A kind of s-triazine derivative and its synthesis method and use

Abstract

The present invention discloses a s-triazine derivative and a synthesis method and use thereof, and specifically relates to the field of pharmaceutical chemistry. The existing AG‑221 has some clinical defects, such as the efficacy is not particularly obvious, and some patients have drug resistance. Therefore, the research of novel IDH2 inhibitors is particularly urgent. A series of novel s-triazine derivatives were synthesized by using a rational design strategy of compounds, and in vitro activity screening was performed using a humanized AM7577 cell model. Two drugs with stronger activity than AG‑221 were found. At the same time, the HuKemia Acute Leukemia xenograft model was used to verify the in vivo activity. Such compounds can significantly enhance the survival of mice. The preferred compound can significantly inhibit the expression of IDH2(R140Q) at a concentration of 10μM.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and more specifically, relates to an s-triazine derivative and a synthesis method and application thereof. Background Art

[0002] Acute myeloid leukemia (AML) is a malignant clonal disease of hematopoietic stem cells. In recent years, many genes that interfere with key processes such as cell self-renewal, proliferation, and differentiation have been found in AML, such as FLT3 internal tandem duplication (FLT3-ITD), nucleophosmin 1 (NPM1), and myeloid transcription factor CCAAT enhancer binding protein-A (CCAAT-en-hancer binding-alpha, CEBPA). It is currently believed that the occurrence of AML is a multifactorial process, and molecular abnormalities alone are not sufficient to cause malignant transformation of hematopoietic stem cells. Since Mardis et al. first reported the presence of isocitrate dehychogenase 1 (IDH1) mutations in AML patients in 2009, multiple studies have reported the effects of IDH1 mutations on the diagnosis, clinical features, prognosis, and treatment of AML patients. IDH2 is a homologous gene of IDH1, and its incidence in AML is more common than IDH1. AML is the most common acute leukemia, with rapid disease progression and poor prognosis. It causes more than 21,000 new cases in the United States each year, and most patients will eventually relapse, and their treatment prospects are extremely bleak. In AML, about 8%-19% of patients carry IDH2 mutations. This mutation inhibits normal blood cell development and causes too many immature blood cells. And studies have also found that IDH2 mutations also exist in childhood AML.

[0003] The IDH2 gene is located on the long arm of human chromosome 15 at 15q26.1. The protein it encodes is located in the mitochondria and catalyzes the same chemical reaction as IDH1, that is, both can catalyze the dehydrogenation and decarboxylation of isocitrate to generate α-ketoglutaric acid (α-KG), accompanied by the generation of reduced nicotinamide dinucleotide phosphate (NADPH). α-KG is involved in the metabolism of glucose, protein, and fat in the body, while NADPH is a hydrogen donor for many anabolic reactions in the body, participates in hydroxylation reactions in the body, and maintains the reducibility of glutathione (GSH).

[0004]

[0005] IDH mutants convert α-KG into the tumor metabolite 2-hydroxyglutarate (2-HG), which causes a class of dioxygenase reactions that depend on α-KG to become disordered, thereby activating the downstream signaling pathways of the cell. The accumulation of 2-HG will cause cell metabolism problems and promote the transformation of normal cells into cancer cells.

[0006] IDH2 mutations mainly occur in IDH2 R140Q (79%) and IDH2 R172Q (21%). In addition, IDH2 mutations have also been reported in tumors such as cholangiocarcinoma, chondrosarcoma, breast cancer, and T-cell lymphoma. Since it was determined that IDH2 mutations are closely related to the occurrence and development of AML, the study of IDH2 inhibitors has gained the research interest of scientists and has made good progress. Fang Wang et al. designed and modified the urea sulfonamide series of drugs to obtain AGI-6780, which can effectively and selectively inhibit IDH2 R140Q mutation, and obtained the crystal structure of the complex (PDB: 4JA8). Wenyuan Lee et al. used PDB: 4JA8 as the target to conduct virtual screening from the TCM database, hoping to screen out traditional Chinese medicine ingredients that have IDH2 inhibitors that inhibit the R140Q mutation. In the virtual docking, it was found that abrin and abrinine bind more firmly to the target protein. Enasidenib (AG-221) is a high-throughput screening of IDH2 by Katharine Yen et al. R140Q Small molecule inhibitors of mutant proteins, and small molecules and IDH2 R140Q The complex crystal structure of the mutant protein (PDB: 5196) achieves the purpose of tumor inhibition by blocking the production of mutant protein 2-HG. In August 2017, the FDA approved AG-221 for marketing, and its efficacy has also been verified in clinical trials. It has been awarded priority review and orphan drug status by the US FDA. The mechanism of action of this drug is to convert isocitrate (IDH2) in AML patients into 2-hydroxyglutarate (2-HG) instead of the usual α-ketoglutarate. AG-221 can inhibit this process, with a remission rate of 56%. If the production of 2-HG can be abolished, malignant cells can return to normal differentiation and growth into normal healthy adult neutrophils.

[0007] Up to now, there is only one drug on the market, Enasidenib (AG-221). Recently, Andrew M. Intlekofer et al. have found that AG-221 has some clinical defects, such as the efficacy is not particularly obvious, and some patients have developed drug resistance. Therefore, the research of novel IDH2 inhibitors is particularly urgent. The present invention uses the rational design strategy of compounds to invent a series of novel s-triazine derivatives, uses the humanized AM7577 cell model for in vitro activity screening, and finds two drugs with stronger activity than AG-221. In vivo activity verification is performed, and the two newly synthesized s-triazine compounds can significantly prolong the median survival of mice. Western Blotting experiments show that compound T-33 can significantly inhibit the expression of IDH2 (R140Q) at a concentration of 10μM. Summary of the invention

[0008] In order to overcome the above-mentioned defects of the prior art, the embodiments of the present invention provide an s-triazine derivative and a synthesis method and use thereof to solve the problems raised in the above-mentioned background technology.

[0009] To achieve the above object, the present invention provides the following technical solutions:

[0010] One object of the present invention is to provide a novel compound capable of treating IDH2 mutation. The compound has the following structure:

[0011]

[0012] Wherein, R is a chiral substituted five-membered cyclic amine or six-membered cyclic amine.

[0013] Preferably, the compound of the present invention is one selected from the following table:

[0014]

[0015]

[0016]

[0017] Another object of the present invention is to provide a pharmaceutical composition for treating IDH2 gene mutation, which comprises the compound of the present invention or its hydrate, solvate, crystalline salt, metabolite, or pharmaceutically acceptable salt or ester or prodrug, and a pharmaceutically acceptable carrier.

[0018] Preferably, the dosage form of the pharmaceutical composition of the present invention is selected from the group consisting of tablets, capsules, pills, granules, syrups, injections and external dosage forms.

[0019] Preferably, the external dosage form is a solution, a suspension or an aerosol.

[0020] The compounds of the present invention can be administered alone or in combination with each other, or in combination with other pharmaceutically acceptable active compounds. The compounds can be administered to humans or animals in need by oral, rectal, parenteral, or topical administration in the form of pharmaceutical compositions.

[0021] The pharmaceutical composition is usually prepared by mixing the active compound with one or more pharmaceutically acceptable carriers according to conventional methods to prepare a suitable dosage form. The pharmaceutically acceptable carrier refers to a conventional inert carrier in the pharmaceutical field.

[0022] In addition to the active compound, the pharmaceutical composition may contain one or more of the following carriers: diluents, such as starch, lactose, sucrose, glucose, mannitol or silicic acid; binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; dispersants, such as polyethylene glycol, polyvinyl pyrrolidone; humectants, such as glycerol; disintegrators, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; slow dissolving agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glyceryl monostearate; adsorbents, such as kaolin; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate; other adjuvants, such as buffers, colorants, flavoring agents, sweeteners, etc. In addition, coating materials may be included to prepare coated preparations. Sustained-release preparations may be prepared by including polymeric substances and waxy substances, so that the active compound is released in a delayed manner in a certain part of the digestive tract.

[0023] Liquid dosage forms for oral administration include emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the pharmaceutical composition may contain one or more of the following carriers: diluents such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances; suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate and agar. In addition, adjuvants such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents and fragrances may be included.

[0024] Dosage forms for parenteral administration include intravenous, subcutaneous, and intramuscular injection preparations. In addition to the active compound, the pharmaceutical composition may contain a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension, or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, and solvents include water, ethanol, polyols, and suitable mixtures thereof.

[0025] Dosage forms for topical administration include ointments, powders, sprays, drops 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 pharmaceutically acceptable salts or esters of the present invention refer to non-toxic salts or esters or their derivatives commonly used in the pharmaceutical industry that can be prepared according to methods well known to those skilled in the art; on the one hand, salts based on basic groups are preferably inorganic salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, phosphate, etc.; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, aromatic sulfonates such as benzenesulfonate, p-toluenesulfonate, maleate, acetate, malate, succinate, fumarate, hemifumarate, citrate, succinate, ascorbate, tartrate, malonate, acetate, trifluoroacetate, lactate, p-toluenesulfonate, oxalate, etc.; and amino acid salts such as arginine, lysine, glycine, ornithine, glutamate, aspartate, etc.; on the other hand, salts based on acidic groups are preferably alkali metal salts such as sodium, potassium, lithium, and alkaline earth salts such as calcium and magnesium. Metal salts, such as metal salts, aluminum salts, and iron salts; inorganic salts such as ammonium salts, tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts, tris(hydroxymethyl)aminomethane salts and other organic salts such as amine salts; and arginine salts, lysine salts, Amino acid salts such as glycine, ornithine, glutamate, aspartate; it should be understood that the non-toxic salts or esters include pharmaceutically acceptable pharmacologically active derivatives of the compounds of the present invention, or compounds significantly related thereto, including but not limited to salts or esters, pharmaceutically acceptable salts or esters, prodrugs, active metabolites, various isomers or mixtures of any ratio of these isomers, crystals, partially crystalline, amorphous forms or polymorphic forms, solvates, hydrates or oxides.

[0027] The pharmaceutically acceptable carriers of the present invention are recognized in the art and refer to pharmaceutically acceptable substances, components or carriers that participate in carrying or transporting any subject composition or its components from one organ or part of the body to another organ or part of the body, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials. The pharmaceutically acceptable carriers may be selected from fillers, binders, disintegrants, lubricants, glidants, wetting agents, flavoring agents, fragrances, colorants, solubility promoters or mixtures thereof. The amount of each pharmaceutically acceptable carrier in the pharmaceutical composition may vary within the conventional range in the art: BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is a graph showing the body weight of mice in different groups during the treatment with the test article in the HuKemia acute leukemia xenograft model AM7577 of the present invention;

[0029] Figure 2 This is a graph showing the weight changes of mice in different groups during treatment with the HuKemia acute leukemia xenograft model AM7577 test product of the present invention;

[0030] Figure 3 The tumor burden of mice in different groups in the HuKemia acute leukemia xenograft model AM7577 of the present invention;

[0031] Figure 4 The FACS display diagrams of PB, SP and BM of AM7577 mice of different groups in the present invention;

[0032] Figure 5 It is a survival curve diagram of each group of AM7577 mice of the present invention;

[0033] Figure 6 2-HG levels in PB, SP and BM of AM7577 mice of different groups in the present invention;

[0034] Figure 7 This is a graph showing the expression level of exogenously expressed IDH2 detected by Western Blotting in the present invention. DETAILED DESCRIPTION

[0035] The present invention is further described below in conjunction with embodiments, the purpose of which is to provide a better understanding of the content of the present invention and to embody the essential features of the present invention. Therefore, the examples given should not be regarded as limiting the scope of protection of the present invention.

[0036] Example 1

[0037] Target compound T 2 The synthetic route:

[0038] Synthesis of intermediate Y1:

[0039]

[0040] Procedure: Add Y1A (100 g, 523.26 mmol, 1 eq) and methanol (800 mL) into a 2 L round bottom flask, then slowly add SOCl 2 (124.50 g, 1.05 mol, 2 eq). The mixture was stirred at 70°C for 12 h until Y1 was completely generated. The solvent was removed under reduced pressure to obtain an off-white intermediate Y1 (100 g, crude product), LC-MS: 205.8.

[0041] Synthesis of intermediate Y3:

[0042]

[0043] Operation steps: Na (13.45 g, 584.99 mmol, 1.2 eq) was added to EtOH (1.50 L), and the mixture was stirred at 15 ° C until Na was completely dissolved. Biuret Y2 (50.25 g, 487.50 mmol, 1 eq) was added to the sodium ethoxide solution at 50 ° C, stirred for 10 min, and then Y1 was added, and the mixture was heated to reflux for 48 h. The raw material disappeared, the reaction solution was concentrated and added to ice water (100 mL), and then concentrated hydrochloric acid (2.5 mL, 0.03 mol) was neutralized to pH 6-7. The precipitate was dried in vacuo to obtain an off-white solid Y3 (40 g, crude product), yield: 32.0%; LC-MS: 302.9; 1 H NMR (400 MHz, DMSO-d 6 )δppm8.09-8.56(m,3H),11.55(br s,1H),12.38(br s,1H).

[0044] Synthesis of intermediate Y4:

[0045]

[0046] Operation steps: Slowly add POCl 3 (175 mL) was added to a round-bottom flask containing Y3 (30.0 g, 116.21 mmol, 1 eq). The mixture was stirred at 100 °C for 48 h. The solvent was removed and dissolved in ethyl acetate (200 mL) at 0 °C. Ice water was slowly added, and the organic layer was washed with saturated ice brine, then Na 2 SO 4 Drying gave Y4 (40.0 g, crude) as a brown solid with a yield of 87.79% and LCMS of 294.9, which was used directly in the next step.

[0047] Synthesis of intermediate Y6:

[0048]

[0049] Procedure: Dissolve Y4 (30.0 g, 101.68 mmol, 1 eq) in THF (150 mL), then Y5 (9.06 g, 101.68 mmol, 1 eq) and NaHCO 3 (12.81 g, 152.52 mmol, 1.5 eq) was added to the above mixed solution, and the mixture was stirred at 30°C for 12 h. The solid was filtered, the filtrate was concentrated, and column chromatography was performed (petroleum ether: ethyl acetate = 3:1-1:1) to obtain a light yellow solid Y6 (14.0 g, 40.26 mmol), with a yield of 39.60%. 1 H NMR (400 MHz, CDCl 3 -d)δppm 1.28-1.34(m,6H),3.51-3.68(m,2H),6.65(br t,J=5.77Hz,1H),7.01(br t, J=5.77Hz, 1H), 7.84 (dd, J=6.78, 1.25Hz, 1H), 8.05 (t, J=8.03Hz, 1H), 8.52-8.66 (m, 1H).

[0050] Synthesis of intermediate Y7:

[0051]

[0052] Procedure: Dissolve Y6 (3.0 g, 8.63 mmol, 1 eq) in MeOH (50 mL), TEA (837.2 mg, 8.63 mmol, 1.2 mL, 1 eq) and Pd(dppf)Cl 2. CH 2 Cl 2 (704.76 mg, 863 umol, 0.1 eq) was added to the above solution, and the mixture was reacted at 8 atm and 60°C for 16 h. The filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain a light yellow compound Y7 (2.0 g, 5.39 mmol, 62.41% yield).

[0053] Synthesis of intermediate Y8:

[0054]

[0055] Procedure: Y7 (2.0 g, 5.39 mmol, 1 eq) was dissolved in THF (15 mL), LiOH. 2O (339.02 mg, 8.08 mmol, 1.5 eq) and H 2 O (15 mL) was added to the above solution, and the mixture was stirred at 20°C for 16 h. The solvent was removed and 1 equivalent of dilute hydrochloric acid was added to pH ~ 5. The aqueous phase was lyophilized to obtain Y8 (2.0 g, crude product) with a yield of 99% and LCMS of 358.1, which was used directly in the next step.

[0056] Target compound T 2 Synthesis of:

[0057]

[0058] Operation steps: Dissolve Y8 (200 mg, 559.77 umol, 1 eq) in DCM (15 mL) and DMF (5.00 mL), add HATU (319.26 mg, 839.66 umol, 1.5 eq), stir at 0 ° C for 10 min, then add substituted amine (839.66 umol, 1.5 eq) and DIEA (144.69 mg, 1.12 mmol, 2 eq), and stir the mixture at 20 ° C for 3 h. Add brine, extract the mixture with DCM, and the organic phase is washed with anhydrous Na 2 SO 4 After drying and concentration, the target compound was purified by preparative liquid phase. All target compounds were synthesized by the same method, the only difference being the different amines used in the last step. The characterization data are shown in the notes to the figures.

[0059] Example 2

[0060] The derivatives provided by the present invention were used for testing to verify the activity on humanized AM7577 cells. AG-221 was used as a positive control.

[0061] 1) Test materials

[0062] CellTiter- Luminescent cell viability assay (Promega, Cat. No. G7572); X-vivo 15 basal growth medium (Lonza, Cat. No. 04-744Q); 96-well plate (Corning, Cat. 3603); Backseal black rubber bottom seal (Perkin Elmer, Cat. No. 6005189); dimethyl sulfoxide (DMSO) (Sigma, Cat. No. D2650); CellTiter- Buffer, CellTiter- Substrate (lyophilized) and positive control AG-221 were purchased from Sigma. Olympus (CKX41SF); microplate reader (EnVision PerkinElmer, 2104-0010A); CO2 incubator (Thermo Scientific, Model 3100 Series); AM7577 cells were from Crown Bioscience.

[0063] 2) Test steps

[0064] The cell viability test was performed using the CTG method, which is briefly described as follows: AM7577 cell suspension was counted using a CountStar cell counter, and the cell suspension was diluted with culture medium to a concentration of 1.1 × 10 5 AM7577 cell suspension was inoculated into 96-well plates at 90 μL of the specified concentration. The plates were incubated at 37°C with 5% CO 2 After culturing in a humidified incubator for 24 hours. 100 μL of reaction solution (50% fresh culture medium, 50% reaction substance added) was added to each well. The compound was dissolved in DMSO and diluted with the entire medium. Then 25uL / well compound was added to a 96-well plate, and the final compound concentrations obtained were 10μM, 2.5μM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, and 0.15nM. After incubation for 72h, the cells were transferred to a 96-well plate and the luminescent signal was measured using a microplate reader. The inhibition rate (%) was calculated as follows:

[0065]

[0066] All data were processed using GraphPad prism. The activity data of some compounds are shown in Table 1: Table 1 shows that T 9 and T 33 The inhibitory effect on AM7577 was comparable to that of the positive control, and T 9 Has a three-fold inhibition rate.

[0067] Table 1 Inhibition of compounds on AM7577

[0068]

[0069]

[0070] Example 3 In vivo activity screening

[0071] Since compound T 9 and T 33They showed obvious cell inhibitory effects. In order to further study their activity, in vivo activity tests were performed. The HuKemia acute leukemia xenograft model (AM7577) was from Crown Bioscience. The operation process is briefly described as follows:

[0072] NOD / SCID; Age: 3-4 weeks; Gender: female; 45 mice in total (30 mice in groups 1-5 + 10 spare mice, 5 mice in groups 6); Animal supplier: Beijing Hengji Biotechnology Co., Ltd.; Animal use application ID: AN-1507-005-38.

[0073] Thaw 1-2 x 10 mice from liquid nitrogen. 6 (about 12 bottles), and then quickly placed in a 37°C water bath; transfer all cells to a 50mL tube and 40mL pre-warmed complete medium; centrifuge at 1000rpm for 7min; wash cells twice with ice-cold PBS; resuspend cells with 2.5mL ice-cold PBS; inject 100uL of PBS containing 1 to 2 million tumor cells into each mouse for tumor growth.

[0074] After inoculation, the animals' eye blood was collected, stained for human CD45, and analyzed by flow cytometry (FACS) to monitor the tumor burden in PB. When the average tumor burden reached 2-10%, the mice were randomly divided into 6 groups. At the same time, after tumor inoculation, the animals were checked for morbidity and mortality every day. While routinely monitoring, the animals were checked for tumor growth and any effects of treatment on normal behavior, such as activity, food and water consumption, weight gain / loss, eye / hair tangling, and any other abnormal effects. Deaths and observed clinical signs were recorded according to the number of animals in each subgroup.

[0075] All animals were studied until death. In the following cases, live experiments were terminated by humane euthanasia of individuals or entire groups of animals before they died or reached a comatose state.

[0076] Spleen and bone marrow were cut into 2 pieces; one was digested into single cells for FACS analysis, and the other was stored at -80°C until 2-HG analysis; at the same time, 2 blood samples were collected from each mouse, one for FACS analysis, and the other (at least 30uL) was stored at -80°C until 2-HG analysis. 2-HG analysis was performed using API4000+Agilent 1200+CTC (TLCM0008), MS conditions: CUR: 20, GS1: 70, GS2: 70, is: -4500, TEM: 550, ihe: ON, CAD: 5, EP: -10, CXP: 19. Molecular ion peak: 2-HG, Q1 mass (amu): 147.0; Q3 mass (amu): 128.9. HPLC conditions: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile, HPLC column: EC-C18 4.0um 2.1X50mm, total time: 2.51min, flow rate: 300μL / min, A%:B%=85:15.

[0077] The median survival time (MST) of each group was calculated. The calculation method of extended life span (ILS) was as follows:

[0078] ILS (%) = 100 × [(median survival time of drug treatment group / median survival time of drug-vehicle group) - 1] (%).

[0079] The body weight and body weight changes of mice in each group Figure 1 , Figure 2 As the disease progressed, the weight of the mice gradually decreased, but the weight loss of Group 5 (Compound Th), especially Group 1 (Vehicle), was faster and more severe than that of the other groups, and was terminated early on day 55 after inoculation. The tumor burden (human CD45-positive leukemia cells) of PB mice after grouping and the tumor burden (human CD45-positive and CD45 / CD15 double-positive leukemia cells) of PB, SP, and BM mice at the end of the study are shown in Figure 2. Figure 3 , Figure 4 As the disease progressed, the percentage of human CD45+ leukemic cells in the PB of each group increased, and when the number of mice decreased, the percentage curve finally decreased. AG-221 treatment induced the expression of the monocyte surface marker CD15+ in human CD45+ blasts, indicating the beginning of differentiation. The survival curves of the five groups of mice are shown in Figure 5 The median survival time of groups 1 to 5 was 55, 56, 57, 58 and 57.5 days, respectively. The corresponding ILS of groups 2-5 were 1.82%, 3.64%, 5.45% and 4.55%, respectively, as shown in Table 2. Figure 6As shown. AG-221 can effectively reduce 2-HG in PB, SP and BM of AM7577 mice. In summary, the synthesized compounds can improve animal survival rate. AG-221 induces dose-dependent expression of monocyte surface marker CD15+ in human CD45+ blasts, indicating the beginning of differentiation. AG-221 can also effectively reduce 2-HG in PB, SP and BM of AM7577 mice. From animal experiments, Ta and Th can improve animal survival rate.

[0080] Table 2. Survival rate of mice in each group

[0081]

[0082] Example 4

[0083] To determine T 9 and T 33 To determine whether it can regulate the expression of mIDH2R140Q, we performed western blotting experiments in TF-1 (IDH2 / R140Q) cells. Figure 7 The results showed that 10 μM Th could significantly reduce the expression level of mIDH2R140Q, while 10 μM AG-221 and T 9 When the final concentration was increased to 20 μM and 50 μM, all these compounds had no effect on the expression level of mIDH2R140Q, except for compound T. 33 The expression of mIDH2R140Q was significantly inhibited at low concentrations, but no significant inhibition was observed at high concentrations. The possible reason is that other compensatory pathways appeared at high concentrations. This phenomenon needs further study.

[0084] Finally: The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A triazine compound having IDH2-R140Q mutation inhibitory activity in acute myeloid leukemia, characterized in that: The compound has the following structure: 。 2. Use of a s-triazine compound having the structure described in claim 1 in the preparation of a drug for treating acute myeloid leukemia caused by IDH2-R140Q mutation.

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