Thiazole compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention belongs to the field of chemical medicines, and particularly relates to a thiazole compound as well as a preparation method, a pharmaceutical composition and application thereof. The structure of the thiazole compound is shown as a formula I, and R1 and R2 are independently selected from one of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, naphthenic base, substituted naphthenic base, aryl, substituted aryl, heteroaryl and substituted heteroaryl. The thiazole compound provided by the invention can inhibit the activity of LSD1 protease, and has the effects of low toxicity, high efficiency, high selectivity and difficulty in off-target. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of chemical medicines, and specifically relates to a thiazole compound and a preparation method, a pharmaceutical composition and use thereof. Background Art

[0002] Cancer is a major public health problem and one of the leading causes of death worldwide. Conventional chemotherapy drugs do not only target cancer cells, but also kill normal cells along with them. In addition, the cytotoxicity of conventional treatments, chemotherapy, and radiotherapy can lead to severe side effects. That is why most research is now devoted to developing targeted therapies that can kill or stop the growth of cancer cells.

[0003] LSD1 uses the non-covalently bound FAD cofactor (which requires a lone pair of electrons in the substrate) as an enzyme to demethylate monomethylated and demethylated histone 3 lysine 4 (H3K4me1, H3K4me2) and histone 3 lysine 9 (H3K9me1, H3K9me2). LSD1 can also demethylate many proteins, indicating that LSD1 has an impact on downstream cellular functions. Histone lysine methylation plays a vital role in chromatin remodeling and gene expression. Overexpression of LSD1 has been found in many cancers. In some animal experiments, small molecule inhibitors inhibited the expression of LSD1 and could effectively inhibit the proliferation, differentiation, invasion and metastasis of cancer cells. It can thus prevent tumor growth, suggesting that LSD1 small molecule inhibitors may become a new approach to treating cancer.

[0004] In recent years, a variety of LSD1 inhibitors have been developed and clinical trials have begun. The earliest developed LSD1 inhibitors were irreversible inhibitors containing a monoamine oxidase structure (e.g., the irreversible inhibitor cypromine, TCP). TCP is a nonspecific inhibitor of LSD1 that covalently binds to the FAD cofactor in LSD1, thereby inhibiting its demethylase activity. Although TCP has demonstrated the therapeutic potential of LSD1 inhibition, its non-selective inhibition of other FAD-dependent enzymes (such as monoamine oxidases MAO A and B) has brought serious safety issues, limiting its clinical application. Therefore, researchers began to develop TCP derivatives to improve its specificity for LSD1 rather than MAO enzymes. These derivatives retain the core structure of TCP and modify its structure to enhance its binding affinity and selectivity to LSD1, acting only on LSD1 without affecting other enzymes. Many LSD1 inhibitors have been developed and entered clinical trials, including ORY-1001, GSK2879552 and INCB059872, which have entered Phase I and Phase II clinical trials to evaluate their safety, tolerability and efficacy in patients with various cancers. Early clinical data have shown encouraging results in hematological malignancies such as acute myeloid leukemia (AML) and chronic myeloid leukemia (SCLC), suggesting that LSD1 plays an important role in the regulation of gene expression in these diseases.

[0005] In addition to oncology, researchers are studying the potential use of LSD1 inhibitors in non-cancer diseases including neurodegenerative diseases such as Alzheimer's and Parkinson's. In these diseases, epigenetic dysregulation plays an important role. These new directions may expand the application of LSD1 inhibitors beyond cancer treatment. Although no LSD1 inhibitors have been successfully marketed, data have shown that LSD1 is an excellent target for tumor treatment. Therefore, the development of new LSD1 inhibitors with low toxicity, high efficiency, good selectivity, and low off-target is crucial for the prevention and treatment of cancer and non-cancer diseases. Summary of the invention

[0006] The purpose of the present invention is to solve the deficiencies of the prior art. The first aspect of the present invention is to provide a thiazole compound which has the effect of inhibiting LSD1 protease activity with low toxicity, high efficiency, high selectivity and low off-target properties. The structure of the thiazole compound is shown in Formula I:

[0007]

[0008] Wherein, R1 and R2 are independently selected from one of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl. Also known as 4-phenyl-2-(1H-pyrazol-1-yl)thiazole compounds.

[0009] In some preferred cases, the structure of the thiazole compound is any one of compound P4 and compounds P8-P21:

[0010]

[0011] Among them, compound P4, compound P10, compound P14 and compound P20 (the diester of compound P4 and compound P8, namely, p-fluorobenzoic acid, p-trifluoromethylbenzoic acid and p-methoxybenzoic acid) have particularly outstanding effects.

[0012] The second invention of the present invention is to provide a method for preparing the above-mentioned thiazole compounds, including route 1 or route 2, and the above-mentioned route 1 is as follows:

[0013]

[0014] The above route 1 includes the following steps:

[0015] (1) dichloromethane (DCM) and p-anisidine are mixed, and triethylamine (TEA) is added under stirring to obtain solution A; acryloyl chloride is mixed with dichloromethane to obtain solution B; solution B is added dropwise to solution A at -40°C to 35°C, and then stirred for 2h to 24h; dichloromethane is removed by concentration to obtain a residue, and then dichloromethane or ethyl acetate is added to dissolve, and water is added to extract 1-5 times, the organic phases are combined, washed, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated, and purified by column chromatography to obtain compound P2;

[0016] (2) Under stirring, the compound P2 is added to THF, and then ethyl acetoacetate and potassium tert-butoxide are added in sequence, and the reaction is carried out at 40° C.-80° C. for 4 h-24 h; the reaction is then quenched with water, extracted with ethyl acetate or dichloromethane 2-5 times, the organic phases are combined, washed, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated, and purified by column chromatography to obtain compound P3;

[0017] (3) Mixing the alcohol and the compound P3 under stirring, then adding the compound P1 and concentrated hydrochloric acid or glacial acetic acid in sequence, and reflux at 60° C.-90° C. for 3 h-24 h; concentrating to remove the alcohol to obtain a residue, then re-dissolving it in ethyl acetate or dichloromethane and extracting it with water for 2-5 times, combining the organic phases, washing, adding anhydrous sodium sulfate to dry, filtering and concentrating the filtrate, and purifying it by column chromatography to obtain the compound P4;

[0018] The preparation process of the compound P1 includes the following steps: mixing alcohol and 2-bromo-1-phenylethanone under stirring, then adding hydrazinethioamide, and heating at 40°C-80°C for 2h-12h; then concentrating to remove the alcohol, dissolving with water, filtering to obtain a filtrate, adjusting the pH of the filtrate to 8-12, filtering to separate the solid, dissolving the solid with alcohol, heating at 30°C-80°C to obtain a saturated solution, filtering while hot, and crystallizing the filtrate to obtain the compound P1, i.e. 2-hydrazino-4-phenylthiazole.

[0019] The above route 2 is as follows:

[0020]

[0021] The above route 2 includes the following steps:

[0022] (1) Mix 2-bromoethanol or 2-chloroethanol with DMF under stirring, then add TBDPSC1 (tert-butyldiphenylsilyl chloride) and imidazole, react at 20° C.-30° C. for 1 h-10 h, and then quench the reaction with water; then add ethyl acetate or dichloromethane to extract 2-5 times, combine the organic phases, wash, add anhydrous sodium sulfate to dry, filter and concentrate the filtrate, and purify by column chromatography to obtain compound P5;

[0023] (2) K2CO3, sodium ethoxide or sodium methoxide and ethanol or methanol are mixed under stirring, and then ethyl acetoacetate is added to obtain a mixture, and when the mixture is heated to 60°C-90°C, ethanol or methanol in which the compound P5 is dissolved is added dropwise to the mixture for reaction for 2h-14h, and then the pH is adjusted to 6, filtered, and the filtrate is concentrated, and then ethyl acetate or dichloromethane is added for extraction 2-5 times, the organic phases are combined, washed, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated, and purified by column chromatography to obtain compound P6;

[0024] (3) Mixing the compound P1 and the compound P6 under stirring, then adding glacial acetic acid or hydrochloric acid, reacting at 60° C.-90° C. for 2 h-24 h, concentrating under reduced pressure to remove the acid to obtain a residue, then adding ethyl acetate or dichloromethane to extract 2-5 times, combining the organic phases, washing, adding anhydrous sodium sulfate to dry, filtering and concentrating the filtrate, and purifying by column chromatography to obtain compound P7;

[0025] (4) Under stirring, the compound P7 is mixed with methanol to obtain a solution C; under stirring, methanol is mixed with concentrated hydrochloric acid to obtain a solution D; under stirring, the solution D is added to the solution C, reacted for 2h-6h, then concentrated to remove methanol to obtain a residue, ethyl acetate or dichloromethane is added to extract 2-5 times, the organic phases are combined, washed, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated, and purified by column chromatography to obtain compound P8;

[0026] (5) Under stirring, the compound P8, DIC (N,N'-diisopropylcarbodiimide) and DMAP (4-dimethylaminopyridine) are added to a DMF solution, and then an organic acid is added. The reaction is carried out at 25°C-60°C for 2h-16h, and the reaction is quenched with water. The mixture is then extracted with dichloromethane or ethyl acetate for 2-5 times. The organic phases are combined, washed, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The mixture is purified by column chromatography to obtain compounds P9-P21.

[0027] In the above process, saturated salt water is used for washing.

[0028] Based on the effects of the thiazole compounds proposed in the present invention, the third aspect of the present invention is to provide a pharmaceutical composition, which includes the thiazole compounds of the present invention or pharmaceutically acceptable salts thereof. The pharmaceutical composition may also include one or more pharmaceutically acceptable excipients, and the dosage form may be any pharmaceutically acceptable dosage form.

[0029] The thiazole compounds proposed in the present invention or the pharmaceutical compositions of the present invention with the thiazole compounds as active ingredients can be well applied to the preparation of LSD1 inhibitors and to the preparation of drugs for treating and / or preventing cancer, especially cancers related to abnormal expression of LSD1 in cells, such as lung cancer, gastric cancer, colorectal cancer, bladder cancer, esophageal cancer, prostate cancer, liver cancer, glioma or acute myeloid leukemia. The third aspect of the present invention is to provide a pharmaceutical composition, which includes

[0030] The beneficial effects of the present invention are as follows: the thiazole compounds proposed in the present invention can inhibit the activity of LSD1 protease, and at the same time have the effects of low toxicity, high efficiency, high selectivity and low off-target effect. DETAILED DESCRIPTION

[0031] The following will be combined with the embodiments to clearly and completely describe the concept and technical effects of the present invention so as to fully understand the purpose, scheme and effect of the present invention. The test reagents used in the following examples are all conventional biochemical reagents unless otherwise specified; the experimental methods are all conventional methods unless otherwise specified.

[0032] The structures of compound P4 and compounds P8-P21 involved in the following examples are shown below:

[0033]

[0034] The synthetic route of compound P4 is shown in route 1:

[0035]

[0036] The synthetic route of compounds P8-P21 is shown in Route 2:

[0037]

[0038] Example 1

[0039] A thiazole compound (Compound P4), the preparation method of which comprises the following steps:

[0040] (1) Preparation of compound P1

[0041] 120 mL of anhydrous methanol solution was added to 2-bromo-1-phenylethanone (2.985 g, 15 mmol) while stirring. Hydrazinethioamide (1.365 g, 15 mmol) was then added to the mixture and heated at 60 ° C for 5 hours. Afterwards, the reaction solution was concentrated to remove the methanol solution, then dissolved with 50 mL of water, filtered and the filtrate retained. The pH value of the solution was adjusted to 10 using NH4OH, and the solid was separated by filtration. The solid was dissolved in methanol, a saturated solution was prepared at 60 ° C, filtered while hot, and the filtrate was placed in a 4 ° C refrigerator for crystallization to obtain white crystalline compound P1 (0.933 g, yield 32.53%).

[0042] Compound P1 was tested and the test results were as follows: mP 164-166; IR (KBr) νmax 3336.92, 3211.27, 1631.16, 1603.21, 1546.7, 1423.83, 595.8 cm -1 ; 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H),7.81–7.76(m,2H),7.36(dd,J=8.4,7.0Hz,2H),7.28–7.20(m,1H),7.10(s,1H),4.95–4.86(m,2H). 13 C NMR(101MHz,Chloroform-d)δ174.97,151.70,134.96,128.61,127.72,125.95,102.96.HRMS(ESI)m / z calcd for C9H9N3S+ [M + H] + 192.05899,found 192.05881.

[0043] (2) Preparation of Compound P2

[0044] 120 mL of dichloromethane was added to p-anisidine (2.956 g, 24 mmol), and triethylamine (5.6 mL, 40 mmol) was added while stirring to obtain solution A. 1.6 mL of acryloyl chloride was added to 30 mL of dichloromethane to obtain solution B. Solution B was slowly added dropwise to solution A at 0°C. After solution B was completely added to solution A, the reaction was stirred at 25°C overnight. The reaction solution was concentrated to remove dichloromethane to obtain a residue. Ethyl acetate was added to the residue to dissolve, and aqueous solution was added to extract 3 times. The combined organic layers were washed with saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 10: 3). White solid compound P2 (3.228 g, yield 91.19%) was obtained.

[0045] Compound P2 was tested and the test results were as follows: mp 97.5-100; IR (KBr) νmax 3276.2, 2836.9, 1660.39, 1510.52, 1416.71, 1237.55, 827.38 cm -1 ; 1 H NMR(400MHz,Chloroform-d)δ7.53–7.44(m,2H),7.45(s,1H),6.90–6.82(m,2H),6.41(dd,J =16.8,1.4Hz,1H),6.24(dd,J=16.8,10.2Hz,1H),5.73(dd,J=10.1,1.4Hz,1H),3.79(s,3H). 13 C NMR(101MHz,Chloroform-d)δ163.47,156.58,131.21,130.85,127.39,121.83,114.18,55.48.HRMS(ESI)m / z calcd for C 10 H 11 NO2 + [M + H] + 178.08626, found 178.08618.

[0046] (3) Preparation of Compound P3

[0047] Compound P2 (3.228 g, 18.24 mmol) was added to 180 mL THF while stirring, and then ethyl acetoacetate (3.078 mL, 27 mmol) was added to the mixture. Potassium tert-butoxide (1.01 g, 9 mmol) was then added to the mixture, and the mixture was heated to 60 ° C and reacted overnight. The reaction was then quenched with water and extracted with ethyl acetate 3 times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 3: 2) gave a light yellow liquid compound P3 (2.1126 g, yield 38.23%).

[0048] Compound P3 was tested and the test results were as follows: IR (KBr) νmax 3301.28, 2937.12, 2836.17, 1734.82, 1713.04, 1602.73, 1511.95, 1412.53, 1244.7, 1033.08, 830.45 cm -1 ; 1 HNMR(400MHz,DMSO-d6)δ9.75(s,0H),7.47(d,J=9.0Hz,1H),6.89–6.83(m,1H),4.13(qd,J=7.1,1.2Hz,1H),3.71 (s,1H),3.67(dd,J=7.9,6.5Hz,0H),2.28(t,J=7.5Hz,1H),2.20(s,1H),2.10–1.92(m,1H),1.19(t,J=7.1Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ171.29,167.59,159.25,149.04,130.51,129.93,121.75,121.68,114.62,114 .17,108.58,61.61,60.36,58.19,55.50,55.47,34.29,31.66,29.27,23.62,21.37,18.51,14.35,14.09.HRM S(ESI)m / z calcd for C 16 H 21 NO5 + [M + H] + 308.14925, found 308.14944.

[0049] (4) Preparation of Compound P4

[0050] 3 mL of methanol was added to compound P3 (114 mg, 0.371 mmol) while stirring, and compound P1 (79 mg, 0.414 mmol) was added to the mixture. Concentrated hydrochloric acid (61 μL, 0.74 mmol) was then added to the mixture. After reflux at 70°C for 6 hours, the mixture was concentrated to remove methanol to obtain a residue, which was redissolved in ethyl acetate and added with water, and extracted 3 times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 1: 4) gave white solid compound P4 (21.9 mg, yield 13.6%).

[0051] Compound P4 was tested and the test results were as follows: mP 230-234; IR (KBr) νmax 3356.7, 3233.5, 1645.3, 1511.35, 1240.7, 1025.8, 829.85, 621.25 cm -1 ; 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),9.76(s,1H),8.03–7.96(m,2H),7.75(s,1H),7.52–7.4 1(m,4H),7.39–7.30(m,1H),6.90–6.81(m,2H),3.70(s,3H),2.59–2.51(m,2H),2.22(s,3H). 13 C NMR(101MHz,DMSO-d6)δ170.56,162.51,155.49,153.32,150.41,149.38,134.35,132.93,12 9.15,128.50,126.39,121.06,114.26,108.98,103.61,55.60,35.68,18.22,11.24.HRMS(ES I)m / z calcd for C 23 H 22 N4O3S + [M + H] + 435.14854, found 435.14868.

[0052] Example 2

[0053] A thiazole compound (Compound P8), the preparation method of which comprises the following steps:

[0054] (1) Preparation of compound P5

[0055] 2-Bromoethanol (3.00 mL, 42.3 mmol) was added to 40 mL DMF while stirring, followed by the addition of TBDPSC 1 (11.6 mL, 44.6 mmol) and imidazole (4.32 g, 63.5 mmol) and the reaction was quenched with water at 25 ° C for 3 hours. Ethyl acetate was added and extracted 3 times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether) gave a colorless liquid compound P5 (12.95 g, yield 84.24%).

[0056] Compound P5 was tested, and the test results were as follows: IR (KBr) νmax 3067.6, 2934.9, 2855.18, 1591.6, 1471.5, 1426.35, 1357.7, 1281.8, 1187, 1104.03, 946.8, 886.74, 821.69, 732.9, 699.24, 611.43, 503.78 cm -1 ; 1 H NMR (400MHz, Chloroform-d) δ7.68–7.66(m,4H),7.42–7.38(m,6H),3.92(t,J=6.4Hz,2H),3.42(t,J=6.4Hz,2H),1.07(s,9H). 13 C NMR (101MH z, Chloroform-d) δ 135.60, 133.27, 129.86, 127.79, 64.01, 33.18, 26.79, 19.28.

[0057] (2) Preparation of Compound P6

[0058] K2CO3 (1.04 g, 7.5 mmol) was added to a round-bottom flask, and 2 mL of anhydrous ethanol was added to the round-bottom flask while stirring. Then ethyl acetoacetate (860 μL, 5 mmol) was added to the mixture and heated to 90°C. Compound P5 (1.02 g, 2.75 mol) was dissolved in 3 mL of anhydrous ethanol and slowly added dropwise to the round-bottom flask and reacted overnight. After the reaction was complete, the pH value of the mixture was adjusted to 6, filtered and the liquid was concentrated. Ethyl acetate was added and extracted 3 times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 35:2) gave a colorless liquid compound P6 (886.5 mg, yield 24.3%).

[0059] Compound P6 was tested and the test results were as follows: IR (KBr) νmax 3070.8, 2931.09, 2856.9, 1714.55, 1471.83, 1427.21, 1359.67, 1245.76, 1110.73, 822.2, 739.85, 700.85, 614.07, 503.82 cm -1 ; 1 H NMR(400MHz,Chloroform-d)δ7.63(dt,J=6.5,1.6Hz,4H),7.43–7.37(m,6H),4.17(qd,J=7.2,5.0Hz,2H),3.78( t,J=7.1Hz,1H),3.67(td,J=5.9,1.7Hz,2H),2.24(s,3H),2.13–2.09(m,2H),1.25(t,J=7.2Hz,3H),1.04(s,9H). 13 C NMR(101MHz,Chloroform-d)δ203.24,169.76,135.59,135.56,135.54,135.52,134.82,133.45,12 9.74,127.74,127.72,61.39,56.27,30.80,29.26,26.83,26.58,19.20,14.08.HRMS(ESI)m / zcalcd for C 24 H 32 O4Si + [M + H] + 413.21426, found 413.21439.

[0060] (3) Preparation of Compound P7

[0061] The prepared compound P1 (85.8 mg, 0.45 mmol) was added to the compound P6 (123.5 mg, 0.3 mmol) while stirring, and then 0.6 mL of glacial acetic acid was added, and then heated to 80 ° C for 24 hours. Next, the solution was concentrated under reduced pressure to remove the acid to obtain a residue. Ethyl acetate was added and extracted 3 times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 5: 1) gave a white solid compound P7 (52.7 mg, yield 32.55%).

[0062] Compound P7 was detected, and the detection results were as follows: mP 165-167; IR (KBr) νmax 3070.8, 2928.5, 2854.87, 1634.52, 1518.921426.98, 1360.8, 1256.5, 1111.54, 1025.8, 918.35y, 820.37, 701.70, 618.09, 504.74cm -1 ; 1 H NMR(400MHz,Chloroform-d)δ9.06(s,1H),7.80(s,2H),7.66–7.59(m,4H),7.46–7.30( m,9H),7.14(s,1H),3.81(t,J=6.7Hz,2H),2.60(s,2H),2.14–2.06(m,3H),1.04(s,9H). 13 C NMR(101MHz,Chloroform-d)δ135.57,133.80,129.58,128.87,127.61,126.08,26.92,25.40,19.18.HRMS(ESI)m / z calcd forC 31 H 33 N3O2SiS + [M + H] + 540.21355, found 540.21381.

[0063] (4) Preparation of Compound P8

[0064] Solution A: Compound P7 (3.25 g, 6.03 mmol) was added to 350 mL of methanol while stirring to obtain solution A. Solution B: 75 mL of anhydrous methanol was added to 13 mL of concentrated hydrochloric acid while stirring to obtain solution B. Solution B was added to solution A while stirring and reacted at 25°C for 3.5 hours. Then concentrated to remove methanol to obtain a residue. Dichloromethane was added and extracted 3 times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography purification (dichloromethane: methanol = 30: 1) gave white solid compound P8 (881.36 mg, yield 45.56%).

[0065] Compound P8 was detected, and the detection results were as follows: mP 188-189; IR (KBr) νmax 2862.2, 1626.49, 1497.69, 1442.76, 1330.11, 1243.9, 1108, 1057.58, 839.33, 772.96, 720.22, 667.47, 573.84 cm-1 ; 1 H NMR(400MHz,Chloroform-d)δ7.82–7.75(m,2H),7.46–7.39(m,2H),7.39–7.31 (m,1H),7.18(s,1H),3.85(t,J=5.9Hz,2H),2.59(t,J=5.8Hz,2H),2.19(s,3H). 13 C NMR(101MHz,Chloroform-d)δ128.86,128.52,126.12,61.87,26.09.HRMS(ESI)m / zcalcd for C 15 H 15 N3O2S + [M + H] + 302.09577, found 302.09558.

[0066] Example 3

[0067] Thiazole compounds (compounds P9-P21), the preparation methods thereof are as follows:

[0068] (1) Preparation of compound P9

[0069] Compound P8 (100 mg, 0.332 mmol), DIC (250 μL, 1.99 mmol) and DMAP (60.8 mg, 0.5 mmol) were added to 615 μL DMF while stirring, and then benzoic acid (324.6 mg, 2.66 mmol) was added. After the mixture was stirred at 40°C overnight, the reaction was quenched with water, and then extracted with ethyl acetate three times. The organic phases were combined and washed with saturated brine, then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 15: 1) gave white solid compound P9 (41.5 mg, yield 19.8%).

[0070] Compound P9 was tested, and the test results are as follows: 1H NMR(400MHz,Chloroform-d)δ8.28–8.21(m,2H),8.05–7.98(m,2H),7.79–7.70(m,1H),7.59–7.50(m,3H),7.41(dd,J=8.4,7.1 Hz,2H),7.26–7.19(m,2H),7.16–7.07(m,2H),6.97(t,J=7.7Hz,2H),4.48(t,J=6.8Hz,2H),2.92(t,J=6.8Hz,2H),2.38(s,3H).

[0071] (2) Preparation of compound P10

[0072] Compound P8 (150 mg, 0.5 mmol), DIC (375 μL, 3 mmol) and DMAP (91.6 mg, 0.75 mmol) were added to 1.3 mL DMF while stirring, and then 4-fluorobenzoic acid (560.4 mg, 4 mmol) was added. After the mixture was stirred at 40°C overnight, the reaction was quenched with water, and then extracted with dichloromethane 3 times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: dichloromethane = 1: 1) gave white solid compound P10 (25 mg, yield 7.3%).

[0073] Compound P10 was detected and the results were as follows: mp 181-183; IR (KBr) νmax 2923.2, 2850.5, 1754.7, 1720, 1600, 1536.8, 1502.1, 1240, 1044.2, 854.74, 763.16, 671.58 cm -1 ; 1 HNMR(400MHz,DMSO-d6)δ8.25–8.16(m,2H),8.00–7.91(m,2H),7.82(s,1H),7.49(t,J=8.8Hz,2H),7.31(t,J=8.8Hz,2H), 7.29–7.23(m,2H),7.19(t,J=7.4Hz,1H),7.02(t,J=7.6Hz,2H),4.43(t,J=6.3Hz,2H),2.92(t,J=6.3Hz,2H),2.33(s,3H). 13C NMR(101MHz,DMSO-d6)δ165.25,162.76,159.33,151.76,151.45,142.49,134.20,134.10,133.68,132.51,13 2.42,128.70,128.51,125.78,124.59,116.95,116.73,116.38,116.16,110.82,108.97,64.13,21.72,13.10. 19 F NMR(377MHz,DMSO-d6)δ-103.21,-105.82,-220.51.HRMS(ESI)m / z calcd for C 29 H 21 F2N3O4S + [M + H] + 546.12936, found 546.12903.

[0074] (3) Preparation of compound P11

[0075] Compound P8 (150 mg, 0.5 mmol), DIC (375 μL, 3 mmol) and DMAP (91.6 mg, 0.75 mmol) were added to 1.3 mL DMF while stirring, and then 4-chlorobenzoic acid (626.6 mg, 4 mmol) was added. After the mixture was stirred at 40°C overnight, the reaction was quenched with water, and then extracted with dichloromethane 3 times. The organic phases were combined and washed with saturated brine, then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: dichloromethane = 5: 1) gave a white solid compound P11 (11.6 mg, yield 5.28%).

[0076] Compound P11 was tested, and the test results are as follows: 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),8.34(d,J=8.5Hz,2H),8.19(d,J=8.5Hz,2H),8.00(d,J=7.7Hz,2H),7.76 (s,1H),7.45(t,J=7.6Hz,2H),7.35(t,J=7.4Hz,1H),4.43(t,J=6.7Hz,2H),2.74(t,J=6.6Hz,2H),2.26(s,3H).

[0077] (4) Preparation of Compound P12

[0078] Compound P8 (150 mg, 0.5 mmol), DIC (375 μL, 3 mmol) and DMAP (91.6 mg, 0.75 mmol) were added to 1.3 mL DMF while stirring, and then 4-iodobenzoic acid (992.1 mg, 4 mmol) was added. After the mixture was stirred at 40 ° C overnight, the reaction was quenched with water, and then extracted with dichloromethane 3 times. The organic phases were combined and washed with saturated brine, then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: dichloromethane = 3: 2) gave a white solid compound P12 (12.6 mg, yield 3.31%).

[0079] Compound P12 was tested, and the test results are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.02(d,J=8.0Hz,2H),7.85(d,J=8.1Hz,2H),7.83–7.76(m,3H),7.62(d,J=8.0Hz,2 H), 7.19 (d, J = 7.5Hz, 3H), 7.01 (t, J = 7.6Hz, 2H), 4.42 (t, J = 6.2Hz, 2H), 2.90 (t, J = 6.3Hz, 2H), 2.32 (s, 3H).

[0080] (5) Preparation of Compound P13

[0081] Compound P8 (150 mg, 0.5 mmol), DIC (375 μL, 3 mmol) and DMAP (91.6 mg, 0.75 mmol) were added to 1.6 mL DMF while stirring, and then 4-nitrobenzoic acid (668.5 mg, 4 mmol) was added. After the mixture was stirred at 40 ° C overnight, the reaction was quenched with water, and then extracted with dichloromethane 3 times. The organic phases were combined and washed with saturated brine, then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: dichloromethane = 3: 2) gave white solid compound P13 (80.8 mg, yield 21.1%).

[0082] Compound P13 was detected, and the detection results were as follows: mp 183-186; IR (KBr) νmax 2919, 2852.7, 1715.73, 1538.55, 1389.3, 1272.3, 1237.6, 1089, 1013.2, 845.65, 747.67, 681.3 cm -1 ; 1H NMR(400MHz,DMSO-d6)δ8.14–8.06(m,2H),7.92–7.85(m,2H),7.83(s,1H),7.74–7.68(m,2H),7 .57–7.51(m,2H),7.26–6.95(m,5H),4.44(t,J=6.3Hz,2H),2.92(t,J=6.3Hz,2H),2.33(s,3H). 13 C NMR(101MHz,DMSO-d6)δ165.37,162.96,159.34,151.75,151.48,142.42,140.45,138.81,132.83,13 1.42,129.81,129.35,128.85,128.64,128.52,126.82,125.78,110.88,109.01,64.30,21.69,13.11.

[0083] (6) Preparation of Compound P14

[0084] Compound P8 (150 mg, 0.5 mmol), DIC (375 μL, 3 mmol) and DMAP (91.6 mg, 0.75 mmol) were added to 1.0 mL DMF while stirring, and then 4-methoxybenzoic acid (608.4 mg, 4 mmol) was added. After the mixture was stirred at 40°C overnight, the reaction was quenched with water, and then extracted with ethyl acetate three times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 10: 1) gave white solid compound P14 (8.6 mg, yield 3.02%).

[0085] Compound P14 was tested, and the test results are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.11–8.04(m,2H),7.93–7.83(m,2H),7.81(s,1H),7.31–7.24(m,2H),7.23–7.11(m,3H), 7.00(dt,J=7.9,3.2Hz,4H),4.38(t,J=6.4Hz,2H),3.94(s,3H),3.82(s,3H),2.87(t,J=6.3Hz,2H),2.32(s,3H).

[0086] (7) Preparation of Compound P15

[0087] Compound P8 (150 mg, 0.5 mmol), DIC (375 μL, 3 mmol) and DMAP (91.6 mg, 0.75 mmol) were added to 1.0 mL DMF while stirring, and then 3-(trifluoromethyl)benzoic acid (761.5 mg, 4 mmol) was added. After the mixture was stirred at 40°C overnight, the reaction was quenched with water, and then extracted with ethyl acetate three times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 30: 1) gave white solid compound P15 (6.8 mg, yield 2.11%).

[0088] Compound P15 was detected and the results were as follows: mp 128-131; IR (KBr) νmax 2922.2, 2855.8, 1771.7, 1721.2, 1613.7, 1537.8, 1386.1, 1334.55, 1251.21, 1168, 1130.1, 1073.2, 975.24, 915.19, 823.53, 754, 693.94, 652.85 cm -1 ; 1 H NMR(400MHz,DMSO-d6)δ8.36(dt,J=7.9,1.5Hz,1H),8.29–8.20(m,2H),8.14 (dd,J=7.9,1.5Hz,1H),8.07(d,J=1.9Hz,1H),7.98(ddd,J=8.6,1.9,0.9Hz,1 H),7.91–7.83(m,1H),7.82(s,1H),7.70(t,J=7.8Hz,1H),7.20–7.10(m,3H), 6.98–6.90(m,2H),4.52(t,J=6.1Hz,2H),2.99(t,J=6.2Hz,2H),2.36(s,3H). 13 C NMR(101MHz,DMSO-d6)δ164.93,162.59,151.71,151.54,142.18,134.75,133.63,133.50,131.81,131.21,13 1.03,130.57,130.28,128.99,128.63,128.44,126.91,125.75,125.61,110.93,109.06,64.50,21.65,13.09. 19F NMR(377MHz, DMSO-d6)δ-61.34(d,J=12.5Hz),-61.58(d,J=9.2Hz).HRMS(ESI)m / z calcd for C 31 H 21 F6N3O4S + [M + H] + 646.12297, found 646.12238.

[0089] (8) Preparation of Compound P16

[0090] Compound P8 (150 mg, 0.5 mmol), DIC (375 μL, 3 mmol) and DMAP (91.6 mg, 0.75 mmol) were added to 0.5 mL DMF while stirring, and then propionic acid (300 μL, 4 mmol) was added. After the mixture was stirred at 40°C overnight, the reaction was quenched with water, and then extracted with ethyl acetate three times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 2: 1) gave a white solid compound P1 (12 mg, yield 6.72%).

[0091] Compound P16 was tested, and the test results are as follows: 1 H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.03–7.91(m,2H),7.75(s,1H),7.48–7.33(m,3H),4.11(t ,J=7.1Hz,2H),2.55(t,J=6.4Hz,2H),2.30(q,J=7.5Hz,2H),2.23(s,3H),1.00(d,J=7.5Hz,3H).

[0092] (9) Preparation of Compound P17

[0093] Compound P8 (150 mg, 0.5 mmol), DIC (375 μL, 3 mmol) and DMAP (91.6 mg, 0.75 mmol) were added to 0.5 mL DMF while stirring, and then 5-fluoropicolinic acid (564.1 mg, 4 mmol) was added. After the mixture was stirred at 40°C overnight, the reaction was quenched with water, and then extracted with dichloromethane three times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (dichloromethane: methanol = 10: 1) gave white solid compound P17 (9.8 mg, yield 4.62%).

[0094] Compound P17 was tested, and the test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.58(d,J=2.8Hz,1H),8.19(dd,J=8.7,4.5Hz,1H),7.80–7.73(m,2H),7.52(ddd,J =8.7,7.9,2.8Hz,1H),7.46–7.31(m,3H),7.15(s,1H),4.54(t,J=7.0Hz,2H),2.87(t,J=7.2Hz,2H),2.24(s,3H).

[0095] (10) Preparation of Compound P18

[0096] Compound P8 (150 mg, 0.5 mmol), DIC (375 μL, 3 mmol) and DMAP (91.6 mg, 0.75 mmol) were added to 0.5 mL DMF while stirring, and then 5-(trifluoromethyl)picolinic acid (764.1 mg, 4 mmol) was added. After the mixture was stirred at 40°C overnight, the reaction was quenched with water, and then extracted with ethyl acetate three times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 3:2) gave white solid compound P18 (14.2 mg, yield 5.99%).

[0097] Compound P18 was tested, and the test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ9.03–8.98(m,1H),8.27(d,J=8.1Hz,1H),8.10(dd,J=8.3,2.2Hz,1H),7.81–7.75(m, 2H),7.47–7.37(m,2H),7.41–7.32(m,1H),7.16(s,1H),4.59(t,J=6.9Hz,2H),2.90(t,J=6.9Hz,2H),2.27(s,3H).

[0098] (11) Preparation of compound P19

[0099] Compound P8 (150 mg, 0.5 mmol), DIC (375 μL, 3 mmol) and DMAP (91.6 mg, 0.75 mmol) were added to 0.5 mL DMF while stirring, and then cyclopropanecarboxylic acid (344.2 mg, 4 mmol) was added. After the mixture was stirred at 40 ° C overnight, the reaction was quenched with water, and then extracted with ethyl acetate 3 times. The organic phases were combined and washed with saturated brine, then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 3: 2) gave a white solid compound P19 (12.8 mg, yield 5.86%).

[0100] Compound P19 was tested, and the test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.78(d,J=7.0Hz,2H),7.43–7.37(m,3H),7.13(s,1H),4.21(d,J=6.9 Hz,2H),2.68(d,J=13.8Hz,2H),2.24(dd,J=17.7,9.3Hz,5H),1.70–1.11(m,2H),1.09–0.66(m,6H).

[0101] (12) Preparation of Compound P20

[0102] Compound P8 (150 mg, 0.5 mmol), DIC (375 μL, 3 mmol) and DMAP (91.6 mg, 0.75 mmol) were added to 0.5 mL DMF while stirring, and then 4-(trifluoromethyl)benzoic acid (760 mg, 4 mmol) was added. After the mixture was stirred at 40°C overnight, the reaction was quenched with water, and then extracted with ethyl acetate three times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 8: 1) gave a white solid compound P20 (16.4 mg, yield 5.08%).

[0103] Compound P20 was detected and the results were as follows: mp 172-175; IR (KBr) νmax 1759, 1724.3, 1537.8, 1411.4, 1328.09, 1278.7, 1174.4, 1130.2, 1067, 1019.5, 867.78, 776.12, 693.94, 589.64 cm -1 ; 1H NMR(400MHz,Chloroform-d)δ8.32–8.26(m,2H),8.09(dt,J=7.8,1.0Hz,2H),7.80–7.73(m,2H),7.72–7.6 2(m,2H),7.17–7.08(m,4H),7.00–6.91(m,2H),4.52(t,J=6.7Hz,2H),2.94(t,J=6.8Hz,2H),2.39(s,3H). 13 C NMR(101MHz,Chloroform-d)δ165.27,159.42,152.68,150.75,142.25,133.63,131.38,130.04,128.1 8,128.01,125.78,125.57,125.42,125.38,108.54,107.95,64.03,22.10,13.10.HRMS(ESI)m / zcalcd for C 31 H 21 F6N3O4S + [M + H] + 646.12297, found 646.12280.

[0104] (13) Preparation of Compound P21

[0105] Compound P8 (150 mg, 0.5 mmol), DIC (375 μL, 3 mmol) and DMAP (91.6 mg, 0.75 mmol) were added to 0.5 mL DMF while stirring, and then pivalic acid (408 mg, 4 mmol) was added. After the mixture was stirred at 40°C overnight, the reaction was quenched with water, and then extracted with ethyl acetate three times. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 8: 1) gave white solid compound P21 (13.7 mg, yield 7.11%).

[0106] Compound P21 was tested, and the test results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.94–7.71(m,2H),7.40(ddd,J=26.0,16.9,7.1Hz,3H),7.13(s, 1H), 4.20 (t, J=7.0Hz, 2H), 2.69 (dt, J=18.4, 7.1Hz, 2H), 2.27–2.19 (m, 3H), 1.26–1.12 (m, 9H).

[0107] Effect Experiment

[0108] (1) LSD1 enzymatic assay of compound P4 and compounds P8-P21

[0109] Based on a multi-step enzymatic reaction, the characteristic of LSD1 that H2O2 is produced during the demethylation of peptide lysine 4 corresponding to the first 21 amino acids of the N-terminal tail of histone H3 is utilized. In the presence of horseradish peroxidase (HRP), H2O2 can be used to react with ADHP (10-acetyl-3,7-dihydroxybenzoxazine) to generate a highly fluorescent compound resorcinol. When the excitation wavelength is 530nm-540nm and the emission wavelength is 585nm-595nm, the LSD1 enzymatic inhibition ability of the compound can be easily detected by analyzing the fluorescence of resorcinol. Example The Cayman LSD1 Inhibitor Screening Assay Kit (No.700120) was used for detection, and the fluorescence readings (λex=535nm; λem=590nm) were recorded by the TECAN SPARK Multifunctional Microplate Reader. The data were analyzed using GraphPad Prism version 9.0 software, IC 50 The values ​​represent three independent replicates ± standard deviation; the results are shown in Table 1.

[0110] Table 1

[0111]

[0112]

[0113] As shown in Table 1, the control positive drug SP-2577 exhibits strong in vitro enzymatic inhibition activity of LSD1. The compound designed and synthesized by the present invention has a different structure from SP-2577, but exhibits the same potential IC 50 Compared with the positive drugs, compounds P4, P10, P14 and P20 (di-esterification products of P4 and P8 with p-fluorobenzoic acid, p-trifluoromethylbenzoic acid and p-methoxybenzoic acid) showed stronger activity than the positive drugs.

[0114] (2) Cell proliferation inhibitory activity test of compound P4 and compounds P8-P21

[0115] The cell proliferation inhibitory activity of compound P4 and compounds P8-P21 was detected by CCK-8 method, specifically:

[0116] Human colorectal cancer cells such as HCT-116 and Lovo were inoculated in 96-well plates with 1000 cells per well and treated with different concentrations of inhibitors in culture medium for 72 hours. Cell viability was determined using a CCK8 kit (Biyuntian) according to the manufacturer's instructions. The results of the CCK8 activity test are shown in Table 2.

[0117] Table 2

[0118] Compound <![CDATA[HCT-116 inhibitory activity (μM) IC 50 > <![CDATA[Lovo inhibitory activity (μM) IC 50 > SP-2577 1.69 1.45 P4 1.44 1.02 P8 1.31 1.89 P9 1.56 1.43 P10 0.45 0.66 P11 2.06 1.77 P12 1.32 1.23 P13 1.44 1.61 P14 1.45 1.67 P15 2.01 1.11 P16 3.12 1.56 P17 1.78 1.32 P18 2.33 1.34 P19 5.73 3.11 P20 0.64 0.53 P21 2.32 3.21

[0119] As can be seen from Table 2, although the positive drugs have strong in vitro enzymatic inhibitory activity, they show weaker activity in cells than the compounds in this batch. Compounds P10 and P20 show strong activity in inhibiting the proliferation of colorectal cancer cells.

[0120] (3) Animal subcutaneous tumor bearing experiments with compounds P10 and P20

[0121] Select 6-8 week old Balb / c-Nude mice and inject subcutaneously with 1*10 6 HCT-116 cells. After about 7 days of subcutaneous growth, the tumor tissue became hard and the average volume reached 100mm 3 And random grouping. In this example, four groups were set up, each with 6 mice; they were divided into a control group, a positive drug group SP-2577 (gavage, 50 mg / kg, once a day), and compound P10 and P20 groups (gavage, 50 mg / kg, once a day). The tumor volume and mouse weight were measured every other day, and the mouse tumor was dissected after 21 days of drug administration. The results are shown in Table 3.

[0122] Table 3

[0123] Grouping Average tumor inhibition rate / % SP-2577 68 Compound P10 92 Compound P20 95

[0124] As shown in Table 3, the average tumor inhibition rate of mice treated with the control drug SP-2577 was 68%, while the tumor inhibition rates of the tumor-bearing mice treated with compounds P10 and P20 were 92% and 95%, respectively, both better than the control group and having good development prospects.

[0125] The above is only a preferred embodiment of the present invention. The present invention is not limited to the above implementation. As long as the technical effect of the present invention is achieved by the same means, it should belong to the protection scope of the present invention. Within the protection scope of the present invention, its technical scheme and / or implementation method can have various modifications and changes.

Claims

1. A thiazole compound, characterized in that: Its structure is shown in Formula I: Wherein, R1 and R2 are independently selected from one of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

2. The thiazole compound according to claim 1, characterized in that Its structure is any one of compound P4 and compound P8-P21:

3. A method for preparing the thiazole compound according to claim 2, characterized in that: The preparation method includes route 1 or route 2, and route 1 is as follows: The second route is as follows:

4. The preparation method according to claim 3, characterized in that: The route 1 comprises the following steps: (1) dichloromethane (DCM) and p-anisidine are mixed, and triethylamine (TEA) is added under stirring to obtain solution A; acryloyl chloride is mixed with dichloromethane to obtain solution B; solution B is added dropwise to solution A at -40°C to 35°C, and then stirred for 2h to 24h; dichloromethane is removed by concentration to obtain a residue, and then dichloromethane or ethyl acetate is added to dissolve, and water is added to extract 1-5 times, the organic phases are combined, washed, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated, and purified by column chromatography to obtain compound P2; (2) Under stirring, the compound P2 is added to THF, and then ethyl acetoacetate and potassium tert-butoxide are added in sequence, and the reaction is carried out at 40° C.-80° C. for 4 h-24 h; the reaction is then quenched with water, extracted with ethyl acetate or dichloromethane 2-5 times, the organic phases are combined, washed, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated, and purified by column chromatography to obtain compound P3; (3) Mixing the alcohol and the compound P3 under stirring, then adding the compound P1 and concentrated hydrochloric acid or glacial acetic acid in sequence, and reflux at 60° C.-90° C. for 3 h-24 h; concentrating to remove the alcohol to obtain a residue, then re-dissolving it in ethyl acetate or dichloromethane and extracting it with water for 2-5 times, combining the organic phases, washing, adding anhydrous sodium sulfate to dry, filtering and concentrating the filtrate, and purifying it by column chromatography to obtain the compound P4; The preparation process of the compound P1 includes the following steps: mixing alcohol and 2-bromo-1-phenylethanone under stirring, then adding hydrazinethioamide, and heating at 40°C-80°C for 2h-12h; then concentrating to remove the alcohol, dissolving with water, filtering to obtain a filtrate, adjusting the pH of the filtrate to 8-12, filtering to separate the solid, dissolving the solid with alcohol, heating at 30°C-80°C to obtain a saturated solution, filtering while hot, and crystallizing the filtrate to obtain the compound P1, i.e. 2-hydrazino-4-phenylthiazole.

5. The preparation method according to claim 4, characterized in that: The second route comprises the following steps: (1) Mix 2-bromoethanol or 2-chloroethanol with DMF under stirring, then add TBDPSC1 (tert-butyldiphenylsilyl chloride) and imidazole, react at 20° C.-30° C. for 1 h-10 h, and then quench the reaction with water; then add ethyl acetate or dichloromethane to extract 2-5 times, combine the organic phases, wash, add anhydrous sodium sulfate to dry, filter and concentrate the filtrate, and purify by column chromatography to obtain compound P5; (2) K2CO3, sodium ethoxide or sodium methoxide and ethanol or methanol are mixed under stirring, and then ethyl acetoacetate is added to obtain a mixture, and when the mixture is heated to 60°C-90°C, ethanol or methanol in which the compound P5 is dissolved is added dropwise to the mixture for reaction for 2h-14h, and then the pH is adjusted to 6, filtered, and the filtrate is concentrated, and then ethyl acetate or dichloromethane is added for extraction 2-5 times, the organic phases are combined, washed, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated, and purified by column chromatography to obtain compound P6; (3) Mixing the compound P1 and the compound P6 under stirring, then adding glacial acetic acid or hydrochloric acid, reacting at 60° C.-90° C. for 2 h-24 h, concentrating under reduced pressure to remove the acid to obtain a residue, then adding ethyl acetate or dichloromethane to extract 2-5 times, combining the organic phases, washing, adding anhydrous sodium sulfate to dry, filtering and concentrating the filtrate, and purifying by column chromatography to obtain compound P7; (4) Under stirring, the compound P7 is mixed with methanol to obtain a solution C; under stirring, methanol is mixed with concentrated hydrochloric acid to obtain a solution D; under stirring, the solution D is added to the solution C, reacted for 2h-6h, then concentrated to remove methanol to obtain a residue, ethyl acetate or dichloromethane is added to extract 2-5 times, the organic phases are combined, washed, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated, and purified by column chromatography to obtain compound P8; (5) Under stirring, the compound P8, DIC (N,N'-diisopropylcarbodiimide) and DMAP (4-dimethylaminopyridine) are added to a DMF solution, and then an organic acid is added. The reaction is carried out at 25°C-60°C for 2h-16h, and the reaction is quenched with water. The mixture is then extracted with dichloromethane or ethyl acetate for 2-5 times. The organic phases are combined, washed, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The mixture is purified by column chromatography to obtain compounds P9-P21.

6. A pharmaceutical composition comprising the thiazole compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2.

7. Use of the thiazole compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 or the pharmaceutical composition according to claim 6 for preparing an LSD1 inhibitor.

8. Use of the thiazole compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating and / or preventing cancer.

9. The use according to claim 8, characterized in that The cancer is a cancer in which LSD1 is abnormally expressed in cells.

10. The use according to claim 8 or 9, characterized in that The cancer is lung cancer, gastric cancer, colorectal cancer, bladder cancer, esophageal cancer, prostate cancer, liver cancer, glioma or acute myeloid leukemia.

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