A thiazole compound, its preparation method, pharmaceutical composition and uses

Abstract

This invention belongs to the field of chemical pharmaceuticals, specifically relating to a thiazole compound, its preparation method, pharmaceutical composition, and uses. The structure of this thiazole compound is shown in Formula I, wherein R1 and R2 are independently selected from one of the following: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. The thiazole compound proposed in this invention can inhibit LSD1 protease activity and simultaneously possesses low toxicity, high efficiency, high selectivity, and minimal off-target effects.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical drugs, and particularly relates to a thiazole compound, a preparation method, a pharmaceutical composition and a use thereof. BACKGROUND

[0002] Cancer is a major public health problem worldwide and one of the leading causes of death. Ordinary chemotherapy drugs not only target cancer cells, but also kill normal cells while killing cancer cells. In addition, the cytotoxicity of traditional therapy, chemotherapy and radiotherapy can cause serious side effects. This is why most current research is focused on developing targeted therapy, which can kill or stop the growth of cancer cells.

[0003] LSD1 uses a non-covalently bound FAD cofactor (which requires a pair of lone pair electrons in the substrate) as an enzyme that can demethylate monomethylated and dimethylated histone 3 lysine 4 (H3K4me1, H3K9me2) and histone 3 lysine 9 (H3K9me1, H3K9me2). LSD1 can also demethylate many proteins, which suggests that LSD1 has an impact on the function of downstream cells. Histone lysine methylation plays a crucial role in chromatin remodeling and gene expression. Overexpression of LSD1 has been found in a variety of cancers. In some animal experiments, small molecule inhibitors inhibited the expression of LSD1, which can effectively inhibit the proliferation, differentiation, invasion and metastasis of cancer cells. Thus it can prevent the growth of tumors, which suggests that LSD1 small molecule inhibitors have the potential to become a new method for treating cancer.

[0004] In recent years, a number of LSD1 inhibitors have been developed and have begun clinical trials. The first LSD1 inhibitor developed was an irreversible inhibitor containing a monoamine oxidase structure (e.g., the irreversible inhibitor tranylcypromine, TCP). TCP is a non-specific inhibitor of LSD1, which can covalently bind to the FAD cofactor in LSD1, thereby inhibiting its demethylase activity. Although TCP demonstrated the therapeutic potential of LSD1 inhibition, its non-selective inhibition of other FAD-dependent enzymes such as monoamine oxidases MAO A and B posed serious safety problems, 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 it to enhance its binding affinity and selectivity for LSD1, acting only on LSD1 without affecting other enzymes. Many LSD1 inhibitors have been developed and entered clinical trials, and several LSD1 inhibitors, including ORY-1001, GSK2879552, and INCB059872, have entered phase I and II clinical trials to evaluate their safety, tolerability, and efficacy in various cancer patients. Early clinical data showed encouraging results in hematological malignancies such as acute myeloid leukemia (AML) and chronic myelogenous leukemia (SCLC), indicating that LSD1 plays an important role in the regulation of gene expression in these diseases.

[0005] In addition to oncology, researchers are investigating the potential application of LSD1 inhibitors in non-cancer diseases, including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In these diseases, epigenetic disorders play an important role. These new directions may extend the application of LSD1 inhibitors beyond cancer treatment. Currently, although no LSD1 inhibitor has 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 potential is crucial for the prevention and treatment of cancer and non-cancer diseases. SUMMARY

[0006] The purpose of the present application is to solve the problems of the prior art, and the first aspect of the present application is to provide a thiazole compound having the effect of inhibiting the activity of LSD1 proteinase with low toxicity, high efficiency, high selectivity, and low off-target potential, which has the structure 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 above-mentioned thiazole compound is as any one of compound P4, compound P8-P21:

[0010]

[0011] Among them, compound P4, compound P10, compound P14 and compound P20 (the p-fluorobenzoic acid, p-trifluoromethylbenzoic acid, p-methoxybenzoic acid double esterification product of compound P4 and compound P8) are particularly effective.

[0012] The second invention of the present application provides a preparation method of the above-mentioned thiazole compound, including route one or route two, and the above-mentioned route one is as follows:

[0013]

[0014] The above-mentioned route one includes the following steps:

[0015] (1) mixing dichloromethane (DCM) with p-anisidine, adding triethylamine (TEA) under stirring condition to obtain solution A; mixing acryloyl chloride with dichloromethane to obtain solution B; adding the solution B to the solution A dropwise under the condition of-40℃-35℃, and then stirring for 2h-24h; removing dichloromethane by concentration to obtain a residue, then dissolving in dichloromethane or ethyl acetate and extracting with water for 1-5 times, combining the organic phase, washing, adding anhydrous sodium sulfate for drying, filtering and concentrating the filtrate, and purifying by column chromatography to obtain compound P2;

[0016] (2) adding the compound P2 to THF under stirring condition, and then adding ethyl acetoacetate and potassium tert-butoxide in sequence, and reacting at 40℃-80℃ for 4h-24h; then quenching the reaction with water, extracting with ethyl acetate or dichloromethane for 2-5 times, combining the organic phase, washing, adding anhydrous sodium sulfate for drying, filtering and concentrating the filtrate, and purifying by column chromatography to obtain compound P3;

[0017] (3) mixing the alcohol with the compound P3 under stirring, then sequentially adding the compound P1 and concentrated hydrochloric acid or glacial acetic acid, refluxing at 60-90°C for 3-24h; removing the alcohol by concentration to obtain a residue, then redissolving the residue with ethyl acetate or dichloromethane and extracting with water for 2-5 times, combining the organic phases, washing, adding anhydrous sodium sulfate for drying, filtering and concentrating the filtrate, and purifying the concentrated filtrate by column chromatography to obtain the compound P4;

[0018] The preparation process of the compound P1 comprises the following steps: mixing an alcohol with 2-bromo-1-phenylethanone under stirring, then adding hydrazine sulfamide, and heating at 40-80°C for 2-12h; then removing the alcohol by concentration, 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 an alcohol, heating at 30-80°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 Two is as follows:

[0020]

[0021] The above Route Two comprises the following steps:

[0022] (1) mixing 2-bromoethanol or 2-chloroethanol with DMF under stirring, then adding TBDPSC1 (tert-butyldiphenylsilyl chloride) and imidazole, reacting at 20-30°C for 1-10h, then quenching the reaction with water; then extracting with ethyl acetate or dichloromethane for 2-5 times, combining the organic phases, washing, adding anhydrous sodium sulfate for drying, filtering and concentrating the filtrate, and purifying the concentrated filtrate by column chromatography to obtain the compound P5;

[0023] (2) mixing K2CO3, sodium ethoxide or sodium methoxide and ethanol or methanol under stirring, then adding ethyl acetoacetate to obtain a mixture, and heating to 60-90°C, then adding the ethanol or methanol dissolving the compound P5 dropwise into the mixture, reacting for 2-14h, then adjusting the pH to 6, filtering, concentrating the filtrate, then extracting with ethyl acetate or dichloromethane for 2-5 times, combining the organic phases, washing, adding anhydrous sodium sulfate for drying, filtering and concentrating the filtrate, and purifying the concentrated filtrate by column chromatography to obtain the compound P6;

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

[0025] (4) mixing the compound P7 with methanol under stirring to obtain solution C; mixing methanol with concentrated hydrochloric acid under stirring to obtain solution D; adding the solution D into the solution C under stirring, reacting for 2-6 hours, then removing methanol by concentration to obtain a residue, extracting with ethyl acetate or dichloromethane for 2-5 times, washing, drying with anhydrous sodium sulfate, filtering and concentrating the filtrate, and purifying by column chromatography to obtain compound P8;

[0026] (5) adding the compound P8, DIC (N,N'-diisopropyl carbodiimide) and DMAP (4-dimethylamino pyridine) into a DMF solution under stirring, then adding an organic acid, reacting at 25-60℃ for 2-16 hours, quenching the reaction with water, then extracting with dichloromethane or ethyl acetate for 2-5 times, washing, drying with anhydrous sodium sulfate, filtering and concentrating the filtrate, and purifying by column chromatography to obtain compounds P9-P21.

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

[0028] Based on the effect of the thiazole compound provided by the present application, the three aspects of the present application provide a pharmaceutical composition comprising the thiazole compound or pharmaceutically acceptable salt thereof. The above pharmaceutical composition can further comprise one or more pharmaceutically acceptable excipients, and the dosage form can be any pharmaceutically acceptable dosage form.

[0029] The thiazole compound provided by the present application or the pharmaceutical composition of the present application as an effective ingredient can be well applied to the preparation of LSD1 inhibitors, and used for the preparation of drugs for treating and preventing cancer, especially related cancer with 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 myelocytic leukemia, etc. Further, the three aspects of the present application provide a pharmaceutical composition comprising

[0030] The thiazole compound provided by the present application can inhibit the activity of LSD1 protease, and at the same time has the effects of low toxicity, high efficiency, high selectivity and not easy to off-target. DETAILED DESCRIPTION

[0031] The concept and technical effects of the present application will be described below in combination with examples for a clear and complete description, so as to fully understand the purpose, scheme and effect of the present application. In the following examples, the test reagents used are conventional biochemical reagents unless otherwise specified; and the experimental methods are 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 synthesis route of compound P4 is shown in Route 1:

[0035]

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

[0037]

[0038] Example 1

[0039] A thiazole compound (compound P4), the preparation method thereof comprising the following steps:

[0040] (1) Preparation of compound P1

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

[0042] Compound P1 was detected, and the detection results are as follows: mP 164-166; IR (KBr) v max 3336.92, 3211.27, 1631.16, 1603.21, 1546.7, 1423.83, 595.8 cm -1 ; 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.81-7.76 (m, 2H), 7.36 (dd, J = 8.4, 7.0 Hz, 2H), 7.28-7.20 (m, 1H), 7.10 (s, 1H), 4.95-4.86 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 174.97, 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] To p-anisidine (2.956 g, 24 mmol) was added 120 mL of dichloromethane, 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. The residue was dissolved with ethyl acetate and extracted with an aqueous solution three times. The organic layer was washed with saturated brine, then dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 10:3). Compound P2 (3.228 g, yield 91.19%) was obtained as a white solid.

[0045] Compound P2 was detected, and the detection results thereof were as follows: mp 97.5-100; IR (KBr) v max 3276.2, 2836.9, 1660.39, 1510.52, 1416.71, 1237.55, 827.38 cm -1 ; 1 H NMR (400 MHz, Chloroform-d) δ 7.53 - 7.44 (m, 2H), 7.45 (s, 1H), 6.90 - 6.82 (m, 2H), 6.41 (dd, J = 16.8, 1.4 Hz, 1H), 6.24 (dd, J = 16.8, 10.2 Hz, 1H), 5.73 (dd, J = 10.1, 1.4 Hz, 1H), 3.79 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 163.47, 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 of THF with stirring, and then ethyl acetoacetate (3.078 mL, 27 mmol) was added to the mixture. Then potassium tert-butoxide (1.01 g, 9 mmol) was added to the mixture, and the mixture was heated to 60 °C for overnight. After that, the reaction was quenched with water and extracted with ethyl acetate for 3 times. The organic phase was combined and washed with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 3:2) gave compound P3 (2.1126 g, yield 38.23%) as a light yellow liquid.

[0048] Compound P3 was detected, and the detection results are as follows: IR (KBr) v max 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 (400 MHz, DMSO-d6) δ 9.75 (s, OH), 7.47 (d, J = 9.0 Hz, 1H), 6.89 - 6.83 (m, 1H), 4.13 (qd, J = 7.1, 1.2 Hz, 1H), 3.71 (s, 1H), 3.67 (dd, J = 7.9, 6.5 Hz, OH), 2.28 (t, J = 7.5 Hz, 1H), 2.20 (s, 1H), 2.10 - 1.92 (m, 1H), 1.19 (t, J = 7.1 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 171.29, 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. HRMS (ESI) m / z calcd for C 16 H 21 NO5 + [M + H] + 308.14925, found 308.14944.

[0049] (4) Preparation of compound P4

[0050] Compound P3 (114 mg, 0.371 mmol) was added to 3 mL of methanol with stirring, and compound P1 (79 mg, 0.414 mmol) was added to the mixture. Then, concentrated hydrochloric acid (61 μL, 0.74 mmol) was added to the mixture. After refluxing at 70°C for 6 hours, it was concentrated to remove methanol to obtain a residue, which was redissolved with ethyl acetate and added to water to be extracted 3 times. The organic phase was combined and washed with saturated brine, then dried with 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 detected, and the detection results are 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 (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.76 (s, 1H), 8.03-7.96 (m, 2H), 7.75 (s, 1H), 7.52-7.41 (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 (101 MHz, DMSO-d6) δ 170.56, 162.51, 155.49, 153.32, 150.41, 149.38, 134.35, 132.93, 129.15, 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 comprising the following steps:

[0054] (1) Preparation of compound P5

[0055] While stirring, 2-bromoethanol (3.00 mL, 42.3 mmol) was added to 40 mL of DMF, followed by TBDPSC l (11.6 mL, 44.6 mmol) and imidazole (4.32 g, 63.5 mmol). The reaction was carried out at 25 °C for 3 hours, followed by quenching with water. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether) was used to purify the colorless liquid compound P5 (12.95 g, 84.24% yield).

[0056] The detection results for compound P5 are 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 ; 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 flask while stirring. Ethyl acetoacetate (860 μL, 5 mmol) was then added to the mixture, and the mixture was 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 the reaction was allowed to proceed overnight. After the reaction was complete, the pH of the mixture was adjusted to 6, filtered, and the liquid was concentrated. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 35:2) was used to purify the colorless liquid compound P6 (886.5 mg, yield 24.3%).

[0059] Compound P6 was detected, and the detection results are as follows: IR (KBr) v max 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 (400 MHz, Chloroform-d) δ 7.63 (dt, J = 6.5, 1.6 Hz, 4H), 7.43 - 7.37 (m, 6H), 4.17 (qd, J = 7.2, 5.0 Hz, 2H), 3.78 (t, J = 7.1 Hz, 1H), 3.67 (td, J = 5.9, 1.7 Hz, 2H), 2.24 (s, 3H), 2.13 - 2.09 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H), 1.04 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 203.24, 169.76, 135.59, 135.56, 135.54, 135.52, 134.82, 133.45, 129.74, 127.74, 127.72, 61.39, 56.27, 30.80, 29.26, 26.83, 26.58, 19.20, 14.08. HRMS (ESI) m / z calcd 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 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 to extract 3 times. The organic phase was combined and washed with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography purification (petroleum ether: ethyl acetate = 5:1) obtained white solid compound P7 (52.7 mg, yield 32.55%).

[0062] Compound P7 was detected and the detection results are as follows: mP 165-167; IR (KBr) v max 3070.8, 2928.5, 2854.87, 1634.52, 1518.92 1426.98, 1360.8, 1256.5, 1111.54, 1025.8, 918.35 y, 820.37, 701.70, 618.09, 504.74 cm -1 ; 1 H NMR (400 MHz, Chloroform-d) δ 9.06 (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 = 6.7 Hz, 2H), 2.60 (s, 2H), 2.14 - 2.06 (m, 3H), 1.04 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 135.57, 133.80, 129.58, 128.87, 127.61, 126.08, 26.92, 25.40, 19.18. HRMS (ESI) m / z calcd for C 31 H 33 N3O2Si S + [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 with stirring to obtain solution A. Solution B: 75 mL of anhydrous methanol was added to 13 mL of concentrated hydrochloric acid with stirring to obtain solution B. Solution B was added to solution A with stirring, and reacted at 25°C for 3.5 hours. Then concentrated to remove methanol to obtain a residue. Dichloromethane was added to extract 3 times. The organic phase was combined and washed with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated. Purified by column chromatography (dichloromethane:methanol = 30:1) to obtain white solid compound P8 (881.36 mg, yield 45.56%).

[0065] Compound P8 was detected and the detection results are as follows: mP 188-189; IR (KBr) v max 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 (400 MHz, Chloroform-d) δ 7.82 - 7.75 (m, 2H), 7.46 - 7.39 (m, 2H), 7.39 - 7.31 (m, 1H), 7.18 (s, 1H), 3.85 (t, J = 5.9 Hz, 2H), 2.59 (t, J = 5.8 Hz, 2H), 2.19 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 128.86, 128.52, 126.12, 61.87, 26.09. HRMS (ESI) m / z calcd for C 15 H 15 N3O2S + [M + H] + 302.09577, found 302.09558.

[0066] Example 3

[0067] Thiazole compounds (compounds P9-P21) were prepared by the following methods, respectively:

[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 of 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 phase was combined and washed with saturated brine, and then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 15: 1) gave compound P9 (41.5 mg, yield 19.8%) as a white solid.

[0070] Compound P9 was tested, and the test results are as follows: 1H NMR (400 MHz, Chloroform-d) δ 8.28 - 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 = 7.7 Hz, 2H), 4.48 (t, J = 6.8 Hz, 2H), 2.92 (t, J = 6.8 Hz, 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 of 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 three times. The organic phases were combined and washed with saturated brine, and then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: dichloromethane = 1:1) gave compound P10 (25 mg, yield 7.3%) as a white solid.

[0073] Compound P10 was tested, and the results of the test were as follows: mp 181-183; IR (KBr) v^ 2923.2, 2850.5, 1754.7, 1720, 1600, 1536.8, 1502.1, 1240, 1044.2, 854.74, 763.16, 671.58 cm -1 ; 1 H NMR (400 MHz, DMSO-d6) δ 8.25 - 8.16 (m, 2H), 8.00 - 7.91 (m, 2H), 7.82 (s, 1H), 7.49 (t, J = 8.8 Hz, 2H), 7.31 (t, J = 8.8 Hz, 2H), 7.29 - 7.23 (m, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.02 (t, J = 7.6 Hz, 2H), 4.43 (t, J = 6.3 Hz, 2H), 2.92 (t, J = 6.3 Hz, 2H), 2.33 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 165.25, 162.76, 159.33, 151.76, 151.45, 142.49, 134.20, 134.10, 133.68, 132.51, 132.42, 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 (377 MHz, 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 of 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 three times. The organic phases were combined and washed with saturated brine, and then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: dichloromethane = 5:1) gave compound P11 (11.6 mg, yield 5.28%) as a white solid.

[0076] Compound P11 was tested, and the results of the test were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.34 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 8.5 Hz, 2H), 8.00 (d, J = 7.7 Hz, 2H), 7.76 (s, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 4.43 (t, J = 6.7 Hz, 2H), 2.74 (t, J = 6.6 Hz, 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 1.6 mL of 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 three times. The organic phases were combined and washed with saturated brine, and then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: dichloromethane = 3:2) gave compound P13 (80.8 mg, yield 21.1%) as a white solid.

[0079] Compound P13 was tested, and the results of the test were as follows: mp 183-186; IR (KBr) v max 2919, 2852.7, 1715.73, 1538.55, 1389.3, 1272.3, 1237.6, 1089, 1013.2, 845.65, 747.67, 681.3 cm 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.1 Hz, 2H), 7.83 - 7.76 (m, 3H), 7.62 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.5 Hz, 3H), 7.01 (t, J = 7.6 Hz, 2H), 4.42 (t, J = 6.2 Hz, 2H), 2.90 (t, J = 6.3 Hz, 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 of 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 three times. The organic phases were combined and washed with saturated brine, and then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: dichloromethane = 3:2) gave compound P13 (80.8 mg, yield 21.1%) as a white solid.

[0082] Compound P13 was tested, and the results of the test were as follows: mp 183-186; IR (KBr) v max 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 (400 MHz, DMSO-d6) δ 8.14 - 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 = 6.3 Hz, 2H), 2.92 (t, J = 6.3 Hz, 2H), 2.33 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 165.37, 162.96, 159.34, 151.75, 151.48, 142.42, 140.45, 138.81, 132.83, 131.42, 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 of 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, and then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (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 (400 MHz, DMSO-d6) δ 8.14 - 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 = 6.3 Hz, 2H), 2.92 (t, J = 6.3 Hz, 2H), 2.33 (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 of 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, and then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 30: 1) gave compound P15 (6.8 mg, yield 2.11%) as a white solid.

[0088] Compound P15 was detected, and the detection results are as follows: mp 128-131; IR (KBr) v max 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 (400 MHz, DMSO-d6) δ 8.36 (dt, J = 7.9, 1.5 Hz, 1H), 8.29 - 8.20 (m, 2H), 8.14 (dd, J = 7.9, 1.5 Hz, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.98 (ddd, J = 8.6, 1.9, 0.9 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.82 (s, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.20 - 7.10 (m, 3H), 6.98 - 6.90 (m, 2H), 4.52 (t, J = 6.1 Hz, 2H), 2.99 (t, J = 6.2 Hz, 2H), 2.36 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.93, 162.59, 151.71, 151.54, 142.18, 134.75, 133.63, 133.50, 131.81, 131.21, 131.03, 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 (377 MHz, DMSO-d6) δ -61.34 (d, J = 12.5 Hz), -61.58 (d, J = 9.2 Hz). 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 of DMF with 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, and then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 2: 1) gave compound P1 (12 mg, yield 6.72%) as a white solid.

[0091] Compound P16 was tested, and the results of the test were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.03 - 7.91 (m, 2H), 7.75 (s, 1H), 7.48 - 7.33 (m, 3H), 4.11 (t, J = 7.1 Hz, 2H), 2.55 (t, J = 6.4 Hz, 2H), 2.30 (q, J = 7.5 Hz, 2H), 2.23 (s, 3H), 1.00 (d, J = 7.5 Hz, 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 of DMF with 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, and then dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (dichloromethane:methanol = 10:1) gave compound P17 (9.8 mg, yield 4.62%) as a white solid.

[0094] Compound P17 was detected, and the detection results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.58 (d, J = 2.8 Hz, 1H), 8.19 (dd, J = 8.7, 4.5 Hz, 1H), 7.80 - 7.73 (m, 2H), 7.52 (ddd, J = 8.7, 7.9, 2.8 Hz, 1H), 7.46 - 7.31 (m, 3H), 7.15 (s, 1H), 4.54 (t, J = 7.0 Hz, 2H), 2.87 (t, J = 7.2 Hz, 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 of DMF under 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 for 3 times. The organic phase was combined and washed with saturated brine, and then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain compound P18 (14.2 mg, yield 5.99%) in white solid.

[0097] Compound P18 was detected, and the detection results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.58 (d, J = 2.8 Hz, 1H), 8.19 (dd, J = 8.7, 4.5 Hz, 1H), 7.80 - 7.73 (m, 2H), 7.52 (ddd, J = 8.7, 7.9, 2.8 Hz, 1H), 7.46 - 7.31 (m, 3H), 7.15 (s, 1H), 4.54 (t, J = 7.0 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H), 2.24 (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 of 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 three times. The organic phase was combined and washed with saturated brine, and then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 3:2) gave compound P19 (12.8 mg, yield 5.86%) as a white solid.

[0100] Compound P19 was tested, and the results of the test are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J = 7.0 Hz, 2H), 7.43 - 7.37 (m, 3H), 7.13 (s, 1H), 4.21 (d, J = 6.9 Hz, 2H), 2.68 (d, J = 13.8 Hz, 2H), 2.24 (dd, J = 17.7, 9.3 Hz, 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 of 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 phase was combined and washed with saturated brine, and then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 8:1) gave compound P20 (16.4 mg, yield 5.08%) as a white solid.

[0103] Compound P20 was tested, and the results of the test are as follows: mp 172-175; IR (KBr) v max 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 (400 MHz, Chloroform-d) δ 8.32 - 8.26 (m, 2H), 8.09 (dt, J = 7.8, 1.0 Hz, 2H), 7.80 - 7.73 (m, 2H), 7.72 - 7.62 (m, 2H), 7.17 - 7.08 (m, 4H), 7.00 - 6.91 (m, 2H), 4.52 (t, J = 6.7 Hz, 2H), 2.94 (t, J = 6.8 Hz, 2H), 2.39 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 165.27, 159.42, 152.68, 150.75, 142.25, 133.63, 131.38, 130.04, 128.18, 128.01, 125.78, 125.57, 125.42, 125.38, 108.54, 107.95, 64.03, 22.10, 13.10. HRMS (ESI) m / z calcd 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 of 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, and then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 8: 1) gave compound P21 (13.7 mg, yield 7.11%) as a white solid.

[0106] Compound P21 was tested, and the test results thereof were as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.94 - 7.71 (m, 2H), 7.40 (ddd, J = 26.0, 16.9, 7.1 Hz, 3H), 7.13 (s, 1H), 4.20 (t, J = 7.0 Hz, 2H), 2.69 (dt, J = 18.4, 7.1 Hz, 2H), 2.27 - 2.19 (m, 3H), 1.26 - 1.12 (m, 9H).

[0107] Effect experiment

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

[0109] Based on multi-step enzymatic reaction, the characteristics of LSD1 in the reaction first demethylate lysine 4 of the peptide corresponding to the first 21 amino acids of the N-terminal tail of histone H3 to produce H2O2. In the presence of horseradish peroxidase (HRP), H2O2 can react with ADHP (10-acetyl-3,7-dihydroxyphenoxazine) to generate highly fluorescent compound resorcinol. When the excitation wavelength is 530-540 nm and the emission wavelength is 585-595 nm, the ability of the compound to inhibit LSD1 enzymology can be easily detected by analyzing the resorcinol fluorescence. The example uses Cayman LSD1 Inhibitor Screening Assay Kit (No. 700120) for detection, and TECAN SPARK Multifunctional Microplate Reader instrument records the fluorescence reading (λex=535 nm; λem=590 nm) The data are analyzed using GraphPad Prism 9.0 software, and IC 50 Values represent three independent replicates ± standard deviation; the results are shown in Table 1.

[0110] Table 1

[0111]

[0112]

[0113] As can be seen from Table 1, the control positive drug SP-2577 shows strong in vitro enzymatic inhibition activity of LSD1. The compounds designed and synthesized by the present application have structural differences from SP-2577, but also show the same potential IC 50 Data. Compared with the positive drug, compounds P4, P10, P14 and P20 (the double esterification products of p-fluorobenzoic acid, p-trifluoromethylbenzoic acid and p-methoxybenzoic acid of P4 and P8) show stronger activity than the positive drug.

[0114] (2) Test of cell proliferation inhibition activity of compound P4 and compounds P8-P21

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

[0116] HCT-116, Lovo and other human colorectal cancer cells were inoculated in 96-well plates at 1000 cells per well and treated with different concentrations of inhibitors in the medium for 72 hours. Cell survival rate was determined using a CCK8 kit (Bi Yun Tian) according to the manufacturer's instructions. The results of the CCK8 activity test are shown in Table 2.

[0117] Table 2

[0118] Compound HCT-116 inhibitory activity (μM) IC 50 ]] 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, the positive drug has strong in vitro enzymatic inhibition activity, but shows weaker activity in cells than the compounds of this batch. Compounds P10 and P20 show strong inhibition of colorectal cancer cell proliferation.

[0120] (3) Animal subcutaneous tumor experiment of compounds P10 and P20

[0121] Six to eight-week-old Balb / c-Nude mice were selected and subcutaneously injected with 1*10 6 HCT-116 cells mixed with Matrigel. The tumor tissue became hard after the cells grew subcutaneously for about 7 days, and the average volume reached 100 mm 3 . The mice were randomly divided into groups. This example set up four groups, each with 6 mice; they were divided into a control group, a positive drug group SP-2577 (gavage administration, 50 mg / kg, once a day), a compound P10 and P20 group (gavage administration, 50 mg / kg, once a day), and the tumor volume and mouse body weight were measured every other day, and the mice were dissected after 21 days of administration. The results are shown in Table 3.

[0122] Table 3

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

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

[0125] The above is only a preferred embodiment of the present application, and the present application is not limited to the above-described embodiments, as long as the same means achieve the technical effects of the present application, it should belong to the protection scope of the present application. The technical solutions and / or embodiments within the protection scope of the present application can have various modifications and changes.

Claims

1. A thiazole compound, characterized by, having the structure of any one of compounds P8-P21:

2. A process for the preparation of a thiazole compound as claimed in claim 1, characterized in that, The preparation method comprises route two; The route two is shown as follows:

3. The production method according to claim 2, characterized by, The route two comprises the following steps: (1) under the condition of stirring, 2-bromoethanol or 2-chloroethanol is mixed with DMF, then TBDPSCl (tert-butyl diphenyl chlorosilane) and imidazole are added, and after reaction at 20-30℃ for 1-10h, the reaction is quenched with water; then ethyl acetate or dichloromethane is added for extraction 2-5 times, the organic phases are combined, washed, dried by adding anhydrous sodium sulfate, filtered and concentrated, and column chromatography purification is performed to obtain compound P5; (2) under the condition of stirring, K2CO3, sodium ethoxide or sodium methoxide and ethanol or methanol are mixed, then ethyl acetoacetate is added to obtain a mixture, and the mixture is heated to 60-90℃; then ethanol or methanol containing the compound P5 is added dropwise into the mixture and reacted for 2-14h, then the pH is adjusted to 6, the filtrate is obtained after filtration, and then concentrated; then ethyl acetate or dichloromethane is added for extraction 2-5 times, the organic phases are combined, washed, dried by adding anhydrous sodium sulfate, filtered and concentrated, and column chromatography purification is performed to obtain compound P6; (3) under the condition of stirring, the compound P1 is mixed with the compound P6, then glacial acetic acid or hydrochloric acid is added, and reaction is performed at 60-90℃ for 2-24h; then the acid is removed by concentration under reduced pressure to obtain a residue, ethyl acetate or dichloromethane is added for extraction 2-5 times, the organic phases are combined, washed, dried by adding anhydrous sodium sulfate, filtered and concentrated, and column chromatography purification is performed to obtain compound P7; (4) under the condition of stirring, the compound P7 is mixed with methanol to obtain solution C; under the condition of stirring, methanol is mixed with concentrated hydrochloric acid to obtain solution D; under the condition of stirring, the solution D is added into the solution C, and reaction is performed for 2-6h; then methanol is removed by concentration to obtain a residue, ethyl acetate or dichloromethane is added for extraction 2-5 times, the organic phases are combined, washed, dried by adding anhydrous sodium sulfate, filtered and concentrated, and column chromatography purification is performed to obtain compound P8; (5) under the condition of stirring, the compound P8, DIC (N,N'-diisopropyl carbodiimide) and DMAP (4-dimethylamino pyridine) are added into a DMF solution, then an organic acid is added, and reaction is performed at 25-60℃ for 2-16h; then the reaction is quenched with water, and dichloromethane or ethyl acetate is added for extraction 2-5 times, the organic phases are combined, washed, dried by adding anhydrous sodium sulfate, filtered and concentrated, and column chromatography purification is performed to obtain compounds P9-P21.

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

5. Use of the thiazole compound or a pharmaceutically acceptable salt thereof according to claim 1 or the pharmaceutical composition according to claim 4 in the preparation of an LSD1 inhibitor.

6. Use of the thiazole compound or a pharmaceutically acceptable salt thereof according to claim 1 or the pharmaceutical composition according to claim 4 in the preparation of a drug for treating and / or preventing cancer; the cancer is a cancer with abnormal expression of LSD1 in cells.

7. Use according to claim 6, characterized in that, The cancer is lung cancer, gastric cancer, colorectal cancer, bladder cancer, esophageal cancer, prostate cancer, liver cancer, glioma, or acute myelocytic leukemia. The cancer is lung cancer, gastric cancer, colorectal cancer, bladder cancer, esophageal cancer, prostate cancer, liver cancer, glioma, or acute myelocytic leukemia. The cancer is lung cancer, gastric cancer, colorectal cancer, bladder cancer, esophageal cancer, prostate cancer, liver cancer, glioma, or acute myelocytic leukemia. The cancer is lung cancer, gastric cancer, colorectal cancer

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