Substituted thiazolidinedione compound and application thereof

Abstract

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

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of substituted thiazolidinedione compounds and applications thereof. 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 can even metastasize to other parts to form cancer. Cancer can occur in any tissue or organ, including skin, lungs, breasts, stomach, liver, colon, etc. Its symptoms depend on the type and location of the cancer. Common symptoms include abnormal lumps, 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. As the number of deaths from cancer increases year by year, the occurrence, development, and metastasis mechanism of cancer, and the development of cancer treatment drugs have always been hot topics of research at home and abroad. There are many causes of cancer. In addition to individual genetic factors, age, eating habits, living environment, etc. are closely related to the occurrence and development of cancer. Diagnosis of cancer usually requires tissue biopsy, imaging examination, and laboratory examination. Methods for treating cancer include surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc.

[0003] Sphingolipids are ubiquitous components in eukaryotic cell membranes. Sphingolipids and their metabolites are involved in many important signal transduction pathways. 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 and 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 is mainly present in the cytoplasm. When acted upon by some stimulating factors, SphK1 needs to be transported to the plasma membrane to be activated, catalyzing the phosphorylation of Sph to form S1P, and then activating five G protein-coupled receptors (S1PR) through autocrine or paracrine means. 1 -5 ), thereby mediating the various physiological effects of S1P, such as the transport of lymphocytes and the regulation of vascular tension. SphK2 is mainly present in the liver and heart, located in the mitochondria, nucleus and endoplasmic reticulum, and can inhibit DNA synthesis and regulate the activity of histone deacetylase (HDAC). 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 folds. It has an N-terminal domain (NTD) and a C-terminal domain (CTD), with an ATP catalytic site between the two domains. The protein structure of SphK2 has not yet been resolved. 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)-propylene]-thiazolidine-2,4-dione, which is one of the most representative SphK2 inhibitors. Its IC for SphK2 is 50 Reaching 4.30 μM, it is usually used as a tool drug. PF-543 is the most potent inhibitor of human SphK1 disclosed. Pfizer found through high-throughput screening that although it has ideal in vitro activity, the compound's short half-life, low metabolic stability or poor overall pharmacokinetic characteristics in vivo 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, a benzene ring intermediate connecting chain and a hydrophobic tail. This study used K145 as a lead compound and synthesized a series of new compounds by optimizing the hydrophobic tail. Summary of the invention

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

[0006] In order to solve the technical problem 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 a pharmaceutically acceptable salt thereof: Formula (I) Among them, R is , , , , , , , , , , , , , , , , , , , , , , , , , , , .

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

[0008] More preferably, said R is: , , , , , , .

[0009] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and 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, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0010] Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, 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 from morpholine, piperazine, and lysine, respectively.

[0011] The term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0012] The second aspect of the technical solution of the present invention is to provide a method for preparing the compound or a pharmaceutically acceptable salt thereof according to the first aspect. The compound of the general formula (I) of the present invention can be prepared by the following method: Among them, R is , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0013] Thiazolidinediones and N -Boc-bromoethylamine reacts to obtain the intermediate tert-butyl 2-(2,4-dioxathiazol-3-yl)ethylcarbamate (3), and ethyl p-hydroxyphenylpropionate undergoes nucleophilic substitution reaction with halogenated hydrocarbons or sulfonyl chloride to obtain substituted methyl phenylpropionate, which is reduced to aldehyde by diisobutylaluminum hydride (DIBAL-H). The generated aldehyde condenses with intermediate 3, and the resulting 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, isomer or solvate thereof, and a pharmaceutically acceptable carrier.

[0015] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, 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 "one dose" is a capsule or tablet.

[0016] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, 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.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers and wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0017] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0018] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations 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 dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0020] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned 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 form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0022] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0023] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.

[0024] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution 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 for topical administration of the compounds of the invention 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.

[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 used alone or in combination with other treatment methods 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 (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and 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 take into account factors such as the route of administration and the health status of the patient, which are all within the skill 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 drugs 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 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.

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

[0033] Beneficial technical effects: (1) The inhibitory rate of the compounds synthesized in the present invention on SphK1 is weaker than that of the positive control drug PF-543 at a concentration of 10 μM, but the inhibitory 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 values ​​of compounds Q5, Q19, Q20, Q24, Q25, Q28, and Q32 for SphK2 are 50 All of them are less than 10μM, which is valuable for anti-tumor research. The seven compounds Q5, Q19, Q20, Q24, Q25, Q28, and Q32 have better inhibitory effects on LOVO and HT-29 tumor cell proliferation than the positive control drug oxaliplatin; the compounds Q5, Q20, Q24, Q25, and Q28 have better inhibitory effects on SW480 tumor cell proliferation than the positive control drug oxaliplatin; the compounds Q5, Q19, Q24, Q25, and Q28 have better inhibitory effects on SW620 tumor cell proliferation than the positive control drug oxaliplatin, which provides an experimental basis for in vivo efficacy evaluation and drugability research, and are ideal compounds for drug development. DETAILED DESCRIPTION

[0035] The present invention's various embodiments specifically describe the preparation methods of the compounds of the present invention, 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 synthetic 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 belongs.

[0036] Unless otherwise specified, the raw materials and reagents used in the process for preparing 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 in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

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

[0039] Preparation method of the compound of the present invention: 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) were dissolved in acetonitrile (50 mL). oC and stirred for 22 hours. The reaction solution was filtered and then dried by spin drying, diluted with water, extracted with ethyl acetate, the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was separated by silica gel column chromatography (mobile phase: n-hexane-ethyl acetate = 25:1) to obtain white solid compound 3. Raw material 4 (methyl p-hydroxyphenylpropionate) (3mmol, 1equiv), halogenated hydrocarbon or sulfonyl chloride (6mmol, 2equiv), cesium carbonate (3mmol, 1equiv) were dissolved in DMF (6mL). Stirred at 70°C for 8 hours, extracted with ethyl acetate, the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was separated by silica gel column chromatography (mobile phase: n-hexane-ethyl acetate = 25:1) to obtain white solid compound 5. Compound 5 (3 mmol, 1 equiv) was dissolved in 3 mL of dichloromethane, precooled at -80 °C for 15 min, and diisobutylaluminum hydride (DIBAL-H) ​​(3.3 mmol, 1.1 equiv) was added dropwise, and the reaction was kept at low temperature for 4 hours. The reaction mixture was quenched with 1N HCl (3.3 ml), extracted with dichloromethane, and the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain product 6. Compound 6 (3 mmol, 1 equiv), intermediate 3 (3.3 mmol, 1.1 equiv), and piperidine (3.3 mmol, 1.1 equiv) were dissolved in anhydrous ethanol (6 mL), reacted at room temperature for 8 h, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was separated by silica gel column chromatography (mobile phase: n-hexane-ethyl acetate = 25:1) to obtain white solid compound 7. Compound 7 (3 mmol, 1 equiv) and trifluoroacetic acid (3 mL) were dissolved in dichloromethane (6 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was spin-dried and the crude product was separated by silica gel column chromatography (dichloromethane-methanol = 15:1) to obtain white solid compounds Q1-Q32.

[0040] Embodiment 1: (E) -3-(2-aminoethyl)-5-(3-(4-((3,4,5-trifluorophenyl)oxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q1): Methyl p-hydroxyphenylpropionate, halogenated hydrocarbon 3,4,5-trifluorobenzyl chloride, and cesium carbonate were dissolved in DMF, stirred at 70 °C for 8 hours, extracted and dried, and separated by silica gel column chromatography. The obtained compound was dissolved in dichloromethane, precooled at -80 °C for 15 minutes, and diisobutylaluminum hydride (DIBAL-H) ​​was added dropwise, and the reaction was maintained at low temperature for 4 hours. Under room temperature, 1 N HCl was quenched, and dichloromethane was extracted and dried to obtain aldehyde compounds. The obtained aldehyde compounds, compound 3, and piperidine were dissolved in anhydrous ethanol, stirred at room temperature for 8 hours, and the solvent was removed by rotary evaporation. 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 Calculate for C 21 H 19 F3N2O3S [M+H] + : 437.1147 found: 437.1146.

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

[0042] Embodiment 2: (E) -3-(2-aminoethyl)-5-(3-(4-((3,5-difluorobenzyl)oxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q2): The halogenated hydrocarbon used was 3,5-difluorobenzyl chloride. Q2 was 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 Calculate for C 21 H 20 F2N2O3S [M+H] + : 419.1241 found:419.1922.

[0043] Embodiment 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 was 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 Calculate for C 21 H 22 N2O3S [M+H] + : 383.1429 found:383.1426.

[0044] Embodiment 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 Calculate for C 17 H 18 N2O3S [M+H] + : 331.1116 found: 331.1098.

[0045] Embodiment 5: (E) -5-(3-(4-(allyloxy)phenyl)propylidene)-3-(2-aminoethyl)thiazolidine-2,4-dione trifluoroacetate (Q5): The halogenated hydrocarbon used was 3-bromopropylene. Q5 was 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 Calculate for C 17 H 20 N2O3S [M+H] + : 333.1273 found: 333.1267.

[0046] Embodiment 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 light yellow solid powder with a yield of 90%. 1 H NMR (800MHz, 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 Calculate for C 20 H 20 ClN3O3S [M+H] + : 418.0992 found: 418.0987.

[0047] Embodiment 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 was 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 Calculate for C 22 H 21 F3N2O3S[M+H] + :451.1303 found: 451.1321.

[0048] Embodiment 8: (E) -3-(2-aminoethyl)-5-(3-(4-(cyclopropylmethoxy)phenyl)propylene)thiazolidine-2,4-dione trifluoroacetate (Q8): The halogenated hydrocarbon used was bromomethylcyclopropane. Q8 was 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 CNMR (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 Calculate for C 18 H 22 N2O3S [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 was 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 Calculate for C 21 H 28 N2O3S [M+H] + : 389.1899 found: 389.1897.

[0050] Embodiment 10: (E) -3-(2-aminoethyl)-5-(3-(4-(cyclopentylmethoxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q10): The halogenated hydrocarbon used was bromomethylcyclopentane. Q10 was 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 N2O3S [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 was 3-trifluoromethylbenzyl chloride. Q11 was 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 F3N2O3S [M+H]+:451.1303 found: 451.1296.

[0052] Example 12: (E)-3-(2-aminoethyl)-5-(3-(4-(non-8-en-1-yloxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q12): The halogenated hydrocarbon used was 9-bromo-1-nonene. Q12 was 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 Calculate for C 23 H 32 N2O3S [M+H] + :417.2212 found: 417.2210.

[0053] Embodiment 13: (E) -3-(2-aminoethyl)-5-(3-(4-((2-fluorobenzyl)oxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q13): The halogenated hydrocarbon used was o-fluorobenzyl chloride. Q13 was 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 = 7.6 Hz, 1H), 7.44 – 7.40 (m, 1H), 7.28 – 7.21(m, 2H), 7.18 (d, J = 8.6 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 8.6 Hz,2H), 5.10 (s, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.39 (s, 2H), 3.03 (t, J = 6.0 Hz,2H), 2.78 (t, 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 Calculate for C 21 H 21 FN2O3S [M+H] + :401.1335 found: 401.1340.

[0054] Embodiment 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 was 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 = 7.6 Hz, 2H), 7.22 (d, J = 6.6 Hz, 2H),7.20 – 7.17 (m, 1H), 7.15 (d, J = 8.6 Hz, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 3.92 (t, J = 6.4 Hz, 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), 2.74 – 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 Calculate for C 23 H 26 N2O3S [M+H]+ : 411.1742 found: 411.1740.

[0055] Embodiment 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 was a white solid powder with a yield of 94%. 1 H NMR (800MHz, 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 (200MHz, 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 Calculate for C 18 H 21 F3N2O3S [M+H] + : 403.1303 found:403.1292.

[0056] Embodiment 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-benzyloxypropane bromide. 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- d6) 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 Calculate for C 24 H 28 N2O4S [M+H] + : 441.1848 found: 441.1835.

[0057] Embodiment 17: (E) -3-(2-aminoethyl)-5-(3-(4-(dodecyloxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q17): The halogenated hydrocarbon used was dodecane 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 Calculate for C 26 H 40 N2O3S [M+H] + : 461.2838 found: 461.2834.

[0058] Embodiment 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%. 1 H NMR (800 MHz, DMSO- d 6) δ 8.02 (s, 2H), 7.14 (d, J = 8.1 Hz, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.85(d, J = 8.1 Hz, 2H), 5.79 (td, J = 16.8, 6.6 Hz, 1H), 5.00 (d, J = 17.1 Hz, 1H),4.93 (d, J= 10.2 Hz, 1H), 3.91 (t, J = 6.6 Hz, 2H), 3.83 (t, J = 5.6 Hz, 2H), 3.04(t, J = 5.9 Hz, 2H), 2.76 (t, J = 7.5 Hz, 2H), 2.01 (q, J = 7.3 Hz, 2H), 1.68 (p, J =6.9 Hz, 2H), 1.47 – 1.12 (m, 11H). 13 C 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 N2O3S [M+H] + : 431.2368 found: 431.2356.

[0059] Embodiment 19: (E) -3-(2-aminoethyl)-5-(3-(4-((4-fluorobenzyl)oxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q19): The halogenated hydrocarbon used was 4-fluorobenzyl chloride. Q19 was 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 = 8.4, 5.5 Hz, 2H), 7.21 (t, J = 8.8 Hz, 2H),7.17 (d, J = 8.2 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.94 (d, J= 8.4 Hz, 2H), 5.05(s, 2H), 3.82 (t, J = 6.0 Hz, 2H), 3.03 (s, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.52(d, 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 Calculate for C 21 H 21 FN2O3S [M+H] + : 401.1335 found:401.1336. Embodiment 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 was a white solid powder with a yield of 93%. 1 H NMR (800MHz, DMSO- d 6) δ 7.28 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 7.5 Hz, 2H), 7.17 (t, J =7.3 Hz, 1H), 7.14 (d, J= 8.6 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 8.6Hz, 2H), 3.96 – 3.92 (m, 2H), 3.81 (t, J = 6.0 Hz, 2H), 3.00 (t, J = 6.0 Hz, 2H),2.76 (t, J = 7.4 Hz, 2H), 2.63 (t, 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 Calculate for C 24 H 28 N2O3S [M+H] + : 425.1899 found: 425.1907. Embodiment 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 Calculate for C 21 H 21 ClN2O3S [M+H] + : 417.1040 found:417.1007.

[0060] Embodiment 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 was 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 Calculate for C 21 H 21 BrN2O3S [M+H] + :461.0535 found: 461.0496.

[0061] Embodiment 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 was a white solid powder with a yield of 93%. 1 H NMR (800 MHz, DMSO- d6) δ 7.97 (s, 2H), 7.20 – 7.12 (m, 2H), 7.02 (t, J J = 7.4 Hz, 1H), 6.89 –6.83 (m, 2H), 5.86 (ddt, J J = 16.9, 10.2, 6.6 Hz, 1H), 5.05 (dq, J J = 17.2, 1.7 Hz,1H), 4.99 (ddt, J J = 10.2, 2.3, 1.3 Hz, 1H), 3.93 (t, J J = 6.4 Hz, 2H), 3.83 (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), 2.54 – 2.51 (m,2H), 2.20 – 2.13 (m, 2H), 1.80 – 1.76 (m, 2H). 13 C NMR (200 MHz, DMSO- d d6) 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 -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 N2O3S [M+H] + : 361.1586 found:361.1578。

[0062] Example 24: (E)-3-(2-aminoethyl)-5-(3-(4-(isopentyloxy)phenyl)propylidene)thiazolidine-2,4-dione trifluoroacetate (Q24): The halogenated hydrocarbon used was 1-bromoisopentane. 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 Calculate for C 19 H 26 N2O3S [M+H]+ : 363.1742 found: 363.1725.

[0063] Embodiment 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%. 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 = 7.4 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 3.91 (t, J = 6.5 Hz, 2H), 3.82 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 6.0Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.52 (d, J = 7.4 Hz, 2H), 1.69 (dt, J = 14.5,6.8 Hz, 2H), 1.36 (dd, J = 39.4, 13.9, 7.5, 6.7 Hz, 4H), 0.89 (t, J = 7.2 Hz,3H). 13 C 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 Calculate for C 19 H 26 N2O3S [M+H] + : 363.1742 found:363.1726. Embodiment 26: (E) -4-(3-(3-(2-aminoethyl)-2,4-dioxothiazolidin-5-ylidene)propyl)benzenesulfonate trifluoroacetate (Q26): Methyl p-hydroxyphenylpropionate, sulfonyl chloride (benzenesulfonyl chloride), and triethylamine were dissolved in dichloromethane, stirred at room temperature for 8 hours, and separated by silica gel column chromatography after being spun dry. The obtained compound was dissolved in dichloromethane, precooled at -80 °C for 15 min, and diisobutylaluminum hydride (DIBAL-H) ​​was added dropwise, and the reaction was kept at low temperature for 4 hours. At room temperature, 1N HCl was quenched, extracted, and spun dry to obtain aldehyde compounds. The synthesized aldehyde compound, intermediate compound 3, and piperidine were dissolved in anhydrous ethanol, stirred at room temperature for 8 hours, spun dry, and 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 (800MHz, 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= 7.4Hz, 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 Calculate for C 20 H 20 N2O5S2[M+H] + : 433.0892 found: 433.0897.

[0064] The preparation methods of the compounds in Examples 27-32 are the same as those in Example 26, except that different sulfonyl chlorides are used. The specific sulfonyl chloride used in each example is indicated in the corresponding example: Embodiment 27: (E) -4-(3-(3-(2-aminoethyl)-2,4-dioxothiazolidin-5-ylidene)propyl)benzene-4-fluorobenzenesulfonate trifluoroacetate (Q27): The sulfonyl chloride used was 4-fluorobenzenesulfonyl chloride. Q27 was 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 Calculate for C 20 H 19 FN2O5S2[M+H] + : 451.0798 found: 451.0789.

[0065] Embodiment 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 Calculate for C 21 H 22 N2O5S2[M+H] + : 447.1048 found: 477.1033.

[0066] Embodiment 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 Calculate for C 21 H 19 F3N2O5S2[M+H] + :501.0766 found: 501.0736. Embodiment 30: (E) -4-(3-(3-(2-aminoethyl)-2,4-dioxothiazolidin-5-ylidene)propyl)benzene-4-bromobenzenesulfonate trifluoroacetate (Q30): The sulfonyl chloride used was 4-bromobenzenesulfonyl chloride. Q30 was 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 Calculate for C 20 H 19 BrN2O5S2[M+H] + : 510.9997 found: 510.9956.

[0067] Embodiment 31: (E )-4-(3-(3-(2-aminoethyl)-2,4-dioxothiazolidin-5-ylidene)propyl)phenyl-4-methoxybenzenesulfonate trifluoroacetate (Q31): The sulfonyl chloride used was p-methoxybenzenesulfonyl chloride. Q31 was a white solid powder with a yield of 95%. 1 H NMR (800MHz, 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= 7.5 Hz, 1H), 6.96 – 6.92 (m, 2H), 3.87 (s, 3H), 3.83 (t, J =6.1 Hz, 2H), 3.36 (s, 2H), 3.04 (t, J = 5.8 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H). 13 CNMR (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 ): 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 Calculate for C 21 H 22 N2O6S2[M+H] + : 463.0998 found: 463.0999. Embodiment 32: (E) -4-(3-(3-(2-aminoethyl)-2,4-dioxothiazolidin-5-ylidene)propyl)benzene-3-fluorobenzenesulfonate trifluoroacetate (Q32): The sulfonyl chloride used was m-fluorobenzenesulfonyl chloride. Q32 was a white solid powder with a yield of 95%. 1 H NMR (800 MHz, Methanol- d 4) δ 7.64 (q, J = 3.5, 2.8 Hz, 2H), 7.55 (d, J= 8.6 Hz, 1H), 7.52(ddt, J = 8.6, 5.0, 2.9 Hz, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.06 (t, J = 7.7 Hz,1H), 6.93 (d, J = 8.5 Hz, 2H), 3.99 – 3.95 (m, 2H), 3.19 (q, J = 5.9, 5.4 Hz,2H), 2.86 (t, J = 7.3 Hz, 2H), 2.55 (q, 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 Calculate for C 20 H 19 FN2O5S2[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 rate and IC of the compounds of the present invention on SphK1 and SphK2 50 result 1. Experimental methods Compounds Q1-Q32 were dissolved in DMSO to prepare 10 mM stock solutions and diluted with kinase buffer (pH = 7.4, composition: 40 mM / L Tris, 10 mM / L MgCl2, 0.1 g / L BSA, 1 mM / L DTT, 10 µM / L ATP). SphK1 / 2 was added to a 96-well plate and then treated with the desired concentration of compounds for 40 min at 30 °C. ATP test solution was added and the mixture was incubated at room temperature for 5 min. Luminescence was measured using a microplate spectrophotometer (AD 340, Beckman, USA). Data were analyzed using Graphpad Prism 7.022 to calculate single concentration inhibition or IC 50 value.

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

[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] The inhibitory rate of the compounds synthesized in the present invention on SphK1 was weaker than that of the positive control drug PF-543 at a concentration of 10 μM, but the inhibitory rate of most compounds on SphK2 was better than that of the positive control drug K145, showing an ideal selective inhibitory effect on SphK2. Then, 8 compounds were selected and the IC values ​​of SphK2 were determined. 50 .

[0072] 3. IC of the preferred compounds against SphK2 50 result Table 2 IC values ​​of compounds for SphK2 50 The IC values ​​of compounds Q5, Q19, Q20, Q24, Q25, Q28, and Q32 for SphK2 were 50 All of them are less than 10μM, which is valuable for anti-tumor research.

[0073] Experimental Example 2: Growth inhibition of LOVO, SW480, SW620, HT-29 and other tumor cells by the compounds of the present invention 1. Experimental Materials Compounds Q5, Q19, Q20, Q24, Q25, Q28, and Q32 were dissolved in dimethyl sulfoxide and prepared to 1 mg / mL in RPMI-1640 medium containing 15% fetal bovine serum for later use. When grouping and dosing, the medium was used to dilute the compound to the desired concentration.

[0074] Cell lines: Human colon cancer cells (LOVO), human colorectal cancer cells (SW480, SW620), and human colorectal cancer cells (HT-29) were purchased from the Cell Bank of the Chinese Academy of Sciences and cultured in a 37°C, 5% CO2 incubator using DMEM (High Glucose) culture medium containing 15% fetal bovine serum.

[0075] 2. Experimental methods: LOVO cells, SW480 cells, SW620 cells, HT-29 cells (6×10 3 Cells were inoculated in 96-well culture plates at 100 μL / well / 100 μL. After incubation for 24 h, 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 incubated for 48 h. After the culture supernatant was removed, 100 μL of basal medium containing 0.5 mg / mL CCK-8 was added to each well. The cells were incubated for 2.5 h at 37°C and 5% CO2. The absorbance (OD) was measured at 450 nm using a multifunctional microplate reader. Cell activity (100%) = OD value of the drug group / OD value of the blank group*100%.

[0076] 3. Statistical analysis: GraphPad Prism9 software was used for statistical drawing. Data were expressed as mean ± SD. Differences between groups were analyzed by one-way ANOVA followed by Dunnett's test. P <0.05 indicated a statistically significant difference.

[0077] 4. Experimental results: Table 3 Inhibitory effect of compounds on tumor cell proliferation Note: Oxaliplatin is the positive control drug oxaliplatin in the cell activity test.

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

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt, isomer or solvate thereof, Formula (I) in, R is , , , , , , , , , , , , , , , , , , , , , , , , , , , 。 2. The compound according to claim 1 or its pharmaceutically acceptable salt, isomer or solvate, characterized in that: The R is: , , , , , , , 。 3. The compound according to claim 2 or its pharmaceutically acceptable salt, isomer or solvate, characterized in that: The R is: , , , , , , 。 4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, isomer or solvate thereof, and a pharmaceutically acceptable carrier.

5. Use of the compound according to any one of claims 1 to 3 or its pharmaceutically acceptable salt, isomer, solvate thereof 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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