Compound used as histone acetyltransferase p300 / CBP bromodomain inhibitor and preparation method and application thereof

Abstract

The invention relates to a compound used as a histone acetyltransferase p300 / CBP bromodomain inhibitor and a preparation method and application thereof. The compound has a structure as shown in the following formula I: # imgabs0 #, wherein R1 to R3, X and Y1 to Y3 are defined in the specification. The invention also relates to a pharmaceutical composition containing the compound or the derivative thereof and application of the pharmaceutical composition as a p300 / CBP bromodomain inhibitor. The compound and the derivative thereof can significantly inhibit the activity of histone acetyltransferase p300 / CBP, have very strong proliferation inhibition activity on multiple myeloma cells OPM-2, prostate cancer cells 22RV1 and the like, have good metabolic stability, safety and drug-likeness, and can be used as an antitumor drug.

Description

Technical Field

[0001] This invention patent belongs to the field of synthetic medicinal chemistry, and particularly relates to compounds or their derivatives used as p300 / CBP bromodomain inhibitors, and their preparation methods and applications. Background Art

[0002] The acetylation and deacetylation of histones are one of the most studied post-translational modifications (PTMs) in epigenetics, occurring on the conserved lysine residues at the N-terminal tails of core histones. The acetylation process of histones is dynamically reversible and is mainly regulated by histone acetyltransferase (HAT), histone deacetylase (HDAC), and bromodomain-containing protein (BCP). The three jointly maintain the histone acetylation balance in the body and play a crucial role in regulating gene expression.

[0003] The highly homologous adenoviral E1A binding protein of 300 kDa (p300) and CREB binding protein (CBP) are a pair of bromodomain-containing proteins with relatively high homology and are often collectively referred to as p300 / CBP. p300 / CBP can recognize acetylated histones carrying different genetic information through its bromodomain, thereby regulating gene expression.

[0004] Studies have found that in various tumor models such as prostate cancer, multiple myeloma, acute myeloid leukemia, and breast cancer, p300 / CBP is highly expressed and functionally abnormal, and inhibiting the function of its bromodomain can block the occurrence and development of tumors. Therefore, targeting the inhibition of the p300 / CBP bromodomain has gradually become a new method for treating cancer, and the research on its inhibitors is an important direction in tumor drug research and development.

[0005] Currently, only two candidate compounds of p300 / CBP bromodomain inhibitors have entered the clinical research stage. Among them, CCS1477 (CAS: 2222941-37-7) developed by Cellcentric is currently in the clinical phase I / II study for the treatment of acute myeloid leukemia, non-Hodgkin lymphoma, multiple myeloma, and metastatic castration-resistant prostate cancer.

[0006] However, there are few structural types and numbers of p300 / CBP bromodomain inhibitors. Therefore, the discovery of p300 / CBP bromodomain inhibitors with novel structures for the treatment of related cancers has gradually become a research hotspot for major pharmaceutical companies and research institutions. The discovery of p300 / CBP bromodomain inhibitors with strong activity, high selectivity, and good drug-likeness is of great significance for the development of epigenetic drugs. Summary of the Invention

[0007] The inventors designed and synthesized a series of novel compounds that can be used as p300 / CBP bromodomain inhibitors. These compounds with the structure of general formula I, together with their pharmaceutically acceptable salts and other derivatives, can all be used as p300 / CBP bromodomain inhibitors.

[0008] The inventors also conducted biological evaluations on the obtained compounds. The results showed that the compounds of the present invention can significantly inhibit the activity of the p300 bromodomain at the molecular level and also showed strong anti-proliferative activity at the cellular level. In the OPM-2 animal model of multiple myeloma, the compounds of the present invention exhibited a strong tumor growth inhibitory effect and could significantly reduce the expression levels of c-Myc in cells and in mice. At the same time, these compounds or their derivatives as the inhibitors can have high selectivity and good metabolic and physicochemical properties, showing great potential for the development of anti-tumor drugs.

[0009] Therefore, in the first aspect, the present invention provides a compound or its derivative (including, for example, deuterated compounds, salts, isomers, crystal forms, or solvates thereof), and the compound has the structure shown in the following formula I:

[0010]

[0011] R1 is selected from substituted or unsubstituted aryl, heteroaryl, and saturated or unsaturated heterocycloalkyl;

[0012] R2 is selected from substituted or unsubstituted alkyl, saturated or unsaturated cycloalkyl, and saturated or unsaturated heterocycloalkyl;

[0013] R3 is selected from substituted or unsubstituted aryl and heteroaryl;

[0014] X is a covalent bond, -CH2-, or -CH2CH2-;

[0015] Y1, Y2, and Y3 are each independently selected from CH and N;

[0016] The derivative is a deuterated compound, salt, isomer, crystal form, and / or solvate.

[0017] The present invention provides, in a second aspect, a pharmaceutical composition comprising: (1) the compound or its derivative according to the first aspect of the present invention; and (2) a pharmaceutically acceptable carrier and / or excipient.

[0018] The present invention provides, in a third aspect, the use of the compound or its derivative according to the first aspect of the present invention as a p300 / CBP bromodomain inhibitor.

[0019] The inventors of the present invention have confirmed through biological experiments that a class of novel-structured compounds provided by the present invention can significantly inhibit the activity of histone acetyltransferase p300 and can be used as p300 / CBP bromodomain inhibitors. Moreover, these compounds of the present invention have excellent inhibitory effects on various tumor cells including prostate cancer cells (such as 22RV1), leukemia cells, breast cancer cells, and multiple myeloma cells (such as OPM-2). These compounds or their derivatives of the present invention also have good metabolic stability, safety, and drug-likeness and can be used as active components of anti-tumor drugs. Therefore, the compounds or their derivatives of the present invention have broad application prospects in the preparation of p300 / CBP inhibitors, as well as drugs for preventing and / or treating tumors and myeloid hematopoietic stem cell diseases or drugs for regulating regulatory T cells. Detailed Embodiments

[0020] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be described more clearly and completely below in conjunction with the detailed embodiments. However, the embodiments described herein are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.

[0021] Definition of terms used in the present invention: Unless otherwise specified, the initial definitions provided for groups or terms herein apply to such groups or terms throughout the specification; for terms not specifically defined herein, they have the meanings commonly understood by those skilled in the art.

[0022] "Hydrogen", "carbon", and "oxygen" in the compounds of the present invention include all their isotopes. Isotopes should be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 12 C, 13 C, and 14 C, and isotopes of oxygen include 16 O and 18 O, etc.

[0023] "Halogen" in the present invention refers to fluorine, chlorine, bromine, and iodine. "Halogenated" in the present invention means being substituted by fluorine, chlorine, bromine, or iodine.

[0024] The minimum and maximum carbon atom contents in the hydrocarbon groups of the present invention are represented by subscripts. For example, the prefix C a-b alkyl represents any alkyl group containing "a" to "b" carbon atoms.

[0025] "Cycloalkyl" in the present invention refers to a cyclic hydrocarbon group. Suitable cycloalkyl groups can be substituted or unsubstituted monocyclic, bicyclic, or tricyclic hydrocarbon groups having 3 - 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Each instance of the cycloalkyl group can be optionally substituted or unsubstituted. When substituted, the substituents can be at any available attachment point.

[0026] "Heterocycloalkyl" in the present invention refers to a group of a 3 - to 12 - membered non - aromatic ring system having 1 to 4 ring heteroatoms (where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon). In a heterocycloalkyl group containing one or more nitrogen atoms, the attachment point can be a carbon or nitrogen atom as long as the valence allows. The heterocycloalkyl group can either be monocyclic ("monocyclic heterocycloalkyl") or a fused, bridged, or spiro ring system (such as a bicyclic system (also known as "bicyclic heterocycloalkyl")). Each instance of the heterocycloalkyl group can be optionally substituted or unsubstituted. When substituted, the substituents can be at any available attachment point.

[0027] "Aryl" in the present invention refers to an aromatic system that can include a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic aromatic system, which contains 6 to 12 carbon atoms. The aryl group can be optionally substituted or unsubstituted. When substituted, the substituents can be at any available attachment point.

[0028] "Heteroaryl" in the present invention refers to an aryl group in which at least one ring - forming carbon atom is replaced by a heteroatom, preferably composed of 5 - 12 atoms, and the heteroatoms are O, S, and N. The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituents can be at any available attachment point.

[0029] "Pharmaceutically acceptable" in the present invention means that a certain carrier, vehicle, diluent, excipient, and / or the formed salt is generally chemically or physically compatible with other components constituting a pharmaceutical dosage form and is physiologically compatible with the receptor.

[0030] "Salt" in the present invention refers to acid - type and / or base - type salts formed by combining any compound described in the present invention with inorganic and / or organic acids and / or bases, also including zwitterionic salts (inner salts), and also including quaternary ammonium salts.

[0031] The "solvate" of the present invention refers to any solvate formed by a compound as described in the present invention and a solvent, where the solvent includes but is not limited to: water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, dichloromethane, etc.

[0032] The "pharmaceutical composition" of the present invention refers to a composition comprising at least one compound of the present invention (including its derivatives, such as corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or their chemically protected forms) and one or more pharmaceutically acceptable carriers; the pharmaceutical composition may further comprise one or more drugs different from the compound of the present invention. One of the purposes of the pharmaceutical composition is to facilitate the administration of the compound of the present invention to an organism.

[0033] As described above, in a first aspect, the present invention provides a compound or its derivative, and the compound has a structure shown in the following formula I:

[0034]

[0035] R1 is selected from substituted or unsubstituted aryl, heteroaryl, and saturated or unsaturated heterocycloalkyl;

[0036] R2 is selected from substituted or unsubstituted alkyl, saturated or unsaturated cycloalkyl, and saturated or unsaturated heterocycloalkyl;

[0037] R3 is selected from substituted or unsubstituted aryl and heteroaryl;

[0038] X is a covalent bond, -CH2-, or -CH2CH2-;

[0039] Y1, Y2, and Y3 are each independently selected from CH and N;

[0040] The derivative is a deuterated compound, salt, isomer, crystal form, and / or solvate.

[0041] Additionally preferably or further preferably, R1 is selected from aryl, heteroaryl, and C5-C7 saturated or unsaturated heterocycloalkyl substituted with 0-4 (e.g., 0, 1, 2, 3, or 4) R5. Among them, R5 is selected from C1-C6 alkyl, C3-C 10 saturated cycloalkyl, C3-C 10 saturated heterocycloalkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with one or more halogens, halogen, and cyano.

[0042] Additionally preferably or further preferably, R2 is selected from C1-C6 alkyl, C3-C 10 saturated or unsaturated cycloalkyl, and C3-C 10A saturated or unsaturated heterocycloalkyl. Among them, R6 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 A saturated or unsaturated cycloalkyl, C3-C 10 A saturated or unsaturated heterocycloalkyl, C1-C6 alkoxy, C1-C6 cycloalkoxy, C1-C6 alkyl acyl, C 3-10 Cycloalkyl acyl, C1-C6 alkyl sulfonyl, C 3-10 Cycloalkyl sulfonyl, C1-C6 alkoxy acyl, hydroxy-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl acyl, C1-C6 alkyl substituted with one or more halogens, =O, =S, halogen, cyano and hydroxy.

[0043] Additionally preferably or further preferably, R3 is selected from aryl and heteroaryl substituted with 0-4 (e.g., 0, 1, 2, 3 or 4) R7. Among them, R7 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 A saturated or unsaturated cycloalkyl, C3-C 10 A saturated or unsaturated heterocycloalkyl, C1-C6 alkoxy, C1-C6 cycloalkoxy, C 1-6 Alkylamino, C1-C6 cycloalkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkylamino acyl, C1-C6 alkyl substituted with one or more halogens, C1-C6 alkoxy substituted with one or more halogens, C 1-6 Alkyl ester group, hydroxy, halogen, cyano, nitro and amino.

[0044] Additionally preferably or further preferably, R1 is selected from one of the following groups:

[0045] Additionally preferably or further preferably, R2 is selected from one of the following groups:

[0046] Additionally preferably or further preferably, R3 is selected from one of the following groups:

[0047] Additionally preferably or further preferably, X is -CH2- or -CH2CH2-, more preferably -CH2CH2-.

[0048] Additionally preferably or further preferably, Y1, Y2 and Y3 are each independently selected from CH; more preferably, Y1, Y2 and Y3 are simultaneously CH.

[0049] In some more preferred embodiments: R1 is R2 is R3 is X is -CH2CH2-; Y1 is CH; Y2 is CH; and / or Y3 is CH.

[0050] In some further preferred embodiments: R1 is R2 is R3 is X is -CH2CH2-; Y1 is CH; Y2 is CH; and Y3 is CH.

[0051] Additionally preferably or further preferably, the compound is one of the following compounds:

[0052]

[0053]

[0054]

[0055] In a second aspect, the present invention provides a pharmaceutical composition, which comprises: (1) the compound or its derivative described in the first aspect of the present invention; and (2) a pharmaceutically acceptable carrier and / or excipient.

[0056] In a third aspect, the present invention provides the use of the compound or its derivative described in the first aspect of the present invention as a p300 / CBP bromodomain inhibitor.

[0057] Additionally preferably or further preferably, the p300 / CBP bromodomain inhibitor is used as a drug for preventing and / or treating tumors, myeloid hematopoietic stem cell malignancies, and regulating regulatory T cells.

[0058] More preferably, the tumor is selected from one or more of hematological malignancies, gastric cancer, intestinal cancer, cervical cancer, bladder cancer, laryngeal cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, or multiple myeloma.

[0059] In a fourth aspect, the present invention provides a method for synthesizing the compound described in the first aspect of the present invention, and the method is synthesized according to the following synthetic route:

[0060]

[0061] wherein, n is 1 or 2, and R1, R2, R3, Y1, Y2, and Y3 are as defined in the first aspect of the present invention;

[0062] and the method comprises the following steps:

[0063] 1) The compound of formula (1) and the compound of formula (2) react through the Chan-Lam reaction to form the compound of formula (3);

[0064] 2) The compound of formula (3) is prepared into the compound of formula (4) through an oxidation reaction;

[0065] 3) The compound of formula (4) reacts with the compounds of formula (5) and formula (6) to form the compound of formula (7);

[0066] 5) The compound of formula (7) and the compound of formula (8) react through the Suzuki reaction to form the compound of formula (I).

[0067] Examples

[0068] The above content of the present invention will be further described in detail below in the form of examples. However, this should not be understood as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope claimed by the present invention.

[0069] Example 1: (S)-5-(3-(Cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one

[0070]

[0071] Step 1: Synthesis of Intermediate 1-2:

[0072]

[0073] Dissolve L-pyroglutamol (1-1) (3.00 g, 26.06 mmol), 3,4-difluorophenylboronic acid (6.17 g, 39.09 mmol), copper(II) acetate monohydrate (5.20 g, 26.06 mmol) and triethylamine (7.24 mL) in 50 mL of acetonitrile, and react at room temperature for 5 h. After the reaction is completed, concentrate the reaction solution under vacuum, dilute it with ethyl acetate (200 mL), wash it once with 1 M hydrochloric acid solution and twice with saturated sodium chloride solution, collect the organic phase, dry it with anhydrous sodium sulfate, concentrate it, and purify it by column chromatography (DCM / MeOH = 30:1) to obtain a colorless oily product (1.83 g, 31%). 11H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.22 (d, J = 2.5 Hz, 2H), 4.22 (s, 1H), 3.75–3.55 (m, 2H), 2.71 (ddd, J = 17.6, 10.0, 7.2 Hz, 1H), 2.56–2.45 (m, 1H), 2.36–2.25 (m, 1H), 2.16 (td, J = 9.4, 4.9 Hz, 1H).

[0074] Step 2: Synthesis of Intermediate 1-3:

[0075]

[0076] Dissolve Intermediate 1-2 (1.83 g, 8.05 mmol) in 30 mL of anhydrous dichloromethane, displace with nitrogen three times, and add Dess-Martin periodinane (CAS: 87413-09-0) (4.14 g, 9.86 mmol) under ice bath conditions. React for 1.5 h. After the reaction is complete, add 50 mL of saturated sodium thiosulfate and 50 mL of saturated sodium bicarbonate and stir for 15 min to quench. Extract twice with 200 mL of dichloromethane, retain the organic phase, wash twice with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain the crude product, which is used directly in the next step without purification.

[0077] Step 3: Synthesis of Intermediate 1-4:

[0078]

[0079] Add 2-amino-4-bromopyridine (1.23 g, 7.11 mmol), cyclohexyl isocyanide (853.75 mg, 7.82 mmol), Intermediate 1-3 (1.83 g, 7.11 mmol), and scandium trifluoromethanesulfonate (279.90 mg, 0.57 mmol) to a 15 mL sealed tube. Use 8 mL of a dichloromethane / methanol (3:1) mixture as the solvent and react at 100 °C for 2 h. After the reaction is complete, cool to room temperature. After concentrating the reaction solution in vacuo, dilute with ethyl acetate (150 mL), wash once with 50 mL of water and twice with saturated sodium chloride solution in sequence, collect the organic phase, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM / MeOH = 30:1) to obtain a white solid product (2.19 g, overall yield of two steps 63%). 11H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.1 Hz, 1H), 7.47 (d, J = 15.8 Hz, 2H), 7.09 (s, 1H), 7.00 (d, J = 9.2 Hz, 1H), 6.83 (d, J = 7.1 Hz, 1H), 5.36 (t, J = 7.0 Hz, 1H), 3.05–2.94 (m, 1H), 2.64 (tdd, J = 28.5, 20.2, 12.4 Hz, 4H), 2.50–2.45 (m, 1H), 1.73 (s, 4H), 1.18 (t, J = 11.7 Hz, 5H).

[0080] Step 4: Synthesis of (S)-5-(3-(Cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one

[0081]

[0082] Intermediate 1-4 (50 mg, 102.2 μmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (33.4 mg, 132.8 μmol), Pd(dppf)Cl2 (7.5 mg, 10.2 μmol) and potassium carbonate (21.2 mg, 153.3 μmol) were dissolved in 3 mL of a mixed solution of 1,4-dioxane / water (3:1). The mixture was purged with nitrogen three times and heated at 85 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated in vacuo. Then it was diluted with ethyl acetate (50 mL), washed successively with 50 mL of water once and saturated sodium chloride solution twice. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain the target product.

[0083] The following Examples 2 to 14 were synthesized by the method described in Example 1 or using the corresponding intermediates in a method similar to Example 1.

[0084]

[0085]

[0086] The target compounds synthesized in Examples 1 to 14, their molecular structures and 1 1H NMR spectra are shown in the following table.

[0087]

[0088]

[0089]

[0090] Example 15: (S)-6-(3-(Cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

[0091]

[0092] Step 1: Synthesis of Intermediate 15-1

[0093]

[0094] Synthesis was carried out in substantially the same manner as Intermediate 1-4, except that the starting material (3,4-difluorophenyl)boronic acid in Step 1 was replaced with (3-fluoro-4-methoxyphenyl)boronic acid, and (S)-5-(hydroxymethyl)pyrrolidin-2-one was replaced with (S)-6-(hydroxymethyl)piperidin-2-one.

[0095] Step 2: Synthesis of (S)-6-(3-(Cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

[0096]

[0097] Synthesis was carried out in substantially the same manner as Example 1, except that Intermediate 1-4 in Step 4 was replaced with Intermediate 15-1.

[0098] The following Examples 16 to 21 were synthesized by the method described in Example 15 or synthesized in a similar manner to Example 15 using the corresponding intermediates.

[0099]

[0100] The target compounds obtained by synthesizing Examples 16 to 21, their molecular structures and 1 1H NMR spectra or MS are shown in the following table.

[0101]

[0102]

[0103] Example 22: (S)-6-(3-((1-Acetylpiperidin-4-yl)amino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

[0104]

[0105] Step 1: Synthesis of Intermediate 22-1

[0106]

[0107] It is synthesized by a method basically the same as that of Intermediate 15-1, except that isocyanocyclohexane in Step 1 is replaced with tert-butyl 4-isocyanopiperidine-1-carboxylate.

[0108] Step 2: Synthesis of Intermediate 22-2

[0109]

[0110] It is synthesized by a method basically the same as that of Example 15, except that Intermediate 15-1 in Step 2 is replaced with Intermediate 22-1.

[0111] Step 3: Synthesis of Intermediate 22-3

[0112]

[0113] Dissolve Intermediate 22-2 (1 g) in 10 mL of dioxane, add 10 mL of 4 M hydrogen chloride dioxane solution thereto under the condition of zero degree, and react at room temperature for 2 h. After the reaction is completed, spin-dry the reaction solution to obtain the crude product, which can be used for the next reaction without purification.

[0114] Step 4: Synthesis of (S)-6-(3-((1-acetylpiperidin-4-yl)amino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

[0115]

[0116] Dissolve Intermediate 22-3 (30 mg, 52.7 μmol) in 3 mL of dichloromethane, add triethylamine (13.3 mg, 131.8 μmol) and acetyl chloride (8.3 mg, 105.4 μmol) thereto under the condition of zero degree, and react at room temperature for 0.5 h. After the reaction is completed, dilute with ethyl acetate (50 mL), wash twice with 50 mL of water and twice with saturated sodium chloride solution successively, collect the organic phase, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain the target compound.

[0117] The following Examples 23 to 29 are synthesized by the method described in Example 23, or synthesized by a method similar to that of Example 23 using the corresponding intermediates.

[0118]

[0119] The target compounds synthesized in Examples 23 to 29, their molecular structures and 1 1H NMR spectra are shown in the following table.

[0120]

[0121]

[0122] Examples 30 to 34 described below were synthesized by the method described in Example 15, or synthesized in a similar method to Example 15 using the corresponding intermediates.

[0123]

[0124] The target compounds synthesized in Examples 30 to 34, their molecular structures and 1 1H NMR spectra are shown in the following table.

[0125]

[0126]

[0127] Detection Example 1: In vitro inhibitory activity detection of the compound against histone acetyltransferase p300

[0128] The inhibition rate of the compound against the bromodomain of p300 protein was detected by AlphaLISA technology.

[0129] AlphaLISA technology mainly relies on the interaction between Alpha donor beads and acceptor beads. When a biological reaction brings the donor beads and acceptor beads close to each other, laser excitation triggers a cascade reaction, resulting in a greatly amplified signal. Specifically, under the irradiation of a 680 nm laser, the photosensitizer on the donor beads converts the oxygen in the surrounding environment into more active singlet oxygen. The singlet oxygen diffuses to the acceptor beads, generating a series of chemiluminescence reactions, and finally transferring the energy to europium, emitting at a wavelength of 615 nm. In the absence of specific interactions between biomolecules, singlet oxygen cannot diffuse to the acceptor beads, and no signal will be generated. The specific experimental steps are as follows:

[0130] 1. Dilute Recombinant p300 protein, biotinylated histone peptide, inhibitor, Ni-Acceptorbeads and Alpha Streptavidin Donor beads with reaction buffer;

[0131] 2. Add the following reagents to a white 384-well microplate in sequence;

[0132] -- 5 μL inhibitor (highest concentration 1 μM, 3-fold dilution) or epigenetic buffer,

[0133] -- 2.5 μL Recombinant p300 protein, bromodomain (aa1041 - 1161)

[0134] -- 2.5 μL biotinylated histone peptide;

[0135] 3. Seal the microplate and incubate at room temperature for 60 minutes;

[0136] 4. Add 10 μL of Ni - Acceptor beads, seal and incubate for 60 minutes

[0137] 5. Add 10 μL of Alpha Streptavidin Donor beads, seal and incubate for 30 minutes;

[0138] 6. Read with a Tecan microplate reader.

[0139] Set up two replicates for each experimental group and a blank control group.

[0140] Inhibition rate (%) = {[(Positive control signal value - Blank control signal value) - (Test compound signal value - Blank control signal value)] / (Positive control signal value - Blank control signal value)} * 100%

[0141] Using the inhibition rate (%) as the ordinate and the compound concentration as the abscissa, use Graphpad prism software to plot the competitive inhibition curves respectively, and calculate the concentration when the binding rate of the compound to the p300 protein is 50% (IC 50 ) The experimental results are shown in Table 1.

[0142] Table 1: In vitro inhibitory activity of compounds against p300

[0143]

[0144]

[0145] Note: ++++: represents IC 50 < 50 nM

[0146] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A compound or its derivative, characterized in that, The compound has the structure shown in Formula I as follows: R1 is selected from substituted or unsubstituted aryl, heteroaryl, and saturated or unsaturated heterocycloalkyl; R2 is selected from substituted or unsubstituted alkyl, saturated or unsaturated cycloalkyl, and saturated or unsaturated heterocycloalkyl; R3 is selected from substituted or unsubstituted aryl and heteroaryl; X is a covalent bond, -CH2-, or -CH2CH2-; Y1, Y2, and Y3 are each independently selected from CH and N; The derivative is a deuterated compound, salt, isomer, crystal form, and / or solvate.

2. The compound or its derivative according to claim 1, wherein: R1 is selected from aryl, heteroaryl, and C5-C7 saturated or unsaturated heterocycloalkyl substituted with 0-4 R5; Among them, R5 is selected from C1-C6 alkyl, C3-C 10 saturated cycloalkyl, C3-C 10 saturated heterocycloalkyl, C1-C6 alkoxy, one or more halogen-substituted C1-C6 alkyl, halogen and cyano.

3. The compound or its derivative according to claim 1 or 2, wherein: R2 is selected from 0 to 4 R6-substituted C1-C6 alkyl groups, C3-C 10 saturated or unsaturated cycloalkyl groups, and C3-C 10 saturated or unsaturated heterocycloalkyl groups; Among them, R6 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 saturated or unsaturated cycloalkyl, C3-C 10 saturated or unsaturated heterocycloalkyl, C1-C6 alkoxy, C1-C6 cycloalkoxy, C1-C6 alkyl acyl, C 3-10 cycloalkyl acyl, C1-C6 alkyl sulfonyl, C 3-10 cycloalkyl sulfonyl, C1-C6 alkyloxy acyl, hydroxy-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl acyl, one or more halogen-substituted C1-C6 alkyl, =O, =S, halogen, cyano and hydroxy.

4. The compound or its derivative according to any one of claims 1 to 3, wherein: R3 is selected from aryl and heteroaryl substituted with 0-4 R7; Among them, R7 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 saturated or unsaturated cycloalkyl, C3-C 10 saturated or unsaturated heterocycloalkyl, C1-C6 alkoxy, C1-C6 cycloalkoxy, C 1-6 alkylamino, C1-C6 cycloalkylamino, C 1-6 alkylacylamino, C 1-6 alkylaminoacyl, C1-C6 alkyl substituted by one or more halogens, C1-C6 alkoxy substituted by one or more halogens, C 1-6 alkyl ester group, hydroxyl, halogen, cyano, nitro and amino.

5. The compound or its derivative according to any one of claims 1 to 4, wherein: R1 is selected from one of the following groups: and / or R2 is selected from one of the following groups: and / or R3 is selected from one of the following groups:

6. The compound or its derivative according to any one of claims 1 to 5, characterized in that, The compound is one of the following compounds:

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (1) The compound or its derivative according to any one of claims 1 to 6; and (2) A pharmaceutically acceptable carrier and / or excipient.

8. Use of the compound or its derivative according to any one of claims 1 to 6 as a BET / p300 bromodomain dual-target inhibitor.

9. The use according to claim 8, wherein: The p300 / CBP bromodomain dual-target inhibitor is used as a drug for preventing and / or treating tumors or myeloid hematopoietic stem cell malignancies, or as a drug for regulating regulatory T cells; Preferably, the tumor is selected from one or more of hematological malignancies, gastric cancer, intestinal cancer, cervical cancer, bladder cancer, laryngeal cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, or multiple myeloma.

10. A method for synthesizing the compound according to any one of claims 1 to 6, characterized in that, The method is synthesized according to the following synthetic route: Wherein, n is 1 or 2; And the method comprises the following steps: 1) Reacting the compound of formula (1) and the compound of formula (2) by Chan-Lam reaction to generate the compound of formula (3); 2) Oxidizing the compound of formula (3) to obtain the compound of formula (4); 3) Reacting the compound of formula (4) with the compounds of formula (5) and formula (6) to obtain the compound of formula (7); 5) Reacting the compound of formula (7) and the compound of formula (8) by Suzuki reaction to obtain the compound of formula (I).

Images