Preparation method and application of BRD4 inhibitor

Abstract

The invention discloses a preparation method and application of a BRD4 inhibitor, belongs to the technical field of medicines, and particularly relates to the BRD4 inhibitor shown in the general formula (I), pharmaceutically acceptable salt or stereoisomer thereof, and R1-R7, X or W are defined in the specification. The invention also relates to a preparation method of the compounds, and a pharmaceutical preparation or a pharmaceutical composition containing the compounds. The BRD4 inhibitor provided by the invention has high selectivity to a second bromo-domain, has stronger inhibitory activity to melanoma cells (A375) than that of a clinical test drug RVX-208, is expected to be applied to preparation of drugs for preventing or / and treating cancers, especially to preparation of drugs for preventing or / and treating melanoma, and has significant medicinal prospects.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to BRD4 inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, a preparation method of the compounds, a pharmaceutical preparation or a pharmaceutical composition containing the compounds, and an application of the compounds in the preparation of a medicine for treating and / or preventing a BRD4-mediated cancer-related disease. BACKGROUND

[0002] Bromodomain-containing protein 4 (BRD4) is a kind of histone acetylation binding protein, which can recognize and bind acetylated lysine residues in the N-terminal tail of histone, recruit chromatin regulatory proteins and transcription factors, etc. BRD4 is extremely important for cell cycle regulation, and recruits transcriptional regulatory complexes to chromatin through BD, ET and CTM domain-mediated protein-protein interactions, and is involved in various cell cycle processes. BRD4 affects cell proliferation, differentiation, migration, apoptosis and transcription, and plays an important role in the occurrence and development of tumors.

[0003] At present, a variety of small molecule inhibitors targeting BRD4 have been reported, and more than 20 inhibitors (such as RVX-208, I-BET762, etc.) have entered clinical trials, but none of them have been approved for marketing. These candidate drugs have exposed some problems in clinical trials, such as easy drug resistance, short drug half-life, and adverse reactions such as thrombocytopenia and gastrointestinal toxicity.

[0004] Therefore, it is still of great significance to develop new and potent BRD4 inhibitors targeting BRD4 with single bromodomain selectivity, which can provide new options for the treatment of diseases such as tumors. SUMMARY

[0005] The present application is made by the applicant aiming to develop BRD4 inhibitors with good effects for treating and / or preventing BRD4-mediated cancer-related diseases or non-cancer-related diseases.

[0006] The present application discloses the following technical scheme for the first time:

[0007] The compound represented by general formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof:

[0008]

[0009] X is selected from -CO-, C1-C6 alkyl and substituted alkyl, or X is absent, and ring W is directly connected to the amino group;

[0010] Ring W is selected from C3-C6 aliphatic ring or a mono-substituted or poly-substituted product thereof, C6-C 12aromatic ring or a mono- or poly-substituted product thereof, C5-C 12 aromatic heterocycle or any one of a mono- or poly-substituted product thereof, or W is not present, R 3 is directly connected to the amino group;

[0011] R 1 is selected from the group consisting of H, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a hydroxyl C1-C6 alkyl group, an amino C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfonyl group, a C4-C 12 aliphatic ring or a mono- or poly-substituted product thereof, C6-C 12 aromatic ring or a mono- or poly-substituted product thereof, C5-C 12 aromatic heterocycle or any one of a mono- or poly-substituted product thereof;

[0012] R 2 is selected from the group consisting of H, a halogen atom, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a hydroxyl C1-C6 alkyl group, an amino C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfonyl group, a C4-C 12 aliphatic ring or a mono- or poly-substituted product thereof, C6-C 12 aromatic ring or a mono- or poly-substituted product thereof, C5-C 12 aromatic heterocycle or any one of a mono- or poly-substituted product thereof;

[0013] or, R 1 is directly connected to the amino group; 2 forms a C5-C 12 aromatic ring, C5-C 12 aromatic heterocycle, C4-C 12 aliphatic ring, C4-C 12 aliphatic ring;

[0014] R 3 is selected from the group consisting of H, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a hydroxyl C1-C6 alkyl group, an amino C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfonyl group, a C4-C 12 aliphatic ring or a mono- or poly-substituted product thereof, C6-C 12 aromatic ring or a mono- or poly-substituted product thereof, C5-C 12 aromatic heterocycle or any one of a mono- or poly-substituted product thereof;

[0015] R 4Selected from H, halogen atom, cyano, nitro, amino, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl carbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkyl sulfonyl, C4-C 12 Aliphatic rings or their mono- or multi-substituted derivatives, C6-C 12 Aromatic rings or their mono- or poly-substituted derivatives, C5-C 12 Any one of aromatic heterocyclic compounds or their mono- or poly-substituted derivatives;

[0016] R 5 Selected from H, halogen atom, cyano, nitro, amino, hydroxyl, C1-C6-alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl carbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkyl sulfonyl, C4-C 12 Aliphatic rings or their mono- or multi-substituted derivatives, C6-C 12 Aromatic rings or their mono- or poly-substituted derivatives, C5-C 12 Any one of aromatic heterocyclic compounds or their mono- or poly-substituted derivatives;

[0017] Or, R 4 With R 5 Formation of C6-C 12 Aromatic rings, C6-C 12 Aromatic heterocycles, C4-C 12 Aliphatic ring, containing 1 to 4 heteroatoms C4-C 12 Any type of adipose ring;

[0018] R 6 Selected from hydrogen, C1-C6-alkyl or its substituted alkyl, sulfonyl, sulfinyl, C1-C6 alkyl carbonyl, C1-C6 alkyl sulfonyl, C3-C8 heterocyclic or 3-8 membered heterocyclic C1-C6 alkyl, C5-C 12 Aromatic rings or their mono- or poly-substituted derivatives;

[0019] R 7 Selected from H, halogen atom, cyano, nitro, amino, hydroxyl, C1-C6-alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl carbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkyl sulfonyl, C4-C 12 Aliphatic rings or their mono- or multi-substituted derivatives, C6-C 12 Aromatic rings or their mono- or poly-substituted derivatives, C5-C 12 Any one of aromatic heterocyclic compounds or their mono- or poly-substituted derivatives;

[0020] The term "halogen atom" as used herein refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. The term "halogenated" as used herein refers to any atom in the group that can be substituted with a halogen atom. The group can be fully halogenated, i.e., all substitutable positions in the group can be replaced with a halogen atom.

[0021] The term "C1-C6alkyl" as used herein refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, and the like. The term "C1-C4alkyl" as used herein refers to the above examples containing from 1 to 3 carbon atoms.

[0022] The term "C1-C6alkoxy" as used herein refers to the group of the term "C1-C6alkyl" attached to the parent molecular moiety through an oxygen atom, such as methoxy, ethoxy, propyloxy, 1-methylethoxy, butoxy, 1-methylpropyloxy, 2-methylpropyloxy, 1,1-dimethylethoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropyloxy, 1,2-dimethylpropyloxy, 2,2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropyloxy, 1,2,2-trimethylpropyloxy, 1-ethyl-1-methylpropyloxy, and 1-ethyl-2-methylpropyloxy. The "C1-C6alkoxy" group also includes alkenyl groups attached to the oxygen ("C1-C6alkenyloxy") or alkynyl groups attached to the oxygen ("C1-C6alkynyloxy").

[0023] The term "C1-C6alkylcarbonyl" as used herein refers to the group of the term "C1-C6alkyl" attached to the parent molecular moiety through a carbonyl group, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, t-butylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, neopentylcarbonyl, hexylcarbonyl, and the like.

[0024] The term "C1-C6alkylcarbonyl" as used herein refers to a group in which the term "C1-C6alkyl" is attached to the parent molecular moiety through a carbonyl group, e.g., acetyl, propionyl, butyryl, isobutyryl, t-butyryl, sec-butyryl, valeryl, amylcarbonyl, hexanoyl, and the like.

[0025] The term "haloC1-C6alkyl", "hydroxyC1-C6alkyl", "aminoC1-C6alkyl" as used herein refers to a group in which one or more of the hydrogen atoms of the term "C1-C6alkyl" are replaced by a halogen atom, a hydroxy group, an amino group, respectively, and which is attached to the parent molecular moiety through an alkyl group.

[0026] The term "C1-C6alkylsulfonyl" as used herein refers to a group in which the term "C1-C6alkyl" is attached to the parent molecular moiety through a sulfonyl group, e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl or isopropylsulfonyl, and the like.

[0027] The term "C4-C 12 The term "alicyclic" as used herein refers to a saturated or unsaturated cyclic hydrocarbon ring containing from 4 to 12 carbon atoms, e.g., cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and the like.

[0028] The "C3-C8 heterocyclyl" group of the present application is a cyclic group containing 3 to 8 ring atoms, at least one of which is a heteroatom selected from N, S, O, SO and / or SO2. The "C3-C8 heterocyclyl" group includes 3-8 membered unsaturated heterocyclyl, 3-8 membered partially saturated heterocyclyl and 3-8 membered saturated heterocyclyl. The 3-8 membered unsaturated heterocyclyl and 3-8 membered partially saturated heterocyclyl refer to 3-8 membered heterocyclic groups having unsaturated bonds in the ring. Specific examples include, but are not limited to, for example, azetidine, 1,2-diazetidine, pyrrole, 4,5-dihydropyrrole, 2,5-dihydropyrrole, imidazole, 4,5-dihydroimidazole, pyrazole, 4,5-dihydropyrazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, 2-pyridone, 4-pyridone, pyridazine, pyridine, pyrazine, 1,2,3-triazine, 1,3-diazepine, 1,4-diazepine, azocine, 1,4-dihydro-1,4-diazocine, 1,2-dithietane, furan, 4,5-dihydrofuran, 2,5-dihydrofuran, thiophene, 2,5-dihydrothiophene, and the like. The 3-8 membered saturated heterocyclyl is a cyclic group containing heteroatoms, all of which are saturated bonds. Specific examples include, but are not limited to, aziridine, azetidine, 1,2-diazetidine, pyrrolidine, imidazolidine, pyrazolidine, hydrogenated pyridone, piperidine, piperazine, oxirane, thiirane, oxetane, 1,2-dioxetane, thietane, tetrahydrofuran, tetrahydrothiophene, 1,3-dioxolane, 1,3-dithiolane, tetrahydropyran, 1,4-dioxane, and the like.

[0029] The "C6-C 12 The "aromatic ring" is a cyclic aromatic group having 6 to 12 carbon atoms in the ring. The "aromatic ring" includes 6-12 membered monocyclic aryl and 8-12 membered fused aryl. The 6-12 membered monocyclic aryl is an aryl group having all unsaturated bonds, for example, phenyl, cyclooctatetraenyl, and the like. The 8-12 membered fused aryl is a cyclic group having at least one ring which is an aromatic ring having all unsaturated bonds, formed by two or more cyclic structures sharing two adjacent carbon atoms with each other. The 8-12 membered fused aryl includes 8-12 membered fully unsaturated fused aryl, naphthyl, anthryl, phenanthryl, and the like, and also includes 8-12 membered partially saturated fused aryl, for example, benzene-3-6 membered saturated cycloalkyl, benzene-3-6 membered partially saturated cycloalkyl, and the like.

[0030] The "C5-C 12 The "heteroaromatic ring" is a cyclic aromatic group having 5 to 12 ring atoms, at least one of which is a heteroatom selected from N, S, O, SO and / or SO2.

[0031] The mono-substituted or multi-substituted product is selected from one or more of the following substitutions: halogen substitution, OH substitution, NH2substitution, hydrazine group substitution, urea group substitution, acyl substitution, aldehyde group substitution, ketone group substitution, acid substitution, ester substitution, amide group substitution.

[0032] The BRD4 inhibitor further comprises any one of the following structural formula or a pharmaceutically acceptable salt, isomer, or pharmaceutically acceptable derivative thereof:

[0033]

[0034] The application further provides the use of the BRD4 inhibitor with anti-tumor activity and / or the BRD4 inhibitor with anti-tumor activity obtained according to the above preparation method in an anti-tumor agent, such as an agent for treating tumors.

[0035] The application has the following beneficial effects:

[0036] The quinazolinone BRD4 inhibitor has high selectivity for the second bromodomain and strong inhibitory activity on melanoma cells (A375) than the clinical trial drug RVX-208. Animal experiment research shows that the tumor inhibition rates of Example 1 (50 mg / kg), Example 1 (25 mg / kg), and Example 7 (50 mg / kg) on A375 transplanted tumor mice are 66.26%, 41.50%, and 61.77%, respectively, and there is no obvious toxic side effect. However, many studies have found that the clinical trial drug RVX-208 does not have anti-tumor effect. Therefore, the quinazolinone BRD4 inhibitor can be used for preparing a drug for preventing or / and treating melanoma, and has significant pharmaceutical prospects. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 The nuclear magnetic resonance hydrogen spectrum of the product obtained in Example 1 of the application.

[0038] Figure 2 The nuclear magnetic resonance hydrogen spectrum of the product obtained in Example 2 of the application.

[0039] Figure 3 The nuclear magnetic resonance hydrogen spectrum of the product obtained in Example 3 of the application.

[0040] Figure 4 The nuclear magnetic resonance hydrogen spectrum of the product obtained in Example 4 of the application.

[0041] Figure 5 The nuclear magnetic resonance hydrogen spectrum of the product obtained in Example 5 of the application.

[0042] Figure 6 The nuclear magnetic resonance hydrogen spectrum of the product obtained in Example 6 of the application.

[0043] Figure 7 NMR of hydrogen for the product obtained in Example 7 of the present application.

[0044] Figure 8 A375 transplanted tumor mouse experiment of Example 1 and 7 of the present application. Body weight change (A), tumor volume (B), tumor weight (C) and tumor actuality (D) graph of control group, Example 1 50 mg / kg group, Example 1 25 mg / kg group and Example 7 50 mg / kg group. DETAILED DESCRIPTION

[0045] The present application is described in detail below with reference to the examples and drawings, but it should be understood that the examples and drawings are only used to exemplarily describe the present application, and cannot constitute any limitation on the protection scope of the present application. All reasonable variations and combinations within the scope of the inventive concept of the present application fall within the protection scope of the present application.

[0046] According to the technical scheme of the present application, a specific preparation method of 5-aminoquinoline-4(3H)-ketone derivative includes:

[0047] (1) 5-nitroanthranilic acid amide shown in formula A reacts with aldehyde shown in formula B to obtain intermediate C;

[0048] (2) Intermediate C is reduced by Zn powder to obtain intermediate D

[0049] (2) BRD4 inhibitor described in formula F is obtained by reductive amination of intermediate D and aldehyde shown in formula E under the condition of sodium triacetoxyborohydride;

[0050] The reaction formula is shown as follows:

[0051]

[0052] Wherein, X is selected from -CO-, C1-C6 alkyl and substituted alkyl, or X is not present, ring W is directly connected to the amino group;

[0053] Ring W is selected from C3-C6 aliphatic ring or its mono-substituted or poly-substituted product, C6-C 12 aromatic ring or its mono-substituted or poly-substituted product, C5-C 12 aromatic heterocycle or its mono-substituted or poly-substituted product, or W is not present, R 3 is directly connected to the amino group;

[0054] R 3H, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6-alkyl group, a haloC1-C6-alkyl group, a hydroxyC1-C6-alkyl group, an aminoC1-C6-alkyl group, a C1-C6-alkoxy group, a C1-C6-alkylcarbonyl group, a C1-C6-alkoxycarbonyl group, a C1-C6-alkylsulfonyl group, a C4-C 12 a C6-Ci2-cycloalkyl group, a C6-Ci2-cycloalkyl group mono- or polysubstituted by a substituent selected from the group consisting of a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6-alkyl group, a haloC1-C6-alkyl group, a hydroxyC1-C6-alkyl group, an aminoC1-C6-alkyl group, a C1-C6-alkoxy group, a C1-C6-alkylcarbonyl group, a C1-C6-alkoxycarbonyl group, a C1-C6-alkylsulfonyl group, a C4-C 12 an aromatic ring or a mono- or polysubstituted derivative thereof, a C5-Ci2-aromatic ring, a C5-Ci2-aromatic ring mono- or polysubstituted by a substituent selected from the group consisting of a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6-alkyl group, a haloC1-C6-alkyl group, a hydroxyC1-C6-alkyl group, an aminoC1-C6-alkyl group, a C1-C6-alkoxy group, a C1-C6-alkylcarbonyl group, a C1-C6-alkoxycarbonyl group, a C1-C6-alkylsulfonyl group, a C4-C 12 an aromatic heterocycle or a mono- or polysubstituted derivative thereof, a C5-Ci2-aromatic heterocycle, a C5-Ci2-aromatic heterocycle mono- or polysubstituted by a substituent selected from the group consisting of a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6-alkyl group, a haloC1-C6-alkyl group, a hydroxyC1-C6-alkyl group, an aminoC1-C6-alkyl group, a C1-C6-alkoxy group, a C1-C6-alkylcarbonyl group, a C1-C6-alkoxycarbonyl group, a C1-C6-alkylsulfonyl group, a C4-C

[0055] R 7 H, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6-alkyl group, a haloC1-C6-alkyl group, a hydroxyC1-C6-alkyl group, an aminoC1-C6-alkyl group, a C1-C6-alkoxy group, a C1-C6-alkylcarbonyl group, a C1-C6-alkoxycarbonyl group, a C1-C6-alkylsulfonyl group, a C4-C 12 a C6-Ci2-cycloalkyl group, a C6-Ci2-cycloalkyl group mono- or polysubstituted by a substituent selected from the group consisting of a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6-alkyl group, a haloC1-C6-alkyl group, a hydroxyC1-C6-alkyl group, an aminoC1-C6-alkyl group, a C1-C6-alkoxy group, a C1-C6-alkylcarbonyl group, a C1-C6-alkoxycarbonyl group, a C1-C6-alkylsulfonyl group, a C4-C 12 an aromatic ring or a mono- or polysubstituted derivative thereof, a C5-Ci2-aromatic ring, a C5-Ci2-aromatic ring mono- or polysubstituted by a substituent selected from the group consisting of a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6-alkyl group, a haloC1-C6-alkyl group, a hydroxyC1-C6-alkyl group, an aminoC1-C6-alkyl group, a C1-C6-alkoxy group, a C1-C6-alkylcarbonyl group, a C1-C6-alkoxycarbonyl group, a C1-C6-alkylsulfonyl group, a C4-C 12 an aromatic heterocycle or a mono- or polysubstituted derivative thereof, a C5-Ci2-aromatic heterocycle, a C5-Ci2-aromatic heterocycle mono- or polysubstituted by a substituent selected from the group consisting of a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6-alkyl group, a haloC1-C6-alkyl group, a hydroxyC1-C6-alkyl group, an aminoC1-C6-alkyl group, a C1-C6-alkoxy group, a C1-C6-alkylcarbonyl group, a C1-C6-alkoxycarbonyl group, a C1-C6-alkylsulfonyl group, a C4-C

[0056] For a further understanding of the application, the preparation method provided by the application is described in more detail below through specific examples, and it should be understood that the protection scope of the application is not limited by the following examples.

[0057] The raw materials involved in the following examples are commercially available.

[0058] Example 1

[0059] 6-nitro-2-(3,4,5-trimethoxyphenyl)-quinolin-4(3H)-one

[0060] Into a reaction flask was added 2-amino-5-nitrobenzamide (181 mg, 1 mmol) and 3,4,5-trimethoxybenzaldehyde (235 mg, 1.2 mmol), and the reaction was dissolved in 10 mL, and then I2(305 mg, 1.2 mmol) was added to the reaction flask. After refluxing for 3 h, thin layer chromatography was used to monitor the complete reaction of the raw material, and then 3 mL of 5% Na2S2O4was added to quench the reaction. A light yellow solid was precipitated in the reaction flask, and the filter cake was washed with water and methanol after suction filtration to obtain the product as a light yellow solid (yield 56%). The nuclear magnetic resonance characterization data are as follows: 1HNMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.82 (d, J = 2.7 Hz, 1H), 8.54 (dd, J = 9.0, 2.7 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.61 (s, 2H), 3.91 (s, 6H), 3.77 (s, 3H).

[0061] 6-amino-2-(3,4,5-trimethoxyphenyl)-quinolin-4(3H)-one

[0062] To the reaction flask was added 6-nitro-2-(3,4,5-trimethoxyphenyl)-quinolin-4(3H)-one (178 mg, 0.5 mmol), activated zinc dust (163 mg, 2.5 mmol) followed by 5 mL of dichloromethane, 1 mL of acetic acid was added under stirring. After 3 h of reaction at room temperature, the product was obtained as a light yellow solid after suction filtration and used directly in the next step.

[0063] 6-(((1-benzylpiperidin-4-yl)methyl)amino)-2-(3,4,5-trimethoxyphenyl)-quinolin-4(3H)-one

[0064] To the reaction flask was added 6-nitro-2-(3,4,5-trimethoxyphenyl)-quinolin-4(3H)-one (178 mg, 0.5 mmol), activated zinc dust (163 mg, 2.5 mmol) followed by 5 mL of dichloromethane, 1 mL of acetic acid was added under stirring. After 3 h of reaction at room temperature, the product was obtained as a light yellow solid after suction filtration and used directly in the next step.

[0065] The product was characterized by proton nuclear magnetic resonance spectroscopy as shown in Figure 1 and the characterization data are as follows: Figure 1 1 ​H NMR (400 MHz, Chloroform-d) δ 11.56 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.42 (s, 2H), 7.38 - 7.29 (m, 5H), 7.24 (d, J = 2.8 Hz, 1H), 7.09 (dd, J = 8.8, 2.8 Hz, 1H), 4.02 (s, 6H), 3.92 (s, 3H), 3.60 (s, 2H), 3.14 (d, J = 4.9 Hz, 2H), 3.01 (d, J = 10.9 Hz, 2H), 2.09 (t, J = 11.3 Hz, 2H), 1.82 (d, J = 12.4 Hz, 2H), 1.56 - 1.44 (m, 2H), 1.21 (s, 1H).

[0066] The structural formula is as follows:

[0067]

[0068] Example 2

[0069] 2-(4-Hydroxy-3,5-dimethoxyphenyl)-6-nitroquinolin-4(3H)-one

[0070] Into a reaction flask was added 2-amino-5-nitrobenzamide (181 mg, 1 mmol) and 4-hydroxy-3,5-dimethylbenzaldehyde (180 mg, 1.2 mmol), and the reaction was dissolved in 10 mL. Then, 12 (305 mg, 1.2 mmol) was added to the reaction flask. After refluxing for 3 h, thin layer chromatography was used to monitor the completion of the reaction. Then, 5% Na2S2O4 was added to quench the reaction. A light yellow solid was precipitated in the reaction flask. After suction filtration, the filter cake was washed with water and methanol to obtain the product as a light yellow solid (yield 52%). The nuclear magnetic resonance characterization data are as follows: 1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 9.17 (s, 1H), 8.78 (d, J = 2.7 Hz, 1H), 8.49 (dd, J = 9.0, 2.7 Hz, 1H), 7.92 (s, 2H), 7.82 (d, J = 9.0 Hz, 1H), 2.24 (s, 6H).

[0071] 2-(4-Hydroxy-3,5-dimethoxyphenyl)-6-nitroquinolin-4(3H)-one

[0072] Into a reaction flask was added 2-(4-hydroxy-3,5-dimethoxyphenyl)-6-nitroquinolin-4(3H)-one (186 mg, 0.6 mmol) and activated zinc powder (195 mg, 3 mmol), and 5 mL of dichloromethane was added. Then, 1 mL of acetic acid was added under stirring. After reaction at room temperature for 3 h, suction filtration was performed to obtain the product as a light yellow solid, which was directly used in the next step.

[0073] 6-(((1 -benzylpiperidin-4-yl)methyl)amino)-2-(4-hydroxy-3,5- dimethoxyphenyl)-quinolin-4(3H)-one

[0074] To a reaction flask was added 2-(4-hydroxy-3,5-dimethoxyphenyl)-6- aminoquinolin-4(3H)-one (337 mg, 1.2 mmol) and N-benzyl-4-piperidinecarboxaldehyde (203 mg, 1 mmol) in 15 mL of 1,2-dichloroethane under ice bath condition. To the reaction flask was added sodium triacetoxyborohydride (636 mg, 3 mmol) and acetic acid (115 μL, 2 mmol). The reaction was stirred at room temperature under N2for 6 h. After the starting material was consumed, the reaction was quenched by the addition of 1 N NaOH (1 mL) to the reaction flask. The reaction was extracted with dichloromethane (10 mL) and water (20 mL). The combined organic layers were washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate and filtered. The resulting solution was evaporated and then purified by silica gel column chromatography (CH2Cl2 / CH3OH 50: 1 to 10: 1) to give the product as a yellow oil solid (239 mg, 51%).

[0075] The resulting product was characterized by proton nuclear magnetic resonance spectroscopy as shown in Figure 3, and the characterization data are as follows: Figure 2 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.79 (s, 1H), 7.78 (s, 2H), 7.44 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 4.4 Hz, 5H), 7.15 (dd, J = 8.9, 2.7 Hz, 1H), 7.03 (d, J = 2.8 Hz, 1H), 6.20 (t, J = 5.5 Hz, 1H), 3.56 (s, 2H), 3.34 (s, 2H), 3.00 (d, J = 5.9 Hz, 2H), 2.89 (s, 2H), 2.23 (s, 6H), 1.84 - 1.76 (m, 2H), 1.68 - 1.60 (m, 1H), 1.29 (d, J = 12.1 Hz, 2H).

[0076] The structural formula is as follows:

[0077]

[0078] Example 3

[0079] 6-nitro-2-(6-(trifluoromethyl)pyridin-3-yl)quinazolin-4(3H)-one

[0080] ​To a reaction flask was added 2-amino-5-nitrobenzamide (271 mg, 1.5 mmol) and 6- trifluoromethylpyridine-3-carboxaldehyde (315 mg, 1.88 mmol) and the reaction was dissolved in 15 mL of dichloromethane. To the reaction flask was added I2(457 mg, 1.8 mmol) and the reaction was refluxed for 3 h. TLC monitoring indicated the reaction was complete and the reaction was quenched with 5% Na2S2O4. A light yellow solid precipitated in the reaction flask and was filtered off and washed with water and methanol to give the product as a light yellow solid (45% yield). Characterization data by NMR is as follows: 1 H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 9.47 (d, J = 2.2 Hz, 1H), 8.87 (d, J = 2.7 Hz, 1H), 8.80 (dd, J = 8.4, 2.2 Hz, 1H), 8.61 (dd, J = 9.0, 2.7 Hz, 1H), 8.17 (dd, J = 8.3, 0.9 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H).

[0081] 6-amino-2-(6-(trifluoromethyl)pyridin-3-yl)quinazolin-4(3H)-one

[0082] To a reaction flask was added 6-nitro-2-(6-(trifluoromethyl)pyridin-3-yl)quinazolin-4(3H)-one (168 mg, 0.5 mmol) and activated zinc dust (163 mg, 2.5 mmol) followed by 5 mL of dichloromethane and 1 mL of acetic acid. The reaction was stirred at room temperature for 3 h. The reaction was filtered off and the product was used directly in the next reaction.

[0083] 6-(((1-benzylpiperidin-4-yl)methyl)amino)-2-(6-(trifluoromethyl)pyridin-3-yl)quinazolin-4(3H)-one

[0084] To a reaction flask was added 6-amino-2-(6-(trifluoromethyl)pyridin-3- yl)quinazolin-4(3H)-one (367 mg, 1.2 mmol) and N-benzyl-4-piperidinecarboxaldehyde (203 mg, 1 mmol) in 15 mL of 1,2-dichloroethane under ice bath condition. To the reaction flask was added sodium triacetoxyborohydride (636 mg, 3 mmol) and acetic acid (115 μL, 2 mmol). The reaction was stirred at room temperature under N2for 6 h. After the starting material was consumed, the reaction was quenched by the addition of 1 N NaOH (1 mL) to the reaction flask. The reaction was extracted with dichloromethane (10 mL) and water (20 mL). The combined organic layers were washed with saturated NaCl solution (10 mL x 3), dried over anhydrous sodium sulfate and filtered. The resulting solution was evaporated and then purified by silica gel column chromatography (CH2Cl2 / CH3OH 50: 1 to 10: 1) to give the product as a yellow oil solid (187 mg, 38%).

[0085] The resulting product was characterized by proton nuclear magnetic resonance spectroscopy as shown in the attached Figure 3 characterization data as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 9.41 (d, J = 2.1 Hz, 1H), 8.71 (dd, J = 8.3, 2.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.37 (p, J = 17.7, 15.9 Hz, 5H), 7.21 (dd, J = 8.9, 2.8 Hz, 1H), 7.10 (d, J = 2.8 Hz, 1H), 6.51 (d, J = 5.8 Hz, 1H), 3.03 (d, J = 6.3 Hz, 3H), 2.22 - 1.46 (m, 5H), 1.40 (s, 2H).

[0086] The structural formula is as follows:

[0087]

[0088] Example 4

[0089] 6-((3-hydroxypropyl)amino)-2-(3,4,5-trimethoxyphenyl)quinazolin-4(3H)-one

[0090] To a reaction flask containing 6-amino-2-(3,4,5-trimethoxyphenyl)- quinolin-4(3H)-one (98 mg, 0.3 mmol) and cesium carbonate (196 mg, 0.6 mmol) was added 5 mL of acetonitrile, 3-bromopropanol (40 μL, 0.48 mmol) and potassium iodide (5 mg, 0.03 mmol) were added under stirring and the reaction was refluxed at 80 °C overnight. After the starting material had disappeared, 15 mL of water and 10 mL of saturated sodium chloride solution were added to the reaction flask, the organic phase was extracted three times with ethyl acetate (15 mL) and dried over anhydrous sodium sulfate, the combined organic phases were purified by column chromatography on silica gel (CH2Cl2 / CH3OH 50:1 to 30:1) to give the product as a white solid (150 mg, 39%).

[0091] The resulting product was characterized by nuclear magnetic resonance hydrogen spectrum, as shown in the attached Figure 4 characterization data as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.83 (d, J = 8.5 Hz, 1H), 7.77 (s, 2H), 7.24 (d, J = 9.2 Hz, 1H), 7.21 (s, 1H), 4.84 (t, J = 5.3 Hz, 2H), 4.00 (s, 6H), 3.92 (s, 3H), 3.84 (t, J = 5.2 Hz, 2H), 2.50 (s, 1H), 2.20 - 2.12 (m, 2H).

[0092] The structural formula is as follows:

[0093]

[0094] Example 5

[0095] 6-((Cyclopropylmethyl)amino)-2-(3,4,5-trimethoxyphenyl)quinazolin-4(3H)-one

[0096] To a reaction vial was added 6-amino-2-(3,4,5-trimethoxyphenyl)- quinolin-4(3H)-one (98 mg, 0.3 mmol) and cyclopropylcarboxaldehyde (19 μL, 0.25 mmol) in 3 mL of 1,2-dichloroethane under ice bath condition. To the reaction vial was added sodium triacetoxyborohydride (159 mg, 0.75 mmol) and acetic acid (30 μL, 0.5 mmol). The reaction was stirred at room temperature under N2for 6 h. After the starting material was consumed, the reaction was quenched by the addition of 1 N NaOH (1 mL) to the reaction vial. The reaction was extracted with dichloromethane (10 mL) and water (20 mL). The combined organic layers were washed with saturated NaCl solution (10 mL x 3), dried over anhydrous sodium sulfate, and filtered. The resulting solution was evaporated and then purified by silica gel column chromatography (CH2Cl2 / CH3OH 100:1 to 50:1) to give the product as a yellow oil solid (72 mg, 63%).

[0097] The resulting product was characterized by proton nuclear magnetic resonance spectroscopy as shown in Figure 1. Figure 5 1 H NMR (400 MHz, Chloroform-d) δ 11.97 (s, 1H), 7.67 (dd, J = 8.8, 1.8 Hz, 1H), 7.49 (d, J = 1.8 Hz, 2H), 7.24 (t, J = 2.3 Hz, 1H), 7.12 (dt, J = 8.8, 2.3 Hz, 1H), 4.19 (d, J = 5.3 Hz, 1H), 4.05 (s, 6H), 3.94 (s, 3H), 3.13 - 3.00 (m, 2H), 1.16 (s, 1H), 0.62 (d, J = 7.5 Hz, 2H), 0.30 (d, J = 5.0 Hz, 2H).

[0098] The structural formula is as follows:

[0099]

[0100] Example 6

[0101] tert-Butyl 4-(((4-oxo-2-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinazolin-6- yl)amino)methyl)piperidine-1-carboxylate

[0102] ​To a reaction flask containing 6-amino-2-(3,4,5-trimethoxyphenyl)- quinolin-4(3H)-one (393 mg, 1.2 mmol) and l-tert-butoxycarbonyl-4- piperidinecarboxaldehyde (213 mg, 1 mmol) was added sodium triacetoxyborohydride (636 mg, 3 mmol) and acetic acid (117 μL, 2 mmol) under ice bath condition. The reaction flask was stirred at room temperature for 6 h under N2 protection. After the starting material was consumed, the reaction was quenched by the addition of 1 N NaOH (1 mL) to the reaction flask. The reaction mixture was extracted with dichloromethane (220 mL) and water (20 mL). The combined organic layers were washed with saturated NaCl solution (10 mL x 3), dried over anhydrous Na2SO4, and filtered. The resulting solution was evaporated and then purified by silica gel column chromatography (CH2Cl2 / CH3OH 100:1 to 50:1) to give the product as a yellow oil solid (319 mg, 61%).

[0103] The resulting product was characterized by proton nuclear magnetic resonance spectroscopy as shown in the attached Figure 6 1 H NMR (400 MHz, Chloroform-d) δ 12.05 (s, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 1.8 Hz, 2H), 7.25 - 7.21 (m, 1H), 7.09 (dd, J = 8.8, 2.8 Hz, 1H), 4.14 (s, 2H), 4.02 (s, 6H), 3.92 (s, 3H), 3.13 (s, 2H), 2.72 (t, J = 13.5 Hz, 2H), 1.88 (s, 1H), 1.80 (d, J = 11.9 Hz, 2H), 1.46 (s, 9H), 1.25 - 1.17 (m, 2H).

[0104] The structural formula is as follows:

[0105]

[0106] Example 7

[0107] 6-((Piperidin-4-ylmethyl)amino)-2-(3,4,5-trimethoxyphenyl)quinazolin-4(3H)-one

[0108] To a reaction flask containing tert-butyl 4-(((4-oxo-2-(3,4,5- trimethoxyphenyl)-3,4-dihydroquinazolin-6-yl)amino)methyl)piperidine- 1-carboxylate (524 mg, 1 mmol) was added 10 mL of dichloromethane. To the reaction mixture was added 1 mL of trifluoroacetic acid dropwise. The reaction was stirred at room temperature for 3 h, and thin layer chromatography was used to monitor the consumption of the starting material. The reaction mixture was evaporated to dryness, and was used directly in the next step. ​

[0109] 6-(((1 -acetylpiperidin-4-yl)methyl)amino)-2-(3,4,5-trimethoxyphenyl)quinazolin- 4(3H)-one

[0110] To a 2-necked flask was added 6-((piperidin-4-yl)methyl)amino)-2-(3,4,5- trimethoxyphenyl)quinazolin-4(3H)-one (153 mg, 0.36 mmol) and 4-dimethylaminopyridine (132 mg, 1.08 mmol) followed by 55 mL of ultra-dry dichloromethane under ice-bath condition. Acetic anhydride (68 μL, 0.72 mmol) was added slowly under N2protection and stirred at room temperature for 10 h. After the starting material spot disappeared, 20 mL of saturated sodium bicarbonate solution was added to the reaction flask, which was extracted with dichloromethane (20 mL) for three times, dried over anhydrous sodium sulfate, and the combined organic phase was purified by silica gel column chromatography (CH2Cl2 / CH3OH 50:1 to 30:1) to give the product as a white solid (119 mg, 71%).

[0111] The resulting product was characterized by proton nuclear magnetic resonance spectroscopy as shown in Figure 7 1 H NMR (400 MHz, Chloroform-d) δ 11.93 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.46 (s, 2H), 7.24 (d, J = 2.8 Hz, 1H), 7.09 (dd, J = 8.8, 2.8 Hz, 1H), 4.02 (s, 6H), 3.91 (s, 3H), 3.47 (t, J = 7.0 Hz, 2H), 3.13 (q, J = 8.2, 7.5 Hz, 2H), 2.56 (td, J = 12.9, 2.6 Hz, 1H), 2.10 (s, 3H), 1.90 - 1.85 (m, 2H), 1.19 (t, J = 7.0 Hz, 4H).

[0112] The structural formula is as follows:

[0113]

[0114] By the same reaction process as in Examples 1-7, some products shown in the following table can be obtained by adjusting the starting materials and corresponding reaction conditions:

[0115] Table 1

[0116]

[0117]

[0118] Some of the prepared compounds randomly selected from Examples 1-7 and other examples of the present application were tested for IC50values against BRD4(1) and BRD4(2)​50 The value determination and NO generation inhibition determination results are shown in Table 2 below:

[0119] Table 2 Activity data of representative examples

[0120]

[0121] Among them, RVX-208 is a BRD4 inhibitor in the prior art. According to the test results, it can be known that some of the compounds prepared in the present application have stronger selectivity for the single bromine domain of BRD4 protein than RVX-208, and the inhibition effect of some of the compounds on A375 is also stronger than that of RVX-208.

[0122] In order to study the in vivo anti-tumor effect of Example 1 and Example 7 on A375 cells, we carried out a xenotransplant mouse tumor growth experiment. After each mouse was inoculated with 7 million cells, the body weight and tumor growth of the mice were observed, and when the tumor grew to 50-100mm 3 (6th day), the corresponding compound was orally administered every day, and after 14 days of treatment, the mice were sacrificed when the average tumor size of the model group reached 1500mm 3 . The results are shown in Figure 8 , and through 20-day body weight observation of the mice, it was found that there was no obvious change in body weight before and after administration, and it was found that after 14 days of administration of Example 1 (50mg / kg), Example 1 (25mg / kg) and Example 7 (50mg / kg), respectively, the tumor growth of the mice was significantly slowed down compared with the model group, and after weighing the tumors, it was found that the tumor inhibition rates of the three administration groups were 66.26%, 41.50% and 61.77%, respectively, compared with the model group.

[0123] The above specific description further details the purpose, technical solutions and beneficial effects of the present application. It should be understood that the above description is only a specific embodiment of the present application and is not intended to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A BRD4 inhibitor comprising a compound having a general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the general formula (I) is as follows: wherein: X is selected from -CO-, C1-C6 alkyl and substituted alkyl, or X is absent, and ring W is directly connected to the amino group; R1 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfanyl, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, C wherein: ​ ring W is selected from C3-C6alicyclic ring or a mono- or poly-substituted version thereof, C6-C 12 aromatic ring or a mono- or poly-substituted version thereof, C5-C 12 aromatic heterocyclic ring or a mono- or poly-substituted version thereof, or W is absent, R 3 is directly attached to the amino group; R 1 selected from the group consisting of H, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a hydroxyl C1-C6 alkyl group, an amino C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfonyl group, a C4-C 12 a C6-C 12 an aromatic ring or a mono- or poly-substituted product thereof, a C5-C 12 any one of an aromatic heterocycle or a mono- or poly-substituted product thereof; R 2 selected from the group consisting of H, a halogen atom, a C1-C6alkyl group, a halogenated C1-C6alkyl group, a hydroxy C1-C6alkyl group, an amino C1-C6alkyl group, a C1-C6alkoxy group, a C1-C6alkylcarbonyl group, a C1-C6alkoxycarbonyl group, a C1-C6alkylsulfonyl group, a C4-C 12 a C6-C 12 an aromatic ring or a mono- or poly-substituted product thereof, a C5-C 12 any one of an aromatic heterocycle or a mono- or poly-substituted product thereof; or R 1 with R 2 form C5-C 12 aromatic ring, C5-C 12 aromatic heterocycle, C4-C 12 alicyclic ring, C4-C 12 alicyclic ring, C4-C R 3 selected from the group consisting of H, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a hydroxyl C1-C6 alkyl group, an amino C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfonyl group, a C4-C 12 a C6-C 12 an aromatic ring or a mono- or poly-substituted product thereof, a C5-C 12 any one of an aromatic heterocycle or a mono- or poly-substituted product thereof; R 4 selected from the group consisting of H, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6alkyl group, a halogenoC1-C6alkyl group, a hydroxyC1-C6alkyl group, an aminoC1-C6alkyl group, a C1-C6alkoxy group, a C1-C6alkylcarbonyl group, a C1-C6alkoxycarbonyl group, a C1-C6alkylsulfonyl group, a C4-C 12 a C6-C 12 an aromatic ring or a mono- or poly-substituted product thereof, a C5-C 12 any one of an aromatic heterocyclic ring or a mono- or poly-substituted product thereof; R 5 selected from the group consisting of H, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a C1-C6-alkyl group, a halogenated C1-C6-alkyl group, a hydroxy C1-C6-alkyl group, an amino C1-C6-alkyl group, a C1-C6-alkoxy group, a C1-C6-alkylcarbonyl group, a C1-C6-alkoxycarbonyl group, a C1-C6-alkylsulfonyl group, a C4-C 12 a C6-C 12 an aromatic ring or a mono- or polysubstituted derivative thereof, a C5-C 12 any one of an aromatic heterocycle or a mono- or polysubstituted derivative thereof; or R 4 with R 5 form C6-C 12 aromatic ring, C6-C 12 aromatic heterocycle, C4-C 12 alicyclic ring, C4-C 12 alicyclic ring containing 1 to 4 heteroatoms R 6 Selected from hydrogen, C1-C6-alkyl or its substituted alkyl, sulfonyl, sulfinyl, C1-C6 alkyl carbonyl, C1-C6 alkyl sulfonyl, C3-C8 heterocyclic or 3-8 membered heterocyclic C1-C6 alkyl, C5-C 12 Aromatic rings or their mono- or poly-substituted derivatives; R 7 Selected from H, halogen atom, cyano, nitro, amino, hydroxyl, C1-C6-alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl carbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkyl sulfonyl, C4-C 12 Aliphatic rings or their mono- or multi-substituted derivatives, C6-C 12 Aromatic rings or their mono- or poly-substituted derivatives, C5-C 12 Any one of aromatic heterocyclic compounds or their mono- or poly-substituted derivatives. ​ ​ ​ ​ ​ ​ ​ ​ said hydroxy C1-C6 alkyl is a group in which one or more hydrogen atoms of a C1-C6 alkyl group is replaced with a hydroxy group and which is attached to the parent molecular moiety through an alkyl group; said amino C1-C6 alkyl is a group in which one or more hydrogen atoms of a C1-C6 alkyl group is replaced with an amino group and which is attached to the parent molecular moiety through an alkyl group; said C1-C6 alkylsulfonyl is a group in which a C1-C6 alkyl group is attached to the parent molecular moiety through a sulfonyl group, including methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl or isopropylsulfonyl; said C4-C 12 alicyclic rings are aliphatic rings containing 4 to 12 carbon atoms, including: cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane; said C3-C8 heterocyclyl is a heterocyclic group containing 3-8 ring atoms, at least one of which is a heteroatom selected from N, S, O, SO and / or SO2, including 3-8 membered unsaturated heterocyclyl, 3-8 membered partially saturated heterocyclyl and 3-8 membered saturated heterocyclyl; said C6-Ci8-aryl is a cyclic aromatic group having 6 to 18 carbon atoms in the ring system, including 6 to 12 membered monocyclic aryl groups and 8 to 12 membered fused ring aryl groups; 12 said C6-Ci8-aryl is a cyclic aromatic group having 6 to 18 carbon atoms in the ring system, including 6 to 12 membered monocyclic aryl groups and 8 to 12 membered fused ring aryl groups The C5-C 12 Aromatic heterocycles are 5-12 membered cyclic aromatic groups containing one or more heteroatoms; said mono- or poly-substitution is selected from one or more of the following substitutions: halogen substitution, OH substitution, NH2substitution, hydrazine substitution, urea substitution, acyl substitution, aldehyde substitution, ketone substitution, acid substitution, ester substitution, amide substitution.

3. The BRD4 inhibitor of claim 2, wherein: said C1-C6 alkoxy group also includes an alkenyl group attached to the oxygen or an alkynyl group attached to the oxygen.

4. The BRD4 inhibitor of claim 2, wherein: said 3-8 membered unsaturated heterocyclyl and 3-8 membered partially saturated heterocyclyl refers to 3-8 membered heterocyclic groups in which there is an unsaturated bond in the ring, including azetidene, 1,2-diazetidene, pyrrole, 4,5-dihydropyrrole, 2,5-dihydropyrrole, imidazole, 4,5-dihydroimidazole, pyrazole, 4,5-dihydropyrazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, 2-pyridone, 4-pyridone, pyridazine, pyridine, pyrazine, 1,2,3-triazine, 1,3-diazepine, 1,4-diazepine, azocine, 1,4-dihydro-1,4-diazocine, 1,2-dithietene, furan, 4,5-dihydrofuran, 2,5-dihydrofuran, thiophene, 2,5-dihydrothiophene, and the like; said 3-8 membered saturated heterocyclyl is a cyclic group containing heteroatoms in which all bonds are saturated, including aziridine, azetidine, 1,2-diazetidine, pyrrolidine, imidazolidine, pyrazolidine, hydrogenated pyridone, piperidine, piperazine, oxirane, thiirane, oxetane, 1,2-dioxetane, thietane, tetrahydrofuran, tetrahydrothiophene, 1,3-dioxolane, 1,3-dithiolane, tetrahydropyran, 1,4-dioxane.

5. The BRD4 inhibitor of claim 2, wherein:

6. A 6-12 membered monocyclic aryl group is an all unsaturated aryl group, such as phenyl, cyclooctatetraenyl, and the like. An 8-12 membered fused aryl group is a cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other, at least one of which is an all unsaturated aromatic ring, including 8-12 membered all unsaturated fused aryl groups, naphthyl, anthryl, phenanthryl, and the like, and also including 8-12 membered partially saturated fused aryl groups, such as benzene-3-6 membered saturated cyclic alkyl, benzene-3-6 membered partially saturated cyclic alkyl, and the like.

6. The BRD4 inhibitor of claim 2, wherein: the heteroatom comprises N, S, O, SO, and / or SO2.

7. The BRD4 inhibitor of any one of claims 1-6, wherein: the BRD4 inhibitor comprises any one of the following structural formulae or pharmaceutically acceptable salts, isomers, or pharmaceutically acceptable derivatives thereof:

8. A pharmaceutical composition, wherein: the composition comprises at least one pharmaceutically acceptable excipient, adjuvant, or carrier, and the BRD4 inhibitor of any one of claims 1-7.

9. Use of the BRD4 inhibitor of any one of claims 1-8 or the pharmaceutical composition of claim 8 in the manufacture of a medicament for treating and / or preventing a BRD4-mediated cancer-related disease.

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