A benzothiophene compound, its preparation method and application

Abstract

This invention belongs to the field of medicinal chemistry, specifically relating to a benzodiazepine compound, its preparation method, and its application. The benzodiazepine compound provided by this invention is a compound represented by Formula I or a pharmaceutically acceptable salt thereof. This invention introduces a hydrogen, benzyl, propargyl, or acyl group at the 10-position of benzodiazepine, and simultaneously introduces an aliphatic amine, aromatic amine, aromatic heteroamine, aliphatic hydrazine, or acyl hydrazine group at the 4-position of benzodiazepine. The resulting compound has a novel skeleton, and experiments have confirmed that this type of compound exhibits good inhibitory activity against LSD1. It can provide a novel structural skeleton for the development of highly effective LSD1-targeted inhibitors or antitumor drugs, and also provide a new direction for the development of LSD1-targeted inhibitory drugs, demonstrating its application potential in the field of LSD1-targeted drugs.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, and specifically relates to a benzodiazepine. Thiophene compounds, their preparation methods, and applications. Background Technology

[0002] Epigenetic modifications are crucial for regulating normal physiological functions and homeostatic gene expression. DNA methylation, histone modifications, and post-translational modifications are the causes of epigenetic variation. These epigenetic variations play a vital role in altering chromatin structure and gene activity by activating or inhibiting regulatory molecules. Increasing evidence suggests that epigenetic variations, particularly those involving histones, are associated with the development and progression of various cancers.

[0003] Histone lysine specific demethylase 1 (LSD1) is the first histone demethylase discovered. It uses flavin adenine dinucleotide (FAD) as a cofactor and catalyzes the demethylation of H3K4me1 / 2 and H3K9me1 / 2 through amine oxidation, thereby regulating the transcription of related genes.

[0004] Clinical studies have shown that LSD1 is highly expressed in various cancers, including prostate cancer, breast cancer, small cell lung cancer, bladder cancer, neuroblastoma, and acute myeloid leukemia. It promotes tumor proliferation, invasion, and metastasis by activating oncogenes or inhibiting tumor suppressor gene expression. Pharmacological inhibition of LSD1 has been shown to suppress the growth of various tumors, making it a potential therapeutic target for multiple cancers.

[0005] Therefore, developing more highly selective LSD1 inhibitors has become a hot topic in the development of anti-tumor drugs. At the same time, research on the mechanism of action of LSD1 in tumors and the development of novel LSD1-targeting drugs are of great significance. Summary of the Invention

[0006] In view of this, one of the objectives of the present invention is to provide a benzodiazepine Thiophene compounds, which have good inhibitory activity against LSD1, can provide a novel structural framework for the development of inhibitory drugs based on the LSD1 target.

[0007] The second objective of this invention is to provide the above-mentioned benzodiazepine. The preparation method of thiophene compounds is simple and mild, making it suitable for the preparation and application of these compounds.

[0008] The third objective of this invention is to provide the above-mentioned benzodiazepine. And the application of thiophene compounds.

[0009] One of the objectives of this invention is achieved through the following technical solution:

[0010] A benzodiazepine Thiophene compounds, which are compounds represented by Formula I or pharmaceutically acceptable salts thereof:

[0011]

[0012] Among them, R1 is selected from H, One of them;

[0013] R2 is selected from

[0014] One of them.

[0015] Based on the consideration of improving the inhibitory activity of the compound against LSD1, as a further improvement, the benzodiazepine... Thiophene compounds, selected from compounds I-1 to I-21 with the following structures:

[0016] Compound I-1: R1 is R2 is Compound I-2: R1 is R2 is

[0017] Compound I-3: R1 is R2 is Compound I-4: R1 is H, R2 is

[0018] Compound I-5: R1 is H, R2 is Compound I-6: R1 is H, R2 is

[0019] Compound I-7: R1 is H, R2 is Compound I-8: R1 is H, R2 is

[0020] Compound I-9: R1 is H, R2 is Compound I-10: R1 is H, R2 is

[0021] Compound I-11: R1 is H, R2 is Compound I-12: R1 is H, R2 is

[0022] Compound I-13: R1 is H, R2 is Compound I-14: R1 is H, R2 is

[0023] Compound I-15: R1 is H, R2 is Compound I-16: R1 is H, R2 is

[0024] Compound I-17: R1 is H, R2 is Compound I-18: R1 is H, R2 is

[0025] Compound I-19: R1 is H, R2 is Compound I-20: R1 is H, R2 is

[0026] Compound I-21: R1 is H, R2 is

[0027] The second objective of this invention is achieved through the following technical solution:

[0028] A benzodiazepine The preparation method of thiophene compounds adopts either synthetic route a or synthetic route b as shown below to produce benzodiazepines. Preparation of thiophene compounds:

[0029]

[0030] Synthetic route a includes the following steps: dissolving compound 1a and the halogenated product in an organic solvent, and then subjecting them to a nucleophilic substitution reaction under the action of a basic substance to obtain benzodiazepine represented by formula I'. Thiophene compounds;

[0031] Synthetic route b includes the following steps: dissolving compound 2a and an amine or hydrazine compound in an organic solvent, allowing a nucleophilic substitution reaction to yield benzodiazepine represented by formula I”. And thiophene compounds.

[0032] As a further improvement, in synthetic route a, the halogenated product is selected from one of benzyl bromide, bromopropyne, and acetyl bromide.

[0033] As a further improvement, in synthetic route a, the alkaline substance is selected from one or more of sodium hydroxide, potassium carbonate, sodium hydride, cesium carbonate, N,N-diisopropylethylamine, and sodium acetate.

[0034] As a further improvement, in synthetic route a, the temperature of the nucleophilic substitution reaction is 0–50 °C.

[0035] As a further improvement, in synthetic route b, the amine or hydrazine compound is selected from one of N-ethylpiperazine, N-phenylpiperazine, N-Boc-piperazine, N-acetylpiperazine, morpholine, thiomorpholine-1,1-dioxide, 4-dimethylaminopiperidine, dimethyl-1,3-diaminopropane, N-(2-aminoethyl)morpholine, 4-aminothiomorpholine-1,1-dioxide, 1-amino-4-methylpiperazine, 4-aminopiperazine-1-carboxylic acid tert-butyl ester, N-aminomorpholine, N-aminopiperidine, 3-pyridinecarboxylhydrazine, and methoxyacetic acid hydrazine.

[0036] As a further improvement, in synthetic route b, the temperature of the nucleophilic substitution reaction is 60–150 °C.

[0037] As a further improvement, in synthetic routes a and b, the organic solvent is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, toluene, tetrahydrofuran, and dioxane.

[0038] The third objective of this invention is achieved through the following technical solution:

[0039] The above benzodiazepines The application of thiophene compounds in the preparation of inhibitors or antitumor drugs targeting LSD1.

[0040] The main beneficial effects of the technical solution of this invention are as follows:

[0041] 1) The benzodiazepine provided by this invention The thiophene compounds have a novel skeleton, and experiments have confirmed that this type of compound has good inhibitory activity against LSD1, which can provide a novel structural skeleton for the development of highly effective LSD1-targeted inhibitors or anti-tumor drugs.

[0042] 2) The benzodiazepine provided by this invention The preparation method of thiophene compounds, in benzodiazepines And a hydrogen, benzyl, propargyl or acyl group is introduced at the 10-position of thiophene, while at the benzodiazepine By introducing aliphatic amines, aromatic amines, aromatic heteroamines, aliphatic hydrazides, or acyl hydrazides at the 4-position of thiophene, a novel class of benzodiazepines was designed and synthesized. Thiophene compounds. The entire preparation process of this invention is characterized by mild reaction conditions, simple operation, and high reaction yield. Furthermore, the prepared compounds exhibit good inhibitory activity against LSD1, making them suitable for benzodiazepines. And the preparation and application of thiophene compounds.

[0043] 3) This invention relates to benzodiazepines. The study of thiophene compounds, involving benzodiazepines Thiophene compounds exhibit good inhibitory activity against LSD1, demonstrating promising drug development potential. They can provide new directions for the development of LSD1-targeted inhibitors or anti-tumor drugs, and also demonstrate their application potential in the field of LSD1-targeted drugs. Detailed Implementation

[0044] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments and experimental examples. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the scope of protection of the invention. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods; the raw materials used, unless otherwise specified, are items commonly used in the art, publicly available, or commercially obtainable.

[0045] Among them, the benzodiazepines involved in Examples 1 to 21 of the present invention Thiophene compounds have the general structural formula shown in Formula I:

[0046]

[0047] Among them, R1 is selected from H, One of them;

[0048] R2 is selected from

[0049] One of them.

[0050] Specifically, the benzodiazepines involved in Examples 1 to 21 below Thiophene compounds, designated as compounds I-1 to I-21 respectively; the specific structures of compounds I-1 to I-21 are as follows:

[0051] Compound I-1: R1 is R2 is Compound I-2: R1 is R2 is

[0052] Compound I-3: R1 is R2 is Compound I-4: R1 is H, R2 is

[0053] Compound I-5: R1 is H, R2 is Compound I-6: R1 is H, R2 is

[0054] Compound I-7: R1 is H, R2 is Compound I-8: R1 is H, R2 is

[0055] Compound I-9: R1 is H, R2 is Compound I-10: R1 is H, R2 is

[0056] Compound I-11: R1 is H, R2 is Compound I-12: R1 is H, R2 is

[0057] Compound I-13: R1 is H, R2 is Compound I-14: R1 is H, R2 is Compound I-15: R1 is H, R2 is Compound I-16: R1 is H, R2 is Compound I-17: R1 is H, R2 is Compound I-18: R1 is H, R2 is Compound I-19: R1 is H, R2 is Compound I-20: R1 is H, R2 is Compound I-21: R1 is H, R2 is The synthetic routes for compounds I-1 to I-3 are as follows:

[0058]

[0059] The synthetic routes for compounds I-4 to I-21 are as follows:

[0060]

[0061] Example 1

[0062] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, and R1 being... R2 is Benzodiazepine The thiophene compounds are designated as compound I-1.

[0063] The preparation method of compound I-1 includes the following steps:

[0064] Compound 1a (400 mg, 1.28 mmol) and sodium hydride (102 mg, 2.56 mmol) were dissolved in anhydrous N,N-dimethylformamide (50 mL), followed by the addition of benzyl bromide (185 μL, 1.52 mmol). The reaction mixture was reacted at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, dichloromethane (50 mL) was added to the resulting reaction system, and the organic phase was washed with saturated brine (3 × 50 mL), dried over anhydrous magnesium sulfate, and purified by column chromatography to obtain compound I-1 in 63.5% yield.

[0065] The structure of compound I-1 was analyzed using nuclear magnetic resonance (NMR) technology. The structural characterization results are as follows: 1 H NMR (400MHz, CDCl3) δ7.45(d,J=7.0Hz,2H),7.28(t,J=1.5Hz,1H),7.25(s,1H),7. 20(m,J=7.3Hz,1H),7.06(dd,J=7.5,2.0Hz,1H),6.97(m,2H),6.88(dd,J=7.6,1.9H z,1H),6.23(d,J=1.2Hz,1H),4.81(d,J=12.0Hz,1H),4.55(d,J=14.4Hz,1H),3.63 (s,2H),3.51(s,2H),2.57(s,2H),2.48(s,2H),2.38(s,3H),2.25(d,J=1.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ157.65,155.38,145.59,143.28,137.52,128.87,128.34,127.87,125.01,124.30 ,124.09,121.90,121.14,121.08,120.37,118.32,117.50,54.89,45.98,15.76.HR-MS(ESI):Calcdfor C 24 H 26 N4S, [M+H] + m / z:403.1951, found:403.1950.

[0066] Example 2

[0067] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, and R1 being... R2 is Benzodiazepine The thiophene compounds are designated as compound I-2.

[0068] The preparation method of compound I-2 was basically the same as in Example 1, except that benzyl bromide was replaced with bromopropyne. The yield of compound I-2 was 71.4%. The structure of compound I-2 was analyzed by nuclear magnetic resonance (NMR), and the structural characterization results are as follows: 1 H NMR (400MHz, CDCl3) δ7.14(d,J=7.3Hz,1H),7.05-6.94(m,3H),6.32(s,1H),4.26(d,J=5.5Hz,2H),3.56(s,4H),2.53-2.43(m,5H),2.35(s,6H). 13 C NMR (100MHz, CDCl3) δ157.24,153.78,144.38,142.97,132.26,127.53,124.98,123.54,1 21.34,121.25,118.08,79.77,74.79,55.11,46.52,46.15,41.33,15.81.HRMS(ESI)calcd for C 20 H 22 N4S[M+H] + ,351.1638; found,351.1640.

[0069] Example 3

[0070] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, and R1 being... R2 is Benzodiazepine The thiophene compounds are designated as compound I-3.

[0071] The preparation method of compound I-3 was basically the same as in Example 1, except that benzyl bromide was replaced with acetyl bromide. The yield of compound I-3 was 79.2%. The structure of compound I-3 was analyzed by nuclear magnetic resonance (NMR), and the structural characterization results are as follows: 1 H NMR (400MHz, CDCl3) δ7.23(d,J=8.5Hz,1H),7.18(d,J=8.7Hz,1H),7.12-7.01(m,2 H),6.46(s,1H),3.62(s,4H),2.49(s,2H),2.41(s,5H),2.33(s,3H),2.07(s,3H). 13CNMR(100MHz,CDCl3)δ171.72,155.46,144.20,138.77,135.18,128.57,127.72,12 6.39,125.11,123.89,121.48,55.14,46.57,46.26,22.09,15.98.HRMS(ESI)calcd forC 19 H 22 N4OS[M+H] + ,355.1587;found,355.1587.

[0072] Example 4

[0073] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-4.

[0074] The preparation method of compound I-4 includes the following steps:

[0075] Compound 2a (250 mg, 1.09 mmol) and N-ethylpiperazine (970 μL, 2.56 mmol) were dissolved in a 1:1 (v / v) mixture of dimethyl sulfoxide and toluene (10 mL). The reaction mixture was reacted at 120 °C, and the reaction progress was monitored by TLC. After the reaction was complete, ethyl acetate (50 mL) was added to the resulting reaction system, and the organic phase was washed with saturated brine (3 × 50 mL), dried over anhydrous magnesium sulfate, and purified by column chromatography to obtain compound I-4 in 17.6% yield.

[0076] The structure of compound I-4 was analyzed using nuclear magnetic resonance (NMR) technology. The structural characterization results are as follows: 1 H NMR (400MHz, CDCl3) δ7.03-7.01(m,1H),6.96(dd,J=11.1,3.9Hz,1H),6.87(td,J=7.6,1.4Hz,1H),6.61(d,J=7.6Hz,1H) ,6.30(s,1H),5.06(s,1H),3.56(s,4H),2.55(t,J=4.6Hz,4H),2.50(q,J=7.3Hz,2H),2.31(s,3H),1.13(t,J=7.2Hz,3H). 13C NMR (100MHz, CDCl3) δ157.55,151.88,142.56,140.95,129.07,128.15,124.67,123 .78,123.01,119.50,118.96,52.79,52.42,46.68,15.46,11.80.HR-MS(ESI):Calcd for C 18 H 22 N4S, [M+H] + m / z:327.1638,found:327.1635.

[0077] Example 5

[0078] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-5.

[0079] The preparation method of compound 5 was basically the same as that of Example 4, except that N-ethylpiperazine was replaced with N-phenylpiperazine, with a yield of 19.2%. The structure of compound I-5 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 H NMR (400MHz, CDCl3) δ7.28(t,J=7.8Hz,2H),7.06(d,J=7.6Hz,1H),6.97(d,J= 7.9Hz,3H),6.88(t,J=7.3Hz,2H),6.61(d,J=7.6Hz,1H),6.34(s,1H),5.05(br s,1H),3.66(s,4H),3.28-3.25(m,4H),2.32(s,3H). 13 C NMR (100MHz, CDCl3) δ157.82,151.33,142.65,129.25,129.18,128.20,124.74, 124.04,122.91,120.05,119.05,116.36,49.42,46.98,15.49.HRMS(ESI)calcd for C 22 H 22 N4S[M+H] + ,375.1638; found,375.1646.

[0080] Example 6

[0081] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-6.

[0082] The preparation method of compound I-6 was basically the same as that in Example 4, except that N-ethylpiperazine was replaced with N-Boc-piperazine, with a yield of 15.3%. The structure of compound I-6 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 HNMR(400MHz, CDCl3)δ7.03-6.95(m,2H),6.88(td,J=7.5,1.7Hz,1H),6.60(dd,J=7.7,1.1Hz,1 H),6.29(d,J=0.9Hz,1H),4.99(s,1H),3.48(dd,J=17.9,5.7Hz,8H),2.31(s,3H),1.48(s,9H). 13 CNMR (100MHz, CDCl3) δ157.73,154.93,152.05,142.46,140.80,129.31,128.20,12 4.74,124.03,122.76,119.42,118.99,79.92,46.83,28.44,15.48.HRMS(ESI)calcd for C 21 H 26 N4O2S[M+H] + ,399.1849;found,399.1849.

[0083] Example 7

[0084] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-7.

[0085] The preparation method of compound I-7 was basically the same as that in Example 4, except that N-ethylpiperazine was replaced with N-acetylpiperazine, with a yield of 9.5%. The structure of compound I-7 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1HNMR (400MHz, CDCl3) δ7.03-6.96 (m, 2H), 6.89 (td, J=7.4, 1.7Hz, 1H), 6.61 (dd, J=7.7, 1.1Hz, 1H), 6. 29(s,1H),5.10(s,1H),3.70-3.67(m,2H),3.55(s,4H),3.44-3.41(m,2H),2.32(s,3H),2.13(s,3H). 13 C NMR (100MHz, CDCl3) δ169.25,157.62,152.39,142.52,140.61,129.46,128.18,124 .74,124.23,122.58,119.13,119.06,46.66,46.13,21.46,15.48.HRMS(ESI)calcd for C 18 H 20 N4OS[M+H] + ,341.1431;found,341.1429.

[0086] Example 8

[0087] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-8.

[0088] The preparation method of compound I-8 includes the following steps: Compound I-6 (500 mg, 1.25 mmol) was dissolved in dichloromethane solution (5 mL), followed by the addition of trifluoroacetic acid (200 μL, 2.5 mmol). The reaction mixture was reacted at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, dichloromethane was removed by rotary evaporation, followed by the addition of water (5 mL) and washing of the reaction mixture with saturated sodium bicarbonate aqueous solution until the pH reached 7. Dichloromethane (50 mL) was added to the resulting reaction system, and the organic phase was washed with saturated brine (3 × 50 mL), dried over anhydrous magnesium sulfate, and purified by column chromatography to obtain compound I-8, with a reaction yield of 63.5%. The structure of compound I-8 was analyzed by nuclear magnetic resonance (NMR), and the structural characterization results are as follows: 1H NMR (400MHz, CDCl3) δ7.02 (dd, J=7.8, 1.5Hz, 1H), 6.96 (td, J=7.6, 1.3Hz, 1H), 6.87 (td, J=7.5, 1.6Hz, 1H), 6.61 (dd, J= 7.7,1.2Hz,1H),6.29(d,J=1.0Hz,1H),5.05(s,1H),3.51(t,J=4.8Hz,4H),2.98(t,J=5.0Hz,4H),2.31(d,J=0.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ157.87,151.94,142.56,140.88,129.19,128.17,124.69,123.88,122.92,119.49,118.97,47.85,45.82,15.46.HRMS(ESI)calcd for C 16 H 18 N4S[M+H] + ,299.1325; found,299.1323.

[0089] Example 9

[0090] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-9.

[0091] The preparation method of compound I-9 was basically the same as in Example 4, except that N-ethylpiperazine was replaced with morpholine, with a yield of 13.7%. The structure of compound I-9 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 H NMR (400MHz, CDCl3) δ7.03-6.95(m,2H),6.89(td,J=7.5,1.7Hz,1H),6.61(dd,J=7.7,1.1H z,1H),6.29(s,1H),4.98(s,1H),3.78(t,J=4.6Hz,4H),3.49(t,J=4.8Hz,4H),2.31(s,3H). 13 C NMR(100MHz, CDCl3)δ157.92,152.08,142.49,140.78,129.31,128.21,124.76,124.04,122.82,119.26,119.00,66.96,47.63,15.46.HRMS(ESI)calcd for C16 H 17 N3OS[M+H] + ,300.1165; found,300.1168.

[0092] Example 10

[0093] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine Thiophene compounds are designated as compound I-10.

[0094] The preparation method of compound I-10 is basically the same as that in Example 4, except that N-ethylpiperazine is replaced with thiomorpholine-1,1-dioxide, with a yield of 11.0%. The structure of compound I-10 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 H NMR (400MHz, CDCl3) δ7.00 (s, 1H), 6.99 (s, 1H), 6.94 (m, 1H), 6.62 (d, J = 7. 7Hz,1H),6.29(s,1H),5.05(s,1H),4.00(s,4H),3.13(s,4H),2.32(s,3H). 13 C NMR(100MHz, CDCl3)δ156.21,153.14,142.41,140.20,130.25,124.96,122.34,119.32,118.28,51.18,45.46,15.61.HRMS(ESI)calcd for C 16 H 17 N3O2S2[M+H] + ,348.0835; found,348.0834.

[0095] Example 11

[0096] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine Thiophene compounds are designated as compound I-11.

[0097] The preparation method of compound I-11 was basically the same as in Example 4, except that N-ethylpiperazine was replaced with 4-dimethylaminopiperidine, with a yield of 14.9%. The structure of compound I-11 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1H NMR (400MHz, MeOD) δ6.95 (s, 3H), 6.72 (s, 1H), 6.42 (s, 1H), 4.18 (d, J = 12.7Hz, 2H), 2.94 ( t,J=12.6Hz,3H),2.62(s,6H),2.33(s,3H),2.04(d,J=10.9Hz,2H),1.70(d,J=8.9Hz,2H). 13 C NMR(100MHz,MeOD)δ160.34,157.55,146.55,130.70,128.12,126.52,125.80 ,123.98,120.54,118.38,64.60,64.29,41.05,28.51,15.17.HRMS(ESI)calcd forC 19 H 24 N4S[M+H] + ,341.1794;found,341.1794.

[0098] Example 12

[0099] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine Thiophene compounds are designated as compound I-12.

[0100] The preparation method of compound I-12 was basically the same as that in Example 4, except that N-ethylpiperazine was replaced with N,N-dimethyl-1,3-diaminopropane, with a yield of 15.2%. The structure of compound I-12 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 H NMR (400MHz, CDCl3) δ6.93-6.86(m,3H),6.77(s,1H),6.53(s,1H),3.62(t,J=6 .1Hz,2H),2.45(t,J=6.2Hz,2H),2.25(s,3H),2.24(s,6H),1.91-1.85(m,2H). 13 CNMR(100MHz,CDCl3)δ142.50,127.83,124.42,121.65,119.74,44.93,41.31,25.81,15.23.HRMS(ESI)calcd for C 17 H 22 N4S[M+H] + ,315.1638; found,315.1636.

[0101] Example 13

[0102] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-13.

[0103] The preparation method of compound I-13 was basically the same as that in Example 4, except that N-ethylpiperazine was replaced with N-(2-aminoethyl)morpholine, with a yield of 16.2%. The structure of compound I-13 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 H NMR (400MHz, CDCl3) δ6.98-6.86(m,3H),6.69(s,1H),6.48(s,1H),3.70(t,J=4. 4Hz, 4H), 3.62 (t, J = 5.4Hz, 2H), 2.66 (t, J = 5.6Hz, 2H), 2.53 (s, 4H), 2.29 (s, 3H). 13 CNMR(100MHz,CDCl3)δ128.21,124.62,121.34,119.48,66.94,53.39,15.27.HRMS(ESI)calcd for C 18 H 22 N4OS[M+H] + ,343.1587;found,343.1587.

[0104] Example 14

[0105] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-14.

[0106] The preparation method of compound I-14 was basically the same as that in Example 4, except that N-ethylpiperazine was replaced with 4-aminothiomorpholine-1,1-dioxide, with a yield of 8.5%. The structure of compound I-14 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 H NMR (400MHz, Acetone) δ8.53(s,1H),7.91(s,1H),6.99-6.97(m,1H),6.94-6.90(m,4H),3.44-3.25(m,8H),2.28(s,3H). 13C NMR(100MHz,Acetone)δ155.43,151.32,138.66,131.77,125.40,124.54,122.53,122.05,120.09,119.60,114.81,53.78,49.70,14.72.HRMS(ESI)calcd for C 16 H 18 N4O2S2[M+H] + ,363.0944; found,363.0951.

[0107] Example 15

[0108] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-15.

[0109] The preparation method of compound I-15 was basically the same as in Example 8, except that compound I-6 was replaced with I-17. The yield of compound I-15 was 78.5%. The structure of compound I-15 was analyzed by nuclear magnetic resonance (NMR), and the structural characterization results were as follows: 1 H NMR (400MHz, DMSO-D6) δ6.96-6.92(m,1H),6.84-6.78(m,3H),6.68(d,J=1.3Hz,1H),3.26(s,4H),2.82(s,2H),2.63(s,2H),2.18(s,1H). 13 C NMR(100MHz,DMSO)δ153.44,150.31,137.57,130.16,123.90,123.38,123.26,121.70,118.80,112.54,51.43,42.17,14.46.HRMS(ESI)calcd for C 16 H 19 N5S[M+H] + ,314.1434;found,314.1430.

[0110] Example 16

[0111] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-16.

[0112] The preparation method of compound I-16 was basically the same as in Example 4, except that N-ethylpiperazine was replaced with 1-amino-4-methylpiperazine, with a yield of 16.2%. The structure of compound I-16 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 H NMR (400MHz, CDCl3) δ8.52 (s, 1H), 6.94-6.85 (m, 3H), 6.76 (d, J = 9.4Hz, 1H) ,6.71(d,J=7.7Hz,1H),5.83(s,1H),2.83(s,7H),2.36(s,4H),2.25(s,3H). 13 C NMR(100MHz, CDCl3)δ154.16,149.00,137.36,131.22,126.05,124.19,123.67,123.51,115.24,54.76,54.30,45.99,15.07.HRMS(ESI)calcd for C 17 H 21 N5S[M+H] + ,328.1590; found,328.1597.

[0113] Example 17

[0114] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-17.

[0115] The preparation method of compound I-17 was basically the same as in Example 4, except that N-ethylpiperazine was replaced with 4-aminopiperazine-1-carboxylic acid tert-butyl ester, with a yield of 8.2%. The structure of compound I-17 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 H NMR (400MHz, CDCl3) δ8.49 (s, 1H), 6.95-6.86 (m, 3H), 6.75 (d, J = 5.8Hz, 1H), 6.71 (d, J = 7.7Hz, 1 H),5.72(s,1H),4.10(s,2H),3.11(s,2H),2.79(s,2H),2.65(s,2H),2.26(s,3H),1.48(s,9H). 13C NMR (100MHz, CDCl3) δ154.91,154.10,137.31,131.01,126.01,123.77,123.67 ,123.39,120.94,119.16,115.09,79.83,54.31,28.44,15.01.HRMS(ESI)calcd for C 21 H 27 N5O2S[M+H] + ,414.1958; found,414.1964.

[0116] Example 18

[0117] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-18.

[0118] The preparation method of compound I-18 was basically the same as in Example 4, except that N-ethylpiperazine was replaced with N-aminomorpholine, with a yield of 21.6%. The structure of compound I-18 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 HNMR (400MHz, CDCl3) δ8.52 (s, 1H), 6.97-6.85 (m, 3H), 6.77 (dd, J = 7.6, 1.3Hz, 1H), 6.71 (dd, J =7.6,1.2Hz,1H),5.67(s,1H),3.97-3.78(m,4H),2.78(d,J=4.1Hz,4H),2.27(d,J=1.0Hz,3H). 13 C NMR(100MHz, CDCl3)δ154.06,148.96,137.27,131.08,125.97,123.88,123.75,123.34,120.92,119.12,115.16,66.71,55.08,14.94.HRMS(ESI)calcd forC 16 H 18 N4OS[M+H] + ,315.1274; found,315.1272.

[0119] Example 19

[0120] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-19.

[0121] The preparation method of compound I-19 was basically the same as in Example 4, except that N-ethylpiperazine was replaced with N-aminopiperidine, with a yield of 17.3%. The structure of compound I-19 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 HNMR (400MHz, CDCl3) δ8.67 (s, 1H), 6.94-6.83 (m, 3H), 6.76 (dd, J = 7.7, 1.7Hz, 1H), 6 .68(dd,J=7.8,1.6Hz,1H),5.66(s,1H),2.70(d,J=96,4H),2.25(s,3H),1.73(s,5H). 13 C NMR (100MHz, CDCl3) δ153.53,148.51,137.12,131.39,125.70,124.19,123.49 ,120.51,119.41,118.68,115.36,55.93,25.91,15.06,14.80.HRMS(ESI)calcd for C 17 H 20 N4S[M+H] + ,313.1481; found,313.1492.

[0122] Example 20

[0123] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine Thiophene compounds are designated as compound I-20.

[0124] The preparation method of compound I-20 is basically the same as that in Example 4, except that N-ethylpiperazine is replaced with 3-pyridinecarboxylhydrazine, with a yield of 11.6%. The structure of compound I-20 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 H NMR (400MHz, DMSO) δ8.83(s,1H),8.65-8.62(m,2H),7.81-7.78(m,1H),7.47(m,1H),7.27(t,J=7.6Hz,1H) ,7.17(d,J=8.0Hz,1H),6.94(d,J=1.4Hz,1H),6.87-6.83(m,1H),6.70(dd,J=8.1,1.4Hz,1H),2.35(s,3H). 13C NMR (100MHz, DMSO-D6) δ152.98,151.01,150.75,150.47,149.59,149.33,144.45,136 .65,129.37,127.85,124.34,122.39,122.12,121.70,112.13,15.30.HRMS(ESI)calcd for C 18 H 15 N5OS[M+H] + ,350.1070; found,350.1086.

[0125] Example 21

[0126] This embodiment provides a benzodiazepine Thiophene compounds, having the general formula I, where R1 is H and R2 is... Benzodiazepine The thiophene compounds are designated as compound I-21.

[0127] The preparation method of compound I-21 was basically the same as in Example 4, except that N-ethylpiperazine was replaced with methoxyacetic acid hydrazine, with a yield of 19.2%. The structure of compound I-21 was analyzed using nuclear magnetic resonance (NMR) technology, and the structural characterization results are as follows: 1 HNMR(400MHz,DMSO)δ8.61(s,1H),7.56(d,J=7.9Hz,1H),7.34(t,J=7.6Hz,1H), 7.19-7.12(m,2H),6.84(d,J=0.9Hz,1H),4.52(s,2H),3.31(s,3H),2.33(s,3H). 13 C NMR(100MHz,DMSO)δ150.99,149.92,149.52,143.80,129.11,128.69,126.18, 125.22,123.93,121.78,121.30,111.97,63.42,57.49,14.66.HRMS(ESI)calcd for C 15 H 16 N4O2SNa + [M+Na] + ,339.0886;found,339.0889.

[0128] Experimental example, LSD1 inhibitory activity assay

[0129] For the LSD1 inhibitory activity assay, the test sample was the benzodiazepine obtained from Examples 1-21. Thiophene compounds I-1 to I-21 were included. The sample stock solution was prepared as follows: 1-2 mg of sample was weighed and dissolved in DMSO to a concentration of 20 mM. The solution was stored at 4°C for later use. During the experiment, the solution was diluted with DMSO to the required concentration. The sample was incubated with LSD1 protein at room temperature, followed by incubation with LSD1 substrate H3K4me2. Finally, Amplex fluorescent dye and horseradish peroxidase HRP were added and incubated at room temperature. Fluorescence values ​​were detected using a microplate reader at excitation light of 530 nm and emission light of 590 nm. The inhibition rate was calculated using the following formula: The inhibition rate test results at various concentrations were used to calculate the IC50 using SPSS software. 50 The values ​​are shown in Table 1.

[0130] Table 1. Benzodiazepines of Examples 1-21 of the present invention LSD1 inhibitory activity and IC50 of thiophene compounds 50 value

[0131]

[0132]

[0133]

[0134] As shown in Table 1, the benzodiazepine provided by this invention... Thiophene compounds exhibit varying degrees of inhibitory activity against LSD1. Among them, compounds I-4, I-5, I-7 to I-20 of this invention achieve an inhibition rate of over 85% for LSD1, and the IC50 concentration is [not specified]. 50 Less than 1.2 μM; in particular, the IC50 of compound I-14 is less than 1.2 μM. 50 The effective concentration is only 0.043 μM. It is evident that some of the compounds provided in this invention exhibit effective LSD1 inhibitory activity at relatively low concentrations, which is beneficial for reducing drug dosage and improving efficacy, demonstrating good potential for drug development targeting LSD1.

[0135] In summary, this invention addresses the issue of benzodiazepines. And a hydrogen, benzyl, propargyl or acyl group is introduced at the 10-position of thiophene, while at the benzodiazepine Introducing a fatty amine, aromatic amine, aromatic amine, fatty hydrazine, or acyl hydrazine group at the 4-position of benzothiophene yields a novel skeletal structure for benzothiophene compounds. Experiments have confirmed that this type of compound exhibits good inhibitory activity against LSD1, providing a novel structural framework for the development of highly effective LSD1-targeted inhibitors or antitumor drugs. It also offers a new direction for the development of LSD1-targeted inhibitor drugs, demonstrating its application potential in the field of LSD1-targeted drugs.

Claims

1. A benzodiazepine Thiophene compounds, characterized in that, The compound represented by Formula I or a pharmaceutically acceptable salt thereof: Where R1 is H; R2 is selected from One of them.

2. A benzodiazepine as described in claim 1 The method for preparing thiophene compounds is characterized by, The benzodiazepines were synthesized using the following synthetic route b. Preparation of thiophene compounds: Synthetic route b includes the following steps: dissolving compound 2a and an amine or hydrazine compound in an organic solvent, allowing a nucleophilic substitution reaction to yield benzodiazepine represented by formula I”. And thiophene compounds.

3. The benzodiazepine according to claim 2 The method for preparing thiophene compounds is characterized by, The amine or hydrazine compound is selected from one of N-phenylpiperazine, thiomorpholine-1,1-dioxide, 4-dimethylaminopiperidine, dimethyl-1,3-diaminopropane, N-(2-aminoethyl)morpholine, 4-aminothiomorpholine-1,1-dioxide, 1-amino-4-methylpiperazine, 4-aminopiperazine-1-carboxylic acid tert-butyl ester, N-aminomorpholine, N-aminopiperidine, 3-pyridinecarboxylhydrazine, and methoxyacetic acid hydrazine.

4. The benzodiazepine according to claim 2 The method for preparing thiophene compounds is characterized by, The nucleophilic substitution reaction is carried out at a temperature of 60–150 °C.

5. The benzodiazepine according to any one of claims 2 to 4 The method for preparing thiophene compounds is characterized by, The organic solvent is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, toluene, tetrahydrofuran, and dioxane.

6. A benzodiazepine as described in claim 1 The application of thiophene compounds is characterized by, Application in the preparation of drugs that target and inhibit LSD1.

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