhibition rate of compounds LJ3, LJ8, LJ22, LJ23 and LJ27 on MDA-MB-231 cells is higher than 50%.

[0118] Example 4

[0119] The half inhibitory concentration (IC 50 ) test.

[0120] The method of Example 3 was used to determine the proliferation inhibition rate of compounds LJ3, LJ8, LJ22, LJ23 and LJ27 at 0.5uM, 1uM, 2.5uM, 5uM, 10uM, 20uM, 50uM and 75uM on MDA-MB-231 cells, and the lead compound ZL170 and the positive drug 5-fluorouracil (5-Fu) were used as controls. The IC was calculated according to the corresponding inhibition rate at the experimental concentration. 50 (uM), the results are shown in Table 2 below:

[0121] Table 2 IC of compounds LJ3, LJ8, LJ22, LJ23 and LJ27 on MDA-MB-231 cells 50 (uM)

[0122]

[0123] In this example, the highly active compounds LJ3, LJ8, LJ22, LJ23 and LJ27 in Example 3 were selected to determine their IC 50 From the results in Table 2, it can be seen that the IC values ​​of LJ8 and LJ23 for MDA-MB-231 cells are 50 They are 36.5uM and 32.1uM respectively, which are lower than the lead compound ZL170 and close to the clinical anti-tumor drug 5-FU.

[0124] Example 5 Test of the inhibitory activity of compound LJ23 on TNBC migration

[0125] The present invention selected the highly active compound LJ23 in Example 4 to further determine its inhibitory effect on the migration of MDA-MB-231 cells. The specific experiment is as follows:

[0126] Transwell experiment

[0127] MDA-MB-231 cells treated with different concentrations of compounds for 48 hours were digested from the well plate and resuspended in DMEM medium. The cells were counted and 12×10 5 The cells were centrifuged, resuspended in 200 μl serum-free culture medium and added to the upper chamber of the chamber, and 1 ml of DMEM containing 10% serum was added to the lower chamber. After culturing in the incubator for 12 hours, the chamber was taken out, fixed with methanol and washed three times with PBS solution. The remaining cells in the upper chamber were gently wiped with a cotton swab, stained, observed and counted.

[0128] Scratch test

[0129] The digested MDA-MB-231 cells in the cell culture dish were centrifuged and resuspended, and then evenly spread in a 96-well plate for overnight culture (20,000 cells per well). Before adding the compound for incubation, the well plate was placed on a cell scratcher for scratching, and the culture medium in the well plate was quickly discarded after the scratching. Add 100 μL PBS to wash, repeat 3 times, dilute the compounds of different concentrations with culture medium, and add 200 μL to each well. After the addition of the drug, the well plate was placed in an enzyme-labeled imager for the first photo, and then placed in a cell culture incubator for 24-48 hours, and the second photo was taken. The data of the two photos were subtracted and compared with the data of the control group to obtain the cell migration rate, which reflects the inhibitory effect of the drug on cell migration.

[0130] Western blot (WB) was used to determine the effect of LJ23 on epithelial-mesenchymal transition (EMT)-related indicators

[0131] RIPA (strong), 5× protein loading buffer, PMSF, and Inhibitor cocktail were mixed evenly according to the proportions, and the same volume of protein lysis buffer was added to each well to extract total cell protein. The protein samples were run on gels, and after transfer, the PVDF membrane was blocked with 5% skim milk, incubated with primary antibodies overnight, and incubated with secondary antibodies at room temperature for one hour, and then developed.

[0132] The results of the above experiments can be found in Figure 1 Transwell and scratch experiments showed that LJ23 could inhibit the migration of MDA-MB-231 cells in a dose-dependent manner at the experimental concentrations (5uM, 10uM and 20uM). WB experiments showed that LJ23 inhibited the migration of MDA-MB-231 cells by affecting the EMT process.

[0133] The above data show that the compound containing 3-(thiazol-4-ylmethylene)indolin-2-one provided by the present invention and having the structure shown in formula (I) has good anti-TNBC proliferation and migration activity, and is expected to further improve the activity through subsequent functional group changes, providing a new structural template for the design of anti-TNBC and even broad-spectrum anti-tumor drugs, and has great potential application value in the fields of medicinal chemistry and biomedicine.

[0134] In the above embodiments, the description of each embodiment has its own emphasis. For parts that are not described in detail in a certain embodiment, reference can be made to the relevant descriptions of other embodiments.

[0135] The above is a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of various equivalent modifications or replacements within the technical scope disclosed by the present invention, and these modifications or replacements should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention shall be based on the protection scope of the claims.

Claims

1. A 3-(thiazol-4-ylmethylene)indolin-2-one compound having anti-triple-negative breast cancer activity, characterized in that: The compound has a general structural formula as shown in formula (1): In formula (1), R 1 is selected from hydrogen, methyl, ethyl, vinyl, cyclopropyl, cyclobutyl, unsubstituted or 4-substituted aromatic groups, wherein the substituents include any one of methyl, tert-butyl, methoxy, halogen, trifluoromethyl, cyano and methanesulfonyl; R 2 Selected from hydrogen, alkyl or cycloalkyl with carbon number C≤6; R 3 is selected from hydrogen, methyl, methoxy, tert-butyl, hydroxy, trifluoromethoxy, halogen or trifluoromethyl; R 4 is selected from hydrogen, methyl, methoxy, tert-butyl, hydroxy, trifluoromethoxy, halogen or trifluoromethyl; R 5 is selected from hydrogen, methyl, methoxy, tert-butyl, hydroxy, trifluoromethoxy, halogen or trifluoromethyl.

2. The compound according to claim 1, characterized in that The structural formula of the compound is at least one of Formulas LJ1-LJ27:

3. The method for preparing 3-(thiazol-4-ylmethylene)indolin-2-one compounds having anti-triple negative breast cancer activity according to claim 1, characterized in that: The synthetic route is as follows: Among them, III and VII have the following structures: In the above synthetic route, R 1 is selected from hydrogen, methyl, ethyl, vinyl, cyclopropyl, cyclobutyl, unsubstituted or 4-substituted aromatic groups, wherein the substituents include any one of methyl, tert-butyl, methoxy, halogen, trifluoromethyl, cyano and methanesulfonyl; R 2 Selected from hydrogen, alkyl or cycloalkyl with carbon number C≤6; R 3 is selected from hydrogen, methyl, methoxy, tert-butyl, hydroxy, trifluoromethoxy, halogen or trifluoromethyl; R 4 is selected from hydrogen, methyl, methoxy, tert-butyl, hydroxy, trifluoromethoxy, halogen or trifluoromethyl; R 5 is selected from hydrogen, methyl, methoxy, tert-butyl, hydroxy, trifluoromethoxy, halogen or trifluoromethyl. The steps in the synthetic route are described in detail as follows: Reacting 1,3-dichloro-2-alkylacetone and thioamide in solvent 1 to obtain a compound represented by formula (II); The compound represented by formula (II) is dissolved in solvent 2, sodium benzoate is added, heated to reflux, and reacted for 8 to 12 hours to obtain the compound represented by formula (IV); The compound represented by formula (IV) is dissolved in solvent 3, base 1 is added, and hydrolyzed at 25°C to the reflux temperature of the system for 2-6 hours to obtain the compound represented by formula (V); The compound represented by formula (V) is dissolved in solvent 4, and reacted at 0°C to the reflux temperature of the system for 1-24 hours in the presence of an oxidant to obtain a compound represented by formula (VI); In the presence of a base 2, the compound represented by formula (VI) and the compound represented by formula (VII) are refluxed in a solvent 5 to obtain a compound represented by formula (I); Wherein, the solvent 1 is at least one of methanol, ethanol, tetrahydrofuran, and toluene; the solvent 2 is at least one of tetrahydrofuran, DMF, acetone, acetonitrile, dioxane, and dimethyl sulfoxide; the solvent 3 is any one of water, a mixture of water and tetrahydrofuran, a mixture of water and dioxane, a mixture of water and ethanol, and a mixture of water and methanol; the solvent 4 is at least one of dichloromethane, dichloroethane, and acetonitrile; the solvent 5 is at least one of water, methanol, ethanol, and acetonitrile.

4. The preparation method according to claim 3, characterized in that: The base 1 is any one of lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, and triethanolamine; the base 2 is any one of piperidine, 4-methylpiperidine, morpholine, sodium hydroxide, and potassium fluoride.

5. The preparation method according to claim 4, characterized in that: The molar ratio of the base 1 to the compound represented by formula (IV) is 3-5:1; the molar ratio of the base 2 to the compound represented by formula (VI) is 3-5:

1.

6. The preparation method according to claim 3, characterized in that: The oxidant is any one of manganese dioxide, Dess-Martin reagent and pyridinium chlorochromate.

7. Use of the 3-(thiazol-4-ylmethylene)indolin-2-one compound with anti-triple-negative breast cancer activity as claimed in claim 1 or 2, or the 3-(thiazol-4-ylmethylene)indolin-2-one compound prepared by the preparation method according to any one of claims 3 to 6 in the preparation of an anti-triple-negative breast cancer active drug.

8. The use according to claim 7, characterized in that The drug is a drug that inhibits the proliferation and migration of triple-negative breast cancer cells.

9. The use according to claim 8, characterized in that The triple-negative breast cancer cells include at least one of MDA-MB-231 and BT-549 cells.

10. A pharmaceutical composition for inhibiting the proliferation and migration of triple-negative breast cancer, characterized in that: The pharmaceutical composition comprises a 3-(thiazol-4-ylmethylene)indolin-2-one compound or a pharmaceutically acceptable salt thereof having anti-triple-negative breast cancer activity according to claim 1 or 2, or a 3-(thiazol-4-ylmethylene)indolin-2-one compound or a pharmaceutically acceptable salt thereof prepared by the preparation method according to any one of claims 3 to 6.

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