Thiazolidinedione compound and application thereof

Abstract

The invention relates to the field of medicinal chemistry, in particular to thiazolidinedione compounds and application thereof. Pharmacological test results show that when the concentration of the synthesized compound is 10 [mu] M, the inhibition rate of the compound on SphK1 is weaker than that of a positive control drug PF-543, but the inhibition rate of the compound on SphK2 is superior to that of a positive control drug K145, and the compound shows an ideal selective inhibition effect on SphK2. The IC50 of the compounds Q24 and Q25 to SphK2 is less than 10 [mu] M, and the compounds Q24 and Q25 have the value of anti-tumor effect research.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly relates to a class of thiazolidinedione compounds and their applications. Background Art

[0002] Cancer is a disease caused by the uncontrolled proliferation and spread of abnormal cells. These abnormal cells can invade surrounding tissues and organs in the body and even metastasize to other parts to form cancer. Cancer can occur in any tissue or organ, including the skin, lungs, breast, stomach, liver, colon, etc. Its symptoms depend on the type and location of the cancer, and common symptoms include abnormal masses, persistent pain, weight loss, fatigue, anemia, fever, etc. Early detection and treatment can improve the cure rate and survival rate of cancer. Cancer is one of the most difficult diseases to overcome in the world today. Since the number of people who die from cancer is increasing year by year, the research on the occurrence, development, and metastasis mechanisms of cancer and the development of cancer treatment drugs have always been hotspots in domestic and foreign research. There are many causes of cancer. In addition to individual genetic factors, age, eating habits, living environment, etc. are all closely related to the occurrence and development of cancer. The diagnosis of cancer usually requires tissue biopsy, imaging examination, laboratory examination, etc. The methods for treating cancer include surgical treatment, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc.

[0003] Sphingolipids are ubiquitous components in the biological membranes of eukaryotic cells. Sphingolipids and their metabolites are involved in many important signal transduction pathways. Among them, sphingosine kinases (SphKs) can catalyze sphingosine (Sph) to generate sphingosine 1-phosphate (S1P). Sphingosine-1-phosphate (S1P) regulates a variety of biological processes, including cell proliferation and differentiation as well as immune cell trafficking. There are two subtypes of SphKs, SphK1 and SphK2, which are expressed by different genes and have high structural homology, but their tissue localization and functions are different. SphK1 is widely expressed in the liver, kidney, lung, heart, spleen, brain, and skeletal muscle and mainly exists in the cytoplasm. When acted on by some stimulating factors, SphK1 needs to be transported to the plasma membrane to be activated, catalyze the phosphorylation of Sph to form S1P, and then activate five G protein-coupled receptors (S1PR 1 -5 ) through autocrine or paracrine methods, thereby mediating various physiological functions of S1P, such as the trafficking of lymphocytes and the regulation of vascular tone, etc. SphK2 mainly exists in the liver and heart and is located in mitochondria, the nucleus, and the endoplasmic reticulum. It can inhibit DNA synthesis and regulate the activity of histone deacetylase (HDAC), and it is highly expressed in inflammation, central nervous system diseases, and tumors of the rectum, stomach, kidney, colon, uterus, ovary, breast, and lung.

[0004] The human SphK1 protein contains 384 amino acid residues, including 9 α-helices and 17 β-sheets. It has an N-terminal domain (NTD) and a C-terminal domain (CTD), and an ATP catalytic site is located between the two domains. The protein structure of SphK2 has not been resolved yet. Representative compounds designed for SphK2 include ABC 294640, SLR080811, K145, etc. The Chinese name of K145 is 3-(2-amino-ethyl)-5-[3-(4-butoxy-phenyl)-propylidene]-thiazolidine-2,4-dione, and it is one of the most representative SphK2 inhibitors, with its IC 50 against SphK2 reaching 4.30 μM, and it is usually used as a tool drug. PF-543 is the most effective inhibitor of human SphK1 disclosed. Pfizer found through high-throughput screening results that although it has ideal in vitro activity, its short compound half-life, low metabolic stability, or poor overall in vivo pharmacokinetic characteristics limit its development as a clinical drug. Currently, PF-543 is often used as a positive tool drug for SphK1. Compound K145 includes a nitrogen-containing polar head, an intermediate connecting chain of benzene rings, and a hydrophobic tail. In this study, a series of novel compounds were synthesized by optimizing the hydrophobic tail using K145 as a lead compound. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a class of substituted thiazolidinedione compounds or their pharmaceutically acceptable salts, their isomers, their solvates, their pharmaceutical compositions, and their use in the preparation of preventing and / or treating SphK2-mediated diseases.

[0006] To solve the technical problems of the present invention, the present invention provides the following technical solutions: The first aspect of the technical solution of the present invention is to provide a compound represented by the general formula (I) or its pharmaceutically acceptable salt: Formula (I) wherein, R is , , , , , , , , , , , , , , , , , , , , , , , , , , , 。

[0007] Preferably, the R is: , , , , , , , 。

[0008] More preferably, the R is: , , , , , , 。

[0009] As used herein, the term "pharmaceutically acceptable salt" refers to salts formed by the compounds of the present invention with acids or bases that are suitable for use as drugs. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed by the compounds of the present invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid.

[0010] Another preferred class of salts are salts formed by the compounds of the present invention with bases, such as alkali metal salts (e.g., sodium salt or potassium salt), alkaline earth metal salts (e.g., magnesium salt or calcium salt), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), e.g., methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed by morpholine, piperazine, lysine, respectively.

[0011] The term "solvate" refers to a complex formed by the coordination of a compound of the present invention with solvent molecules in a specific ratio.

[0012] The second aspect of the technical solution of the present invention is to provide a preparation method of the compound described in the first aspect or a pharmaceutically acceptable salt thereof. The compound of general formula (I) of the present invention can be prepared by the following method: wherein R is , , , , , , , , , , , , , , , , , , , , , , , , , , , 。

[0013] The thiazolidinedione reacts with N -Boc-bromoethylamine to obtain the intermediate tert-butyl 2-(2,4-dioxothiazol-3-yl)ethylcarbamate (3). Ethyl 4-(4-hydroxyphenyl)butyrate undergoes a nucleophilic substitution reaction with a halogenated hydrocarbon or sulfonyl chloride to obtain a substituted methyl 4-(4-hydroxyphenyl)butyrate, which is reduced to an aldehyde by diisobutylaluminum hydride (DIBAL-H). The resulting aldehyde undergoes condensation with the intermediate 3, and the obtained product is treated with trifluoroacetic acid to obtain the target compound.

[0014] The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt thereof, its isomers, its solvates, and a pharmaceutically acceptable carrier.

[0015] The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof within a safe and effective amount range, and a pharmaceutically acceptable excipient or carrier. The "safe and effective amount" herein refers to: an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dose, and more preferably, contains 10 - 1000 mg of the compound of the present invention per dose. Preferably, the "per dose" is a capsule or a tablet.

[0016] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gelling substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that the components in the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifying and wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0017] The pharmaceutical composition is an injection, a capsule, a tablet, a pill, a powder or a granule.

[0018] There is no particular limitation on the administration mode of the compound or pharmaceutical composition of the present invention. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0019] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dibasic calcium phosphate, or is mixed with the following components: (a) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxypropylmethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizing agents, such as paraffin wax; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

[0020] Solid dosage forms, such as tablets, dragees, capsules, pills, and granules, can be prepared with coatings and shell materials, such as enteric coatings and other materials well known in the art. They can contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax-like substances. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0021] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms can contain inert diluents conventionally used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances, etc.

[0022] In addition to these inert diluents, the composition can also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0023] In addition to the active compound, the suspension can contain suspending agents, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum monostearate, and agar, or mixtures of these substances, etc.

[0024] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstituting into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0025] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

[0026] The compounds of the present invention can be administered alone, or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0027] The treatment method of the present invention can be administered alone, or in combination with other treatment means or therapeutic drugs.

[0028] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal in need of treatment (such as a human), wherein the dosage during administration is an effective dosage considered pharmaceutically. For a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also consider factors such as the administration route and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0029] The fourth aspect of the technical solution of the present invention is to provide the use of the compound described in the first aspect and the pharmaceutical composition described in the third aspect in the preparation of a drug for preventing and / or treating SphK2-mediated diseases.

[0030] The SphK2-mediated diseases include cancer, inflammatory diseases, ischemia-reperfusion injury, renal fibrosis, Alzheimer's disease, diabetic retinopathy, and diabetic nephropathy.

[0031] The cancer includes rectal cancer, gastric cancer, renal cancer, colon cancer, uterine cancer, ovarian cancer, breast cancer, lung cancer, glioma, germ cell tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, and spinal neurofibroma.

[0032] Preferably, the cancer is colorectal cancer and colon cancer.

[0033] Beneficial technical effects: (1) When the concentration of the compound synthesized in the present invention is 10 μM, the inhibition rate of SphK1 is weaker than that of the positive control drug PF-543, but the inhibition rate of most compounds on SphK2 is better than that of the positive control drug K14, that is, the designed and synthesized compounds have ideal inhibitory activity on SphK2 and show ideal selectivity for SphK2.

[0034] (2) In the present invention, the IC 50 of compounds Q5, Q19, Q20, Q24, Q25, Q28, and Q32 on SphK2 are all less than 10 μM, and they have the value of conducting anti-tumor effect research. These 7 compounds, Q5, Q19, Q20, Q24, Q25, Q28, and Q32, have better inhibitory effects on the proliferation of LOVO and HT-29 tumor cells than the positive control drug oxaliplatin; compounds Q5, Q20, Q24, Q25, and Q28 have better inhibitory effects on the proliferation of SW480 tumor cells than the positive control drug oxaliplatin; compounds Q5, Q19, Q24, Q25, and Q28 have better inhibitory effects on the proliferation of SW620 tumor cells than the positive control drug oxaliplatin, providing an experimental basis for in vivo efficacy evaluation and drug-likeness research, and are ideal compounds for drug development. Detailed implementation manners

[0035] The specific embodiments of the present invention describe the preparation methods of the compounds involved in the present invention in detail, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthesis methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains.

[0036] Unless otherwise specified, the raw materials and reagents used in the preparation process of the compounds of the present invention and the reagents used in the pharmacological experiments of the present invention can be purchased through commercial channels.

[0037] The experimental methods without specific conditions noted in the following examples are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0038] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for illustrative purposes only.

[0039] Preparation method of the compounds of the present invention: Dissolve 2( N –Boc-bromoethylamine) (10 mmol, 1 equiv), 1 (2,4-thiazolidinedione) (11 mmol, 1.1 equiv), potassium carbonate (11 mmol, 1.1 equiv), tetrabutylammonium iodide (TBAI) (1 mmol, 0.1 equiv) in acetonitrile (50 mL). 40 oReact under heating and stirring for 22 h. After filtration of the reaction solution, it is concentrated by rotary evaporation, diluted with water, extracted with ethyl acetate. The organic phase is washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent is removed by distillation under reduced pressure. The crude product is separated by silica gel column chromatography (mobile phase: n-hexane - ethyl acetate = 25:1) to obtain white solid compound 3. Dissolve the raw material 4 (methyl 4-hydroxybenzenepropionate) (3 mmol, 1 equiv), the halogenated hydrocarbon or sulfonyl chloride (6 mmol, 2 equiv), and cesium carbonate (3 mmol, 1 equiv) in DMF (6 mL). React under stirring at 70 °C for 8 h, extract with ethyl acetate. The organic phase is washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent is removed by distillation under reduced pressure. The crude product is separated by silica gel column chromatography (mobile phase: n-hexane - ethyl acetate = 25:1) to obtain white solid compound 5. Dissolve compound 5 (3 mmol, 1 equiv) in 3 mL of dichloromethane, pre-cool at -80 °C for 15 min, and slowly add dropwise diisobutylaluminum hydride (DIBAL-H) (3.3 mmol, 1.1 equiv), and keep the reaction at low temperature for 4 h. Quench the reaction mixture with 1N HCl (3.3 ml), extract with dichloromethane. The organic phase is washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent is removed by distillation under reduced pressure to obtain product 6. Dissolve compound 6 (3 mmol, 1 equiv), intermediate 3 (3.3 mmol, 1.1 equiv), and piperidine (3.3 mmol, 1.1 equiv) in anhydrous ethanol (6 mL), react at room temperature for 8 h, extract with ethyl acetate. The organic phase is washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent is removed by distillation under reduced pressure. The crude product is separated by silica gel column chromatography (mobile phase: n-hexane - ethyl acetate = 25:1) to obtain white solid compound 7. Dissolve compound 7 (3 mmol, 1 equiv) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL), stir and react at room temperature for 1 h. Concentrate the reaction solution by rotary evaporation, and separate the crude product by silica gel column chromatography (dichloromethane - methanol = 15:1) to obtain white solid compounds Q1 - Q32.

[0040] Example 1: (E) -3-(2-Aminoethyl)-5-(3-(4-((3,4,5-Trifluorophenyl)oxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q1): Methyl 4-hydroxycinnamate, halogenated hydrocarbon 3,4,5-trifluorobenzyl chloride, and cesium carbonate were dissolved in DMF and stirred at 70 °C for 8 hours. After extraction and evaporation to dryness, the mixture was separated by silica gel column chromatography. The resulting compound was dissolved in dichloromethane, pre-cooled to -80 °C for 15 min, and then diisobutylaluminum hydride (DIBAL-H) was added dropwise. The reaction was maintained at low temperature for 4 hours. At room temperature, the reaction was quenched with 1 N HCl, and after extraction with dichloromethane and evaporation to dryness, an aldehyde compound was obtained. The obtained aldehyde compound, compound 3, and piperidine were dissolved in absolute ethanol and stirred at room temperature for 8 h. The solvent was removed by rotary evaporation, and the crude product was separated and purified by silica gel column chromatography to obtain compound Q1. Q1 is a white solid powder with a yield of 90%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 8.00 (s, 2H), 7.45 – 7.38 (m, 2H), 7.18 (d, J = 8.6 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 5.07 (s, 2H),3.83 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.54– 2.51 (m, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.10, 165.02, 158.70, 158.55,158.39, 157.73, 156.76, 151.32, 150.03, 139.21, 137.86, 135.17, 133.34,129.87, 125.73, 118.42, 116.93, 115.29, 112.50, 112.48, 67.90, 39.43, 37.21,33.41, 32.59. IR (KBr, cm -1): 800.26, 1042.84, 1149.87, 1177.71, 1201.14, 1234.55, 1339.17, 1360.96, 1385.71, 1448.97, 1456.87, 1513.95, 1531.14, 1635.46, 1681.02, 1736.83, 3035.42, 3419.40, 800.26, 1042.84, 1149.87, 1177.71, 1201.14, 1234.55, 1339.17, 1360.96, 1385.71, 1448.97, 1456.87, 1513.95, 1531.14, 1635.46, 1681.02, 1736.83, 3035.42, 3419.40. HRMS (ESI): m / z Calcd for C 21 H 19 F 3 N 2 O 3 S [M+H] + : 437.1147 Found: 437.1146。

[0041] The preparation method of the compounds in Examples 2-25 is the same as that in Example 1, except that different halogenated hydrocarbons are used. The halogenated hydrocarbons used in each specific example are indicated in the corresponding example.

[0042] Example 2: (E) -3-(2-Aminoethyl)-5-(3-(4-((3,5-difluorobenzyl)oxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q2): The halogenated hydrocarbon used is 3,5-difluorobenzyl chloride. Q2 is a white solid powder with a yield of 91%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.97 (s, 2H), 7.18 (dd, J = 13.0, 8.4 Hz, 5H), 7.02 (t, J = 7.4 Hz, 1H), 6.97 – 6.93 (m, 2H), 5.12 (s, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.04 (s, 2H), 2.78 (t,J = 7.4 Hz, 2H), 2.53 (d, J = 7.3 Hz, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ168.11, 165.03, 163.46, 162.30, 156.83, 142.47, 137.90, 133.28, 129.87, 125.72, 115.28, 110.85, 110.74, 103.55, 68.21, 37.26, 34.70, 33.41, 32.60. IR(KBr, cm -1 ): 854.94, 1120.47, 1156.23, 1175.55, 1200.45, 1242.98, 1333.13, 1360.68, 1385.44, 1433.50, 1463.98, 1513.18, 1597.89, 1632.66, 1681.70, 1739.85, 3037.45. HRMS (ESI): m / z calcd for C 21 H 20 F 2 N 2 O 3 S [M+H] + : 419.1241 found:419.1922。

[0043] Example 3: (E) -3-(2-Aminoethyl)-5-(3-(4-(benzyloxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q3): The halogenated hydrocarbon used was benzyl bromide. Q3 is a white solid powder with a yield of 92%. 1 H NMR (800 MHz, DMSO- d 6 ) δ7.41 (m, 5H), 7.32 (t, J = 6.5 Hz, 1H), 7.16 (d, J = 8.6 Hz, 2H), 7.01 (t, J = 7.4Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 5.07 (s, 3H), 3.79 (t,J = 6.0 Hz, 2H), 2.98 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.52 (d, J = 7.3 Hz, 2H). 13 C NMR (200MHz, DMSO- d 6 ) δ 168.09, 165.04, 157.29, 137.93, 137.66, 132.89, 129.80, 128.88, 128.25, 128.11, 125.71, 115.24, 69.59, 55.39, 37.49, 33.46, 32.62. IR (KBr, cm -1 ): 1142.59, 1176.35, 1203.26, 1225.88, 1361.17, 1386.09, 1508.41, 1521.71, 1540.80, 1636.42, 1646.92, 1653.78, 1685.02, 1716.05, 1742.89, 2342.25, 2359.65. HRMS (ESI): m / z calcd for C 21 H 22 N 2 O 3 S [M+H] + : 383.1429 found: 383.1426。

[0044] Example 4: (E) -3-(2-Aminoethyl)-5-(3-(4-(prop-2-yn-1-yloxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q4): The halogenated hydrocarbon used was 3-bromopropyne. Q4 was a white solid powder with a yield of 92%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 8.00 (s, 2H), 7.21 – 7.16 (m, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.94 – 6.89 (m, 2H), 4.76 (d, J= 2.4 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.55 (t, J = 2.4 Hz,1H), 3.03 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2.52 (t, J = 7.4 Hz, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.11, 165.04, 156.16, 137.88, 133.45, 129.76,125.74, 115.28, 79.86, 78.59, 55.81, 39.43, 37.23, 33.40, 32.61. IR (KBr, cm -1 ): 721.81, 1017.98, 1142.05, 1181.80, 1204.04, 1361.14, 1383.05, 1432.35,1510.79, 1637.28, 1688.36, 1741.97, 3070.18, 3274.15. HRMS (ESI): m / z calcd forC 17 H 18 N 2 O 3 S [M+H] + : 331.1116 found: 331.1098。

[0045] Example 5: (E) -5-(3-(4-(allyloxy)phenyl)propylidene)-3-(2-aminoethyl)thiazolidine-2,4-dione trifluoroacetate (Q5): The halogenated hydrocarbon used was 3-bromopropene. Q5 is a white solid powder with a yield of 90%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 8.19 (d, J = 35.6 Hz, 3H), 7.16 (d, J = 8.6 Hz, 2H), 7.01 (t, J= 7.5 Hz, 1H), 6.90 – 6.86 (m, 2H), 6.06 – 5.98 (m, 1H), 5.38 (dd, J = 17.3, 1.8 Hz, 1H), 5.24 (dd, J = 10.5, 1.7 Hz, 1H), 4.56 – 4.50 (m, 2H), 3.83 (t, J = 6.1 Hz, 2H), 3.36 (s, 2H), 3.00 (d, J = 5.4 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.10, 165.01, 157.12, 137.85, 134.32, 132.78, 129.78, 125.75, 117.78, 115.09, 68.57, 39.36, 37.00, 33.46, 32.62. IR (KBr, cm -1 ): 1394.27, 1507.05, 1558.00, 1635.87, 1644.89, 1652.24, 1683.36, 1698.23, 1715.56, 2914.91. HRMS (ESI): m / z calcd for C 17 H 20 N 2 O 3 S [M+H] + : 333.1273 found: 333.1267。

[0046] Example 6: (E) -3-(2-Aminoethyl)-5-(3-(4-((6-chloropyridin-3-yl)methoxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q6): The halogenated hydrocarbon used was 2-chloro-5-chloromethylpyridine. Q6 was a pale yellow solid powder with a yield of 90%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 8.51 (d, J= 2.5 Hz, 1H), 7.97 (s, 3H), 7.94 (dd, J = 8.2, 2.5Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.21 – 7.16 (m, 2H), 7.02 (t, J = 7.5 Hz, 1H),6.99 – 6.95 (m, 2H), 5.14 (s, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.04 (t, J = 5.9 Hz,2H), 2.78 (t, J = 7.4 Hz, 2H), 2.55 – 2.51 (m, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ168.12, 165.03, 156.87, 150.18, 149.63, 139.77, 137.89, 133.31, 132.89,129.88, 125.73, 124.67, 115.31, 66.44, 39.43, 37.26, 33.42, 32.60. IR (KBr,cm -1 ): 721.52, 798.13, 831.66, 1019.49, 1110.52, 1155.47, 1173.09, 1199.61,1237.85, 1333.14, 1363.50, 1386.16, 1429.92, 1459.68, 1508.66, 1539.94,1589.63, 1609.64, 1637.72, 1684.49, 1740.82, 2949.64, 3033.10. HRMS (ESI): m / z calcd for C 20 H 20 ClN 3 O 3 S [M+H] + : 418.0992 found: 418.0987。

[0047] Example 7: (E)-3-(2-Aminoethyl)-5-(3-(4-((4-(Trifluoromethyl)benzyl)oxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q7): The halogenated hydrocarbon used was 4-(trifluoromethyl)benzyl chloride. Q7 is a white solid powder with a yield of 90%. 1 H NMR (800MHz, DMSO- d 6 ) δ 7.94 (s, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 7.9 Hz, 2H),7.18 (d, J = 8.5 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 5.20(s, 2H), 3.83 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.54 – 2.48 (m, 4H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 166.96, 163.87, 155.82, 141.45, 136.74, 132.01,128.70, 127.22, 124.63, 124.56, 124.22, 114.10, 67.52, 38.26, 36.10, 32.25,31.44. IR (KBr, cm -1 ): 721.84, 797.26, 836.82, 1016.29, 1065.98, 1121.44,1160.05, 1201.13, 1218.96, 1328.22, 1361.38, 1384.25, 1431.70, 1511.81,1637.31, 1686.02, 1742.80, 3041.82. HRMS (ESI): m / z calcd for C 22 H 21 F 3 N 2 O 3 S [M+H] +: 451.1303 found: 451.1321.

[0048] Example 8: (E) -3-(2-Aminoethyl)-5-(3-(4-(cyclopropylmethoxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q8): The halogenated hydrocarbon used was bromomethylcyclopropane. Q8 is a white solid powder with a yield of 90%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.97 (s, 2H), 7.14 (d, J = 8.6 Hz, 2H), 7.01 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 6.3 Hz, 2H), 3.82 (t, J = 6.0 Hz, 2H), 3.77 (d, J = 7.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.51 (d, J = 7.6 Hz, 2H), 1.19 (dd, J = 10.5, 7.3, 3.7 Hz, 1H), 0.58 – 0.52 (m, 2H), 0.30 (q, J = 5.1, 4.5 Hz, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.12, 165.03, 157.58, 137.95, 132.45, 129.74, 125.69, 114.88, 72.37, 39.42, 37.24, 33.49, 32.61, 10.65, 3.54. IR (KBr, cm -1): 1155.82, 1173.03, 1200.98, 1248.23, 1363.36, 1386.08, 1431.17, 1509.14, 1541.74, 1637.89, 1647.74, 1655.14, 1686.03, 1718.56, 1735.92, 1741.73. HRMS(ESI): m / z calcd for C 18 H 22 N 2 O 3 S [M+H] + : 347.1429 found: 347.1430。

[0049] Example 9 (E) -3-(2-Aminoethyl)-5-(3-(4-(cyclohexylmethoxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q9): The halogenated hydrocarbon used was bromomethylcyclohexane. Q9 is a white solid powder with a yield of 95%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.95 (s, 2H), 7.14 (d, J = 8.6 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.84(d, J = 8.6 Hz, 2H), 3.82 (t, J = 6.0 Hz, 2H), 3.73 (d, J = 6.4 Hz, 2H), 3.03 (t, J =6.1 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.51 (d, J = 7.6 Hz, 2H), 1.79 (d, J = 9.2Hz, 2H), 1.73 – 1.67 (m, 3H), 1.65 (d, J = 12.9 Hz, 1H), 1.27 – 1.13 (m, 4H),1.02 (d, J = 12.5, 3.5 Hz, 2H). 13 C NMR (200 MHz, DMSO-d 6 ) δ 166.10, 163.01, 155.75, 135.96, 130.42, 127.72, 123.67, 112.85, 71.11, 35.55, 35.24, 31.47, 30.59, 27.73, 24.50, 23.72. IR (KBr, cm -1 ): 721.95, 798.15, 1023.17, 1144.76, 1177.46, 1204.92, 1248.07, 1360.95, 1385.21, 1434.43, 1513.21, 1612.60, 1638.96, 1687.11, 1743.27, 2856.10, 2926.44, 3039.05. HRMS (ESI): m / z calcd for C 21 H 28 N 2 O 3 S [M+H] + : 389.1899 found: 389.1897。

[0050] Example 10: (E) -3-(2-Aminoethyl)-5-(3-(4-(cyclopentylmethoxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q10): The halogenated hydrocarbon used is bromomethylcyclopentane. Q10 is a white solid powder with a yield of 95%. 1H NMR (800 MHz, DMSO-d6) δ 7.14 (d, J = 8.5 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 3.80 (dd, J = 16.3, 8.0 Hz, 4H), 3.01 (t, J = 5.8 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.27 (p, J = 7.4 Hz, 1H), 1.75 (dt, J = 12.3, 5.9 Hz, 2H), 1.60 (t, J = 6.5 Hz, 2H), 1.53 (d, J = 4.3 Hz, 2H), 1.35 – 1.28 (m, 3H). 13C NMR (200 MHz, DMSO-d6) δ 168.08, 165.02, 157.77, 137.90, 132.48, 129.73, 125.69, 114.90, 72.01, 39.03, 33.50, 32.62, 29.47, 25.41. IR (KBr, cm -1 ): 721.68, 733.36, 797.38, 838.12, 1030.07, 1145.03, 1176.70, 1204.14, 1247.31, 1360.97, 1384.55, 1431.78, 1466.84, 1512.80, 1581.72, 1612.50, 1637.98, 1687.96, 1744.02, 2864.84, 2955.07. HRMS (ESI): m / z calcd for C 20 H 26 N 2 O 3 S [M+H]+: 375.1742 found: 375.1746。

[0051] Example 11: (E)-3-(2-Aminoethyl)-5-(3-(4-((3-(Trifluoromethyl)benzyl)oxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q11): The halogenated hydrocarbon used is 3-(trifluoromethyl)benzyl chloride. Q11 is a white solid powder with a yield of 94%. 1H NMR (800 MHz, DMSO-d6) δ 7.95 (s, 2H), 7.80 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 8.6 Hz, 2H), 5.19 (s, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2.52 (t, J = 7.4 Hz, 2H). 13C NMR (200 MHz, DMSO-d6) δ 166.19, 163.11, 156.65, 156.49, 155.10, 137.30, 135.99, 131.25, 130.13, 128.10, 127.93, 127.77, 127.61, 123.79, 123.41, 123.04, 122.47, 122.06, 113.34, 66.78, 37.49, 35.33, 31.49, 30.68. IR (KBr, cm -1 ): 1136.48, 1177.96, 1210.70, 1237.76, 1327.02, 1360.46, 1383.03, 1508.08, 1515.28, 1532.56, 1539.65, 1635.86, 1646.55, 1653.03, 1689.33, 1716.23, 1747.20, 3031.40. HRMS (ESI): m / z calcd for C 22 H 21 F 3 N 2 O 3 S [M+H]+: 451.1303 found: 451.1296。

[0052] Example 12: (E)-3-(2-aminoethyl)-5-(3-(4-(nona-8-en-1-yloxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q12): The halogenated hydrocarbon used is 9-bromo-1-nonene. Q12 is a white solid powder with a yield of 94%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.96 (s, 2H), 7.14 (d, J = 8.6 Hz, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.87– 6.82 (m, 2H), 5.80 (dd, J = 16.9, 10.2, 6.7 Hz, 1H), 5.00 (d, J = 17.2, 1.7 Hz,1H), 4.96 – 4.92 (m, 1H), 3.91 (t, J = 6.5 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H),3.03 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.54 – 2.51 (m, 2H), 2.04 –1.99 (m, 2H), 1.71 – 1.65 (m, 2H), 1.35 (dd, J = 56.9, 28.4, 14.9, 7.7 Hz, 9H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.11, 165.03, 157.63, 139.28, 137.96, 132.46,129.74, 125.69, 115.13, 114.85, 39.42, 37.25, 33.62, 33.50, 32.62, 29.16,29.05, 28.93, 28.67, 25.95. HRMS (ESI): m / z calcd for C 23 H 32 N 2 O 3 S [M+H] + :417.2212 found: 417.2210。

[0053] Example 13: (E)-3-(2-Aminoethyl)-5-(3-(4-((2-fluorobenzyl)oxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q13): The halogenated hydrocarbon used is o-fluorochlorobenzene. Q13 is a white solid powder with a yield of 94%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.94 (s, 3H), 7.55 (t, J J = 7.6 Hz, 1H), 7.44 – 7.40 (m, 1H), 7.28 – 7.21(m, 2H), 7.18 (d, J J = 8.6 Hz, 2H), 7.02 (t, J J = 7.4 Hz, 1H), 6.97 (d, J J = 8.6 Hz,2H), 5.10 (s, 2H), 3.83 (t, J J = 6.0 Hz, 2H), 3.39 (s, 2H), 3.03 (t, J J = 6.0 Hz,2H), 2.78 (t, J J = 7.4 Hz, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.13, 165.04,161.46, 160.24, 157.14, 137.95, 133.15, 131.15, 130.84, 130.80, 129.85,125.72, 124.99, 124.41, 124.34, 115.90, 115.79, 115.16, 63.93, 39.43, 37.27,33.44, 32.61. IR (KBr, cm -1 ): 403.81, 720.96, 752.66, 1136.05, 1180.24,1204.57, 1250.25, 1361.10, 1384.93, 1510.83, 1629.93, 1637.07, 1655.17,1686.09, 1718.22, 1735.87, 1745.77. HRMS (ESI): m / z calcd for C 21 H 21 FN2 O 3 S [M+H] + : 401.1335 found: 401.1340。

[0054] Example 14: (E) -3-(2-Aminoethyl)-5-(3-(4-(3-phenylpropoxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q14): The halogenated hydrocarbon used was 1-bromo-3-phenylpropane. Q14 is a white solid powder with a yield of 95%. 1 H NMR (800MHz, DMSO- d 6 ) δ 7.95 (s, 2H), 7.28 (t, J J = 7.6 Hz, 2H), 7.22 (d, J J = 6.6 Hz, 2H),7.20 – 7.17 (m, 1H), 7.15 (d, J J = 8.6 Hz, 2H), 7.02 (t, J J = 7.5 Hz, 1H), 6.86 (d, J J = 8.6 Hz, 2H), 3.92 (t, J J = 6.4 Hz, 2H), 3.82 (t, J J = 6.0 Hz, 2H), 3.03 (t, J J =6.0 Hz, 2H), 2.77 (t, J J = 7.4 Hz, 2H), 2.74 – 2.71 (m, 2H), 2.03 – 1.97 (m,2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.12, 165.04, 157.56, 141.87, 137.97,132.60, 129.78, 128.81, 126.30, 125.70, 114.91, 67.05, 37.26, 33.48, 32.62,31.95, 30.88. IR (KBr, cm -1): 721.51, 1152.93, 1174.32, 1200.38, 1244.19, 1332.77, 1362.75, 1386.04, 1430.85, 1510.65, 1609.24, 1637.65, 1685.88, 1743.47, 2950.90, 3027.41. HRMS (ESI): m / z calcd for C 23 H 26 N 2 O 3 S [M+H] + : 411.1742 found: 411.1740。

[0055] Example 15: (E) -3-(2-Aminoethyl)-5-(3-(4-(4,4,4-trifluorobutoxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q15): The halogenated hydrocarbon used was 1-bromo-4,4,4-trifluorobutane. Q15 is a white solid powder with a yield of 94%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.95 (s, 3H), 7.16 (d, J = 8.6 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 4.00 (t, J = 6.2 Hz, 3H), 3.82 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.52 (d, J = 7.4 Hz, 2H), 2.45 – 2.38 (m, 3H), 1.94 – 1.87 (m, 3H). 13 C NMR (200 MHz, DMSO- d 6) δ 168.12, 165.03, 157.25, 137.93, 132.88, 129.81, 128.81, 127.43, 125.71, 114.95, 66.14, 37.25, 33.46, 32.61, 30.18, 30.04, 29.90, 29.76, 22.13. IR (KBr, cm -1 ): 721.36, 836.45, 1030.06, 1153.46, 1173.56, 1200.02, 1244.79, 1332.25, 1363.53, 1385.33, 1431.35, 1512.22, 1538.40, 1611.16, 1642.63, 1688.04, 1743.88, 2359.27, 3037.09. HRMS (ESI): m / z calcd for C 18 H 21 F 3 N 2 O 3 S [M+H] + : 403.1303 found: 403.1292。

[0056] Example 16: (E) -3-(2-Aminoethyl)-5-(3-(4-(3-(Benzyloxy)propoxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q16): The halogenated hydrocarbon used was 3-benzyloxybromopropane. Q16 was a white solid powder with a yield of 92%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.94 (s, 2H), 7.35 – 7.30 (m, 4H), 7.29 – 7.26 (m, 1H), 7.15 (d, J = 8.6 Hz, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 4.48 (s, 2H), 4.01 (t, J = 6.3 Hz, 2H), 3.82 (t, J = 6.0 Hz, 2H), 3.58 (t, J= 6.3 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.52 (d, J = 7.4 Hz, 2H), 1.97 (p, J = 6.3 Hz, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.12, 165.03, 157.53, 139.02, 137.97, 132.60, 129.78, 128.70, 127.86, 127.82, 125.70, 114.89, 72.34, 66.73, 64.96, 39.42, 37.25, 33.49, 32.62, 29.62. IR (KBr, cm -1 ): 720.84, 1095.50, 1132.14, 1179.74, 1204.90, 1245.83, 1338.69, 1363.50, 1386.12, 1428.21, 1510.42, 1636.27, 1653.45, 1689.95, 1744.25, 2853.96, 2955.82, 3032.31. HRMS(ESI): m / z calcd for C 24 H 28 N 2 O 4 S [M+H] + : 441.1848 found: 441.1835。

[0057] Example 17: (E) -3-(2-Aminoethyl)-5-(3-(4-(dodecyloxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q17): The halogenated hydrocarbon used was dodecyl bromide. Q17 was a white solid powder with a yield of 91%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.99 – 7.93 (m, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.02 (t, J= 7.4 Hz, 1H), 6.84 (d, J = 8.3 Hz, 2H), 3.91 (t, J = 6.5 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.03 (s, 2H), 2.76 (t, J = 7.4 Hz, 2H), 1.68 (p, J = 6.7 Hz, 2H), 1.39 (p, J = 7.6, 7.1 Hz, 2H), 1.32 – 1.22 (m, 17H), 0.86 (t, J = 7.1 Hz, 3H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.11, 157.63, 137.96, 132.45, 129.73, 125.69, 114.84, 67.78, 39.42, 37.25, 33.51, 32.62, 31.77, 29.51, 29.48, 29.47, 29.46, 29.24, 29.19, 26.00, 22.57, 14.42. IR (KBr, cm -1 ): 1507.41, 1516.28, 1521.06, 1540.58, 1558.32, 1652.99, 1683.15, 1698.22, 1716.37, 1733.69, 3648.47, 3734.63, 3852.92. HRMS (ESI): m / z calcd for C 26 H 40 N 2 O 3 S [M+H] + : 461.2838 found: 461.2834。

[0058] Example 18: (E) -3-(2-Aminoethyl)-5-(3-(4-(dec-9-en-1-yloxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q18): The halogenated hydrocarbon used was 10-bromo-1-decene. Q18 was a white solid powder with a yield of 91%. 11H NMR (800 MHz, DMSO- d 6 ) δ 8.02 (s, 2H), 7.14 (d, J J = 8.1 Hz, 2H), 7.02 (t, J J = 7.5 Hz, 1H), 6.85(d, J J = 8.1 Hz, 2H), 5.79 (td, J J = 16.8, 6.6 Hz, 1H), 5.00 (d, J J = 17.1 Hz, 1H),4.93 (d, J J = 10.2 Hz, 1H), 3.91 (t, J J = 6.6 Hz, 2H), 3.83 (t, J J = 5.6 Hz, 2H), 3.04(t, J J = 5.9 Hz, 2H), 2.76 (t, J J = 7.5 Hz, 2H), 2.01 (q, J J = 7.3 Hz, 2H), 1.68 (p, J J =6.9 Hz, 2H), 1.47 – 1.12 (m, 11H). 13 13C NMR (200 MHz, DMSO- d 6 ) δ 168.12, 165.02,157.63, 139.28, 137.92, 132.46, 129.74, 125.70, 115.12, 114.85, 67.78, 33.65,33.50, 32.62, 29.29, 29.21, 29.18, 28.93, 28.72, 25.98. HRMS (ESI): m / z calcdfor C 24 H 34 N 2 O 3 S [M+H] + : 431.2368 found: 431.2356。

[0059] Example 19: (E) -3-(2-Aminoethyl)-5-(3-(4-((4-Fluorobenzyl)oxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q19): The halogenated hydrocarbon used is 4-fluorobenzyl chloride. Q19 is a white solid powder with a yield of 92%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.94 (s, 1H), 7.49 (dd, J J = 8.4, 5.5 Hz, 2H), 7.21 (t, J J = 8.8 Hz, 2H),7.17 (d, J J = 8.2 Hz, 2H), 7.02 (t, J J = 7.4 Hz, 1H), 6.94 (d, J J = 8.4 Hz, 2H), 5.05(s, 2H), 3.82 (t, J J = 6.0 Hz, 2H), 3.03 (s, 2H), 2.77 (t, J J = 7.4 Hz, 2H), 2.52(d, J J = 7.4 Hz, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.12, 165.04, 162.79, 161.59,157.18, 137.93, 133.88, 132.96, 130.37, 129.81, 125.72, 115.74, 115.64,115.25, 68.87, 39.42, 37.26, 33.44, 32.61. IR (KBr, cm -1 ): 721.71, 837.80,1015.80, 1156.36, 1173.10, 1199.32, 1227.31, 1239.91, 1331.43, 1364.03,1386.06, 1430.59, 1512.51, 1538.75, 1608.45, 1643.28, 1684.15, 1741.24,2949.38, 3031.35. HRMS (ESI): m / z calcd for C 21 H 21 FN 2 O 3 S [M+H] + : 401.1335 found:401.1336。 Example 20: (E) -3-(2-Aminoethyl)-5-(3-(4-(4-Phenylbutoxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q20): The halogenated hydrocarbon used was 4-phenyl-1-butyl bromide. Q20 is a white solid powder with a yield of 93%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.28 (t, J J = 7.6 Hz, 2H), 7.21 (d, J J = 7.5 Hz, 2H), 7.17 (t, J J = 7.3 Hz, 1H), 7.14 (d, J J = 8.6 Hz, 2H), 7.01 (t, J J = 7.4 Hz, 1H), 6.84 (d, J J = 8.6 Hz, 2H), 3.96 – 3.92 (m, 2H), 3.81 (t, J J = 6.0 Hz, 2H), 3.00 (t, J J = 6.0 Hz, 2H), 2.76 (t, J J = 7.4 Hz, 2H), 2.63 (t, J J = 6.9 Hz, 3H), 2.51 (s, 2H), 1.72 – 1.68 (m, 5H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 166.97, 163.90, 156.47, 141.35, 136.81, 131.38, 128.62, 127.64, 125.05, 124.57, 113.75, 66.52, 39.30, 36.23, 34.12, 32.36, 31.49, 27.64, 26.81. IR (KBr, cm -1 ): 1149.45, 1198.70, 1361.66, 1513.45, 1634.84, 1652.51, 1689.18, 1732.10, 1743.74, 2945.92. HRMS (ESI): m / z calcd for C24 H 28 N 2 O 3 S [M+H] + : 425.1899 found: 425.1907。 Example 21: (E) -3-(2-Aminoethyl)-5-(3-(4-((4-chlorobenzyl)oxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q21): The halogenated hydrocarbon used was 4-chlorobenzyl bromide. Q21 was a white solid powder with a yield of 95%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.94 (s, 1H), 7.50 (s, 1H), 7.45 – 7.37 (m, 3H), 7.17 (d, J = 8.6 Hz,2H), 7.02 (t, J = 7.4 Hz, 1H), 6.97 – 6.93 (m, 2H), 5.10 (s, 2H), 3.82 (t, J =6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.52 (d, J = 7.4Hz, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.12, 165.03, 157.03, 140.30, 137.92,133.56, 133.11, 130.83, 129.84, 128.15, 127.69, 126.58, 125.72, 115.26,68.65, 39.47, 37.26, 33.42, 32.61. IR (KBr, cm -1): 1156.93, 1173.87, 1200.10, 1240.38, 1362.72, 1387.43, 1430.90, 1458.54, 1508.81, 1522.88, 1560.43, 1637.52, 1647.95, 1655.03, 1664.44, 1676.87, 1685.64, 1700.97, 1718.43, 1735.63, 1742.26. HRMS (ESI): m / z calcd for C 21 H 21 ClN 2 O 3 S [M+H] + : 417.1040 found: 417.1007。

[0060] Example 22: (E) -3-(2-Aminoethyl)-5-(3-(4-((4-bromobenzyl)oxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q22): The halogenated hydrocarbon used was 4-bromobenzyl bromide. Q22 is a white solid powder with a yield of 95%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.58 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.04 – 7.00 (m, 1H), 6.94 (d, J = 8.6 Hz, 2H), 5.06 (s, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.38 (s, 3H), 3.04 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H). 13 C NMR (200MHz, DMSO- d 6) δ 168.12, 165.03, 157.07, 137.91, 137.16, 133.05, 131.80,130.19, 129.82, 125.72, 121.33, 115.27, 68.77, 39.43, 37.25, 33.43, 32.61. IR(KBr, cm -1 ): 721.95, 798.48, 1012.99, 1155.42, 1173.20, 1200.51, 1238.37,1332.80, 1363.84, 1386.07, 1429.92, 1508.38, 1540.17, 1608.50, 1638.44,1685.07, 1740.74, 2949.83, 3032.52. HRMS (ESI): m / z calcd for C 21 H 21 BrN 2 O 3 S [M+H] + :461.0535 found: 461.0496。

[0061] Example 23: (E) -3-(2-Aminoethyl)-5-(3-(4-(pent-4-en-1-yloxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q23): The halogenated hydrocarbon used was 5-bromo-1-pentene. Q23 is a white solid powder with a yield of 93%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.97 (s, 2H), 7.20 – 7.12 (m, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.89 –6.83 (m, 2H), 5.86 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.05 (dq, J = 17.2, 1.7 Hz,1H), 4.99 (ddt, J = 10.2, 2.3, 1.3 Hz, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.83 (t, J= 6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.54 – 2.51 (m, 2H), 2.20 – 2.13 (m, 2H), 1.80 – 1.76 (m, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ168.12, 165.03, 157.57, 138.47, 137.95, 132.56, 129.77, 125.70, 115.68, 114.88, 67.15, 39.42, 37.25, 33.48, 32.62, 30.09, 28.35. IR (KBr, cm -1 ): 721.15, 797.78, 835.17, 1154.17, 1172.89, 1199.15, 1245.25, 1330.75, 1363.50, 1385.07, 1430.90, 1510.61, 1538.03, 1610.40, 1640.88, 1687.98, 1743.56, 2951.23, 3033.46. HRMS (ESI): m / z calcd for C 19 H 24 N 2 O 3 S [M+H] + : 361.1586 found: 361.1578。

[0062] Example 24: (E) -3-(2-Aminoethyl)-5-(3-(4-(isopentoxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q24): The halogenated hydrocarbon used was 1-bromo-3-methylbutane. Q24 was a white solid powder with a yield of 94%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.95 (s, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H), 6.86 (d,J = 8.5 Hz, 2H), 3.95 (t, J = 6.7 Hz, 2H), 3.82 (t, J = 6.0 Hz, 2H), 3.03 (t, J =6.1 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.52 (d, J = 7.4 Hz, 2H), 1.76 (d, J = 13.5,6.7 Hz, 1H), 1.59 (q, J = 6.7 Hz, 2H), 0.92 (d, J = 6.7 Hz, 6H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.12, 165.04, 157.63, 137.97, 125.70, 114.88, 66.23, 39.42, 37.96, 37.25, 33.49, 32.62, 25.04, 22.90. IR (KBr, cm -1 ): 721.68, 1155.06, 1172.53, 1200.36, 1244.81, 1331.85, 1363.31, 1385.37, 1430.95, 1511.47, 1541.11, 1609.62, 1639.71, 1686.56, 1742.32, 2870.39, 2953.37, 3034.35. HRMS(ESI): m / z calcd for C 19 H 26 N 2 O 3 S [M+H] + : 363.1742 found: 363.1725。

[0063] Example 25: (E) -3-(2-Aminoethyl)-5-(3-(4-(pentyloxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q25): The halogenated hydrocarbon used was 1-bromopentane. Q25 was a white solid powder with a yield of 94%. 11H NMR (800 MHz, DMSO- d 6 ) δ 7.97 (s, 2H), 7.14 (d, J J = 8.6 Hz, 2H), 7.01 (t, J J = 7.4 Hz, 1H), 6.85 (d, J J = 8.6 Hz, 2H), 3.91 (t, J J = 6.5 Hz, 2H), 3.82 (t, J J = 6.0 Hz, 2H), 3.03 (t, J J = 6.0Hz, 2H), 2.76 (t, J J = 7.4 Hz, 2H), 2.52 (d, J J = 7.4 Hz, 2H), 1.69 (dt, J J = 14.5,6.8 Hz, 2H), 1.36 (dd, J J = 39.4, 13.9, 7.5, 6.7 Hz, 4H), 0.89 (t, J J = 7.2 Hz,3H). 13 13C NMR (200 MHz, DMSO- d 6 ) δ 166.90, 163.81, 156.42, 136.74, 131.24,128.53, 124.48, 113.64, 66.56, 38.20, 36.03, 32.28, 31.40, 27.67, 26.99,21.15, 13.17. IR (KBr, cm -1 ): 721.83, 733.02, 797.57, 1074.39, 1145.36,1177.27, 1205.10, 1250.10, 1360.95, 1384.32, 1434.89, 1472.30, 1513.25,1538.79, 1558.14, 1615.44, 1635.94, 1653.26, 1685.96, 1745.56, 2864.40,2938.21, 3040.90. HRMS (ESI): m / z calcd for C 19 H 26 N 2 O 3 S [M+H]+ : 363.1742 found: 363.1726. Example 26: (E) -4-(3-(3-(2-Aminoethyl)-2,4-dioxothiazolidin-5-ylidene)propyl)benzenesulfonate trifluoroacetate (Q26): Methyl 4-hydroxybenzenepropionate, sulfonyl chloride (benzenesulfonyl chloride), and triethylamine were dissolved in dichloromethane and stirred at room temperature for 8 hours. After evaporation, the residue was separated by silica gel column chromatography. The resulting compound was dissolved in dichloromethane, pre-cooled to -80 °C for 15 min, and diisobutylaluminum hydride (DIBAL-H) was added dropwise. The reaction was maintained at low temperature for 4 hours, quenched with 1N HCl at room temperature, extracted, and evaporated to obtain an aldehyde compound. The synthesized aldehyde compound, intermediate compound 3, and piperidine were dissolved in absolute ethanol and stirred at room temperature for 8 h. After evaporation, the crude product was separated by silica gel column chromatography to obtain compound Q26. Q26 is a white solid powder with a yield of 85%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.95 (s, 2H), 7.87 – 7.80 (m, 3H), 7.69 – 7.66 (m, 2H), 7.26 (d, J = 8.6 Hz, 2H), 6.99 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 5.9 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.52 (d, J = 7.4 Hz, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.47, 165.01, 147.86, 140.28, 137.49, 135.47, 134.81, 130.35, 130.25, 128.64, 125.94, 122.47, 39.42, 37.24, 32.92, 32.67. IR (KBr, cm -1): 423.06, 863.97, 1093.39, 1138.57, 1178.26, 1201.09, 1354.33, 1381.64, 1501.70, 1507.81, 1637.41, 1655.06, 1686.02, 1718.37, 1746.01. HRMS (ESI): m / z calcd for C 20 H 20 N 2 O 5 S 2 [M+H] + : 433.0892 found: 433.0897。

[0064] The preparation methods of the compounds in Examples 27 - 32 are the same as that in Example 26, except that different sulfonyl chlorides are used. The sulfonyl chlorides used in each specific example are indicated in the corresponding example: Example 27: (E) -4-(3-(3-(2-Aminoethyl)-2,4-dioxothiazolidin-5-ylidene)propyl)phenyl 4-fluorobenzenesulfonate trifluoroacetate (Q27): The sulfonyl chloride used is 4-fluorobenzenesulfonyl chloride. Q27 is a white solid powder with a yield of 87%. 1 H NMR (800 MHz, Chloroform- d ) δ 11.82 (dd, J = 8.8, 5.0 Hz, 2H), 11.30 (t, J = 8.6 Hz, 2H), 11.16(d, J = 8.4 Hz, 2H), 11.01 (t, J = 7.6 Hz, 1H), 10.88 (d, J = 8.5 Hz, 2H), 7.96 – 7.86 (m, 2H), 7.18 – 7.09 (m, 2H), 6.82 (t, J = 7.3 Hz, 2H), 6.52 (q, J = 7.4 Hz, 2H). 13 C NMR (200 MHz, Chloroform- d) δ 171.93, 170.76, 169.49, 168.94, 152.07,143.76, 141.21, 135.32, 135.23, 133.48, 129.66, 126.05, 120.32, 120.20,42.52, 41.69, 36.68, 36.49. IR (KBr, cm -1 ): 549.34, 840.58, 877.14, 1094.76,1151.19, 1181.75, 1203.00, 1235.54, 1358.32, 1381.23, 1494.94, 1503.77,1539.00, 1591.74, 1641.67, 1652.33, 1688.78, 1747.30, 3044.10. HRMS (ESI): m / z Calculated for C 20 H 19 FN 2 O 5 S 2 [M+H] + : 451.0798 found: 451.0789。

[0065] Example 28: (E) -4-(3-(3-(2-Aminoethyl)-2,4-dioxothiazolidin-5-ylidene)propyl)phenyl-4-methylbenzenesulfonate trifluoroacetate (Q28): The sulfonyl chloride used was p-toluenesulfonyl chloride. Q28 was a white solid powder with a yield of 87%. 1 H NMR (800 MHz, DMSO- d 6 ) δ 7.98 (s, 2H), 7.72 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.26(d, J = 8.1 Hz, 2H), 7.00 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 3.85 –3.81 (m, 2H), 3.35 (s, 2H), 3.03 (t, J= 5.6 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.42 (s, 3H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.10, 165.01, 147.91, 146.21, 140.19, 137.49, 131.94, 130.66, 130.32, 128.66, 125.94, 122.48, 39.42, 37.24, 32.94, 32.68. IR (KBr, cm -1 ): 550.29, 721.71, 735.73, 798.40, 809.51, 840.00, 864.67, 1095.18, 1141.59, 1175.52, 1200.40, 1351.53, 1381.30, 1434.59, 1504.14, 1524.95, 1598.93, 1636.72, 1688.76, 1747.93, 3035.20. HRMS (ESI): m / z calcd for C 21 H 22 N 2 O 5 S 2 [M+H] + : 447.1048 found: 477.1033。

[0066] Example 29: (E) -4-(3-(3-(2-Aminoethyl)-2,4-dioxothiazolidin-5-ylidene)propyl)phenyl-4-(trifluoromethyl)benzenesulfonate trifluoroacetate (Q29): The sulfonyl chloride used was p-trifluoromethylbenzenesulfonyl chloride. Q29 was a white solid powder with a yield of 88%. 1 H NMR (800MHz, DMSO- d 6 ) δ 8.16 – 8.03 (m, 4H), 7.29 (d, J = 8.5 Hz, 2H), 7.01 (dd, J = 8.1, 5.9 Hz, 3H), 3.83 (t, J= 6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.83 (t, J = 7.5Hz, 2H), 2.53 (d, J = 7.4 Hz, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 168.10, 165.01,158.62, 158.47, 147.68, 140.64, 138.74, 137.48, 134.83, 134.66, 130.52,129.80, 127.48, 125.94, 124.30, 122.94, 122.47, 39.42, 37.25, 32.91, 32.67.IR (KBr, cm -1 ): 603.76, 721.63, 838.87, 872.05, 1063.12, 1094.81, 1108.91,1147.04, 1178.41, 1202.83, 1324.13, 1360.15, 1381.63, 1407.04, 1502.75,1637.53, 1690.38, 1745.61. HRMS (ESI): m / z calcd for C 21 H 19 F 3 N 2 O 5 S 2 [M+H] + :501.0766 found: 501.0736。 Example 30: (E) -4-(3-(3-(2-Aminoethyl)-2,4-dioxothiazolidin-5-ylidene)propyl)phenyl 4-bromobenzenesulfonate trifluoroacetate (Q30): The sulfonyl chloride used was 4-bromobenzenesulfonyl chloride. Q30 is a white solid powder with a yield of 90%. 1 H NMR (800 MHz,DMSO- d 6 ) δ 7.95 (s, 2H), 7.89 (d, J = 8.6 Hz, 2H), 7.77 (d, J= 8.6 Hz, 2H), 7.28(d, J = 6.6 Hz, 2H), 7.01 (d, J = 7.4 Hz, 1H), 7.00 – 6.97 (m, 2H), 3.83 (t, J =6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.52 (t, J = 7.5Hz, 2H). 13 C NMR (200 MHz, DMSO- d 6 ) δ 165.63, 162.54, 145.28, 138.00, 135.03,131.54, 130.93, 128.12, 127.98, 127.23, 123.47, 120.03, 36.95, 34.77, 30.44,30.21. IR (KBr, cm -1 ): 595.12, 721.49, 734.72, 796.53, 833.09, 863.01, 874.57,1069.31, 1093.18, 1141.89, 1183.53, 1203.94, 1356.84, 1381.08, 1503.77,1523.97, 1541.30, 1577.07, 1637.57, 1648.38, 1688.47, 1748.09, 3034.27. HRMS(ESI): m / z calcd for C 20 H 19 BrN 2 O 5 S 2 [M+H] + : 510.9997 found: 510.9956。

[0067] Example 31: (E )-4-(3-(3-(2-Aminoethyl)-2,4-dioxothiazolidin-5-ylidene)propyl)phenyl-4-methoxybenzenesulfonate trifluoroacetate (Q31): The sulfonyl chloride used was 4-methoxybenzenesulfonyl chloride. Q31 is a white solid powder with a yield of 95%. 11H NMR (800 MHz, DMSO- d 6 ) δ 7.79 – 7.72 (m, 2H), 7.27 – 7.25 (m, 2H), 7.17 – 7.14 (m, 2H), 7.00 (t, J J = 7.5 Hz, 1H), 6.96 – 6.92 (m, 2H), 3.87 (s, 3H), 3.83 (t, J J = 6.1 Hz, 2H), 3.36 (s, 2H), 3.04 (t, J J = 5.8 Hz, 2H), 2.82 (t, J J = 7.5 Hz, 2H). 13 13C NMR (200 MHz, DMSO- d 6 ) δ 168.10, 165.01, 164.44, 147.96, 140.11, 137.47, 131.06, 130.28, 126.01, 125.94, 122.54, 115.36, 56.40, 39.42, 37.21, 32.94, 32.69. IR (KBr, cm -1 -1): 1374.03, 1457.35, 1489.48, 1498.13, 1506.94, 1521.44, 1540.91, 1558.53, 1635.88, 1647.02, 1653.21, 1670.24, 1684.02, 1699.31, 1716.79, 1733.80, 1749.06, 3566.89, 3587.41, 3629.27, 3649.18, 3675.73, 3735.26, 3745.26, 3750.99, 3838.98, 3853.98. HRMS (ESI): m / z calcd for C 21 H 22 N 2 O 6 S 2 [M+H] + : 463.0998 found: 463.0999。 Example 32: (E) -4-(3-(3-(2-Aminoethyl)-2,4-dioxothiazolidin-5-ylidene)propyl)phenyl 3-fluorobenzenesulfonate trifluoroacetate (Q32): The sulfonyl chloride used is m-fluorobenzenesulfonyl chloride. Q32 is a white solid powder with a yield of 95%. 1 H NMR (800 MHz, Methanol- d 4 ) δ 7.64 (q, J J = 3.5, 2.8 Hz, 2H), 7.55 (d, J J = 8.6 Hz, 1H), 7.52(ddt, J J = 8.6, 5.0, 2.9 Hz, 1H), 7.21 (d, J J = 8.5 Hz, 2H), 7.06 (t, J J = 7.7 Hz,1H), 6.93 (d, J J = 8.5 Hz, 2H), 3.99 – 3.95 (m, 2H), 3.19 (q, J J = 5.9, 5.4 Hz,2H), 2.86 (t, J J = 7.3 Hz, 2H), 2.55 (q, J J = 7.4 Hz, 2H). 13 C NMR (200 MHz, Methanol- d 4 ) δ 175.03, 171.87, 167.96, 165.00, 162.95, 161.71, 148.10,139.96, 137.25, 131.40, 129.58, 125.74, 124.35, 122.01, 121.46, 115.20,38.58, 37.75, 32.76, 32.57. HRMS (ESI): m / z calcd for C 20 H 19 FN 2 O 5 S 2 [M+H] + : 451.0798 found: 451.0787。

[0068] The pharmacological activity experiments of the compounds of the present invention are as follows: Experimental Example 1: Inhibition rates and IC 50 Results 1. Experimental method Dissolve compounds Q1-Q32 in DMSO to prepare a 10 mM stock solution, and dilute it with kinase buffer (pH = 7.4, components: 40 mM / L Tris, 10 mM / L MgCl 2 , 0.1 g / L BSA, 1 mM / L DTT, 10 µM / L ATP). Add SphK1 / 2 to a 96-well plate, and then treat it with the compound at the desired concentration for 40 minutes at 30 °C. Add the ATP test solution, and incubate the mixture at room temperature for 5 minutes. Measure the luminescence using a microplate spectrophotometer (AD 340, Beckman, USA). Analyze the data using Graphpad Prism 7.022, and calculate the single-concentration inhibition rate or IC 50 value.

[0069] 2. The experimental results are shown in the following table.

[0070] Table 1 Inhibition rate of compounds (10 μM) on SphKs Note: a IC 50 value, b ND means not tested, PF-543 and K145 are positive control drugs.

[0071] When the concentration of the compounds synthesized in the present invention is 10 μM, the inhibition rate on SphK1 is weaker than that of the positive control drug PF-543, but the inhibition rate of most compounds on SphK2 is better than that of the positive control drug K145, showing an ideal selective inhibitory effect on SphK2. Then, 8 compounds were preferably selected to determine the IC 50 .

[0072] 3. IC 50 results of the preferred compounds on SphK2 Table 2 IC 50 For the tested compounds, except Q29, the IC 50 of compounds Q5, Q19, Q20, Q24, Q25, Q28, Q32 on SphK2 are all less than 10 μM, and they have the value for studying the anti-tumor effect.

[0073] Experimental Example 2: Growth inhibitory effect of the compounds of the present invention on tumor cells such as LOVO, SW480, SW620, HT-29 1. Experimental materials Dissolve compounds Q5, Q19, Q20, Q24, Q25, Q28, and Q32 in dimethyl sulfoxide and prepare a 1 mg / mL stock solution using RPMI-1640 medium containing 15% fetal bovine serum. When grouping and administering the drugs, dilute the stock solution with this medium to the desired concentration by serial dilution.

[0074] Cell lines: Human colon cancer cells (LOVO), human colorectal cancer cells (SW480, SW620), and human colorectal carcinoma cells (HT-29) were purchased from the Cell Bank of the Chinese Academy of Sciences and cultured in DMEM (High Glucose) medium containing 15% fetal bovine serum at 37°C in a 5% CO 2 incubator.

[0075] 2. Experimental methods: LOVO cells, SW480 cells, SW620 cells, and HT-29 cells (6×10 3 cells / well / 100 μL) were seeded in 96-well culture plates. After incubation for 24 h, the test compounds (0.1, 0.3, 1, 3, 10, 30, and 100 μM) and oxaliplatin (0.1, 0.3, 1, 3, 10, 30, and 100 μM) were added, and incubation continued for 48 h. After aspirating the culture supernatant, 100 μL of basal medium containing 0.5 mg / mL CCK-8 was added to each well, and incubation continued for 2.5 h at 37°C and 5% CO 2 conditions. The absorbance (OD) was measured at 450 nm using a multi-functional microplate reader. Cell viability (100%) = OD value of the treatment group / OD value of the blank group × 100%.

[0076] 3. Statistical analysis: GraphPad Prism 9 software was used for statistical plotting. Data were expressed as mean ± standard deviation (Mean ± SD). One-way analysis of variance (One-way ANOVA) was used to analyze the data differences between different groups, followed by Dunnett's test. A P p < 0.05 indicated a significant statistical difference.

[0077] 4. Experimental results: Table 3 Inhibitory effects of compounds on tumor cell proliferation Note: Oxaliplatin is the positive control drug for cell viability testing.

[0078] By observing the above experimental data, it was found that among the 7 compounds Q5, Q19, Q20, Q24, Q25, Q28, and Q32, the inhibitory effects on the proliferation of LOVO and HT-29 tumor cells were better than those of the positive control drug oxaliplatin; the inhibitory effects of compounds Q5, Q20, Q24, Q25, and Q28 on the proliferation of SW480 tumor cells were better than those of the positive control drug oxaliplatin; the inhibitory effects of compounds Q5, Q19, Q24, Q25, and Q28 on the proliferation of SW620 tumor cells were better than those of the positive control drug oxaliplatin, providing an experimental basis for in vivo efficacy evaluation and drug-likeness research, and being ideal compounds for drug development.

Claims

1. A trifluoroacetate salt of a compound, characterized in that The structural formula of the trifluoroacetate salt of the compound is: , , 。 2. The trifluoroacetate salt of the compound according to claim 1, characterized in that The structural formula of the trifluoroacetate salt of the compound is: , 。 3. The trifluoroacetate salt of the compound according to claim 2, characterized in that The structural formula of the trifluoroacetate salt of the compound is: .

4. A pharmaceutical composition comprising the trifluoroacetate salt of the compound according to any one of claims 1 to 3, and a pharmaceutically acceptable carrier.

5. Use of the trifluoroacetate salt of the compound according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4 in the preparation of a medicament for preventing and / or treating a disease mediated by SphK2.

6. The use according to claim 5, characterized in that: The SphK2-mediated diseases include cancer, inflammatory diseases, ischemia-reperfusion injury, renal fibrosis, Alzheimer's disease, diabetic retinopathy, and diabetic nephropathy.

7. The use according to claim 6, characterized in that: The cancers include colorectal cancer, gastric cancer, kidney cancer, colon cancer, uterine cancer, ovarian cancer, breast cancer and lung cancer, glioma, germ cell tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibroma.

8. The use according to claim 7, characterized in that: The cancer is colorectal cancer or colon cancer.

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