Compound capable of being used as BET / p300 bromodomain double-target inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a compound capable of being used as a BET / p300 bromodomain double-target inhibitor or a derivative thereof as well as a preparation method and application of the compound. The compound has a structure as shown in a formula I, wherein substituent groups R1 to R4 in the formula # imgabs0 are defined in the specification. The invention also relates to a pharmaceutical composition containing the compound or the derivative thereof, application of the compound or the derivative thereof as a BET / p300 bromodomain double-target inhibitor, and a preparation method of the compound or the derivative thereof. The compound or the derivative thereof can significantly inhibit the activity of BET / p300 bromodomain, has a significant anti-proliferation effect on cancer cells and multiple myeloma cells, and also has good metabolic stability, safety and drug-likeness, so that the compound or the derivative thereof has a wide application prospect.

Description

Technical Field

[0001] This invention patent belongs to the field of synthetic pharmaceutical chemistry, and particularly relates to a novel compound that can be used as a dual-target inhibitor of BET / p300 bromodomains, and its preparation method and application. Background Art

[0002] The acetylation and deacetylation of histone lysine residues are reversible post-translational modifications. Proteins modified by acetylation can carry different genetic information and play a crucial role in regulating gene expression, which is a key research content in epigenetics.

[0003] Bromodomain-containing proteins (BCPs) can recognize acetylated histone lysine residues (KAc) through bromodomains, read the genetic information carried by post-translationally modified histones, and thus regulate gene expression. Therefore, bromodomains are currently highly attractive targets for regulating gene expression, and the research on their inhibitors is an important direction in tumor drug development.

[0004] Bromodomain and extraterminal domain (BET) family proteins and p300 / CBP family proteins composed of highly homologous adenoviral E1A-binding protein of 300 kDa (p300) and CREB-binding protein (CBP) are two of the most studied bromodomain-containing proteins and are considered the most promising epigenetic tumor treatment targets.

[0005] The abnormal functions of BET and p300 / CBP bromodomains are closely related to the occurrence and development of various tumors such as prostate cancer, multiple myeloma, acute myeloid leukemia, and breast cancer. Therefore, targeting BET or p300 / CBP bromodomains can be used to treat cancer. Currently, many selective BET inhibitors or p300 / CBP bromodomain inhibitors are in the clinical research stage.

[0006] The BET and p300 / CBP bromodomains can work synergistically in vivo. Inhibiting only one family of proteins will lead to the compensation of the other family of proteins. Therefore, combination therapy has become a better tumor treatment option. Meanwhile, the discovery of dual-target inhibitors has also become a research hotspot for medicinal chemists. However, currently, only one dual-target inhibitor, NEO2734, is in clinical research. Therefore, there is a need to discover novel BET / p300 bromodomain dual-target inhibitors with strong activity and good drug-likeness to meet clinical needs. Summary of the Invention

[0007] The inventors designed and synthesized a series of novel BET / p300 bromodomain dual-target inhibitors, provided compounds with the structure of general formula (Ⅰ) or their derivatives such as pharmaceutically acceptable salts as BET / p300 bromodomain dual-target inhibitors, and conducted biological evaluations on them. It was found that small molecule compounds with excellent activity at the molecular and cellular levels and good drug-likeness can be used as BET / p300 bromodomain dual-target inhibitors.

[0008] Biological experiment results show that the compounds and their derivatives of the present invention, as BET / p300 bromodomain dual-target inhibitors, have inhibitory effects equivalent to or even superior to the clinically studied compound NEO2734 at the molecular and cellular levels. In animal models, the compounds of the present invention exhibit strong tumor growth inhibitory effects and can significantly reduce the expression levels of c-Myc in cells and in mice. Meanwhile, these compounds or their derivatives have good physicochemical properties and bioavailability, meeting the development requirements of anti-tumor drugs.

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

[0010]

[0011] Wherein:

[0012] R1 is selected from hydrogen, unsubstituted or substituted alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl, aryl and heteroaryl;

[0013] R2 is selected from hydrogen, unsubstituted or substituted alkyl, saturated or unsaturated cycloalkylmethylene, saturated or unsaturated heterocycloalkylmethylene and benzyl;

[0014] R3 and R4 are independently selected from the structures shown in the following formulas II, III, IV and V:

[0015]

[0016]

[0017] R5 and R6 are independently selected from hydrogen, alkyl, allyl, propargyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl;

[0018] R7 is selected from hydrogen, alkyl, allyl, propargyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl, alkoxyacyl, alkylaminoacyl, allylaminoacyl, propargylaminoacyl, haloalkylaminoacyl, saturated or unsaturated cycloalkylaminoacyl and saturated or unsaturated heterocycloalkylaminoacyl;

[0019] Y1, Y2 and Y3 are independently selected from CH and N;

[0020] In a second aspect, the present invention provides a pharmaceutical composition, which comprises: (1) the compound or its derivative according to the first aspect of the present invention (the derivative of the compound may be a deuterated compound, salt, isomer, crystal form or its solvate); and (2) a pharmaceutically acceptable carrier and / or excipient.

[0021] In a third aspect, the present invention provides the use of the compound or its derivative according to the first aspect of the present invention (the derivative of the compound may be a deuterated compound, salt, isomer, crystal form or its solvate) as a BET / p300 bromodomain dual-target inhibitor.

[0022] The inventors of the present invention have confirmed through biological experiments that the compounds or their derivatives provided by the present invention are a class of structurally novel BET / p300 bromodomain dual-target inhibitors, which can significantly inhibit the activity of the BET / p300 bromodomain, and the compounds or their derivatives of the present invention have excellent anti-proliferative effects on a variety of tumor cells including prostate cancer cells, leukemia cells, breast cancer cells and multiple myeloma cells, and the inhibitory effect is far better than that of the in-research drug NEO2734 (CAS No.: 2081072-29-7) of the same type in clinical trials. The compounds or their derivatives of the present invention also have good metabolic stability, safety and drug-likeness, and can be used as candidate molecules for the development of anti-tumor drugs. Therefore, the compounds and their derivatives of the present invention have broad application prospects as BET / p300 bromodomain dual-target inhibitors in the preparation of drugs for preventing and / or treating tumors, myeloid hematopoietic stem cell diseases and drugs for regulating regulatory T cells. Detailed implementation manners

[0023] 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 specific 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 making creative efforts shall fall within the scope of protection of the present invention.

[0024] 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, meanings that can be given to them by those skilled in the art should be provided based on the disclosure and context.

[0025] "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.

[0026] "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.

[0027] The minimum and maximum carbon atom contents in the hydrocarbon groups of the present invention are represented by subscripts. For example, subscript C a-b alkyl represents any alkyl group containing "a" to "b" carbon atoms.

[0028] "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 to 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.

[0029] "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 heterocyclic group containing one or more nitrogen atoms, the attachment point can be a carbon or nitrogen atom as long as the valence permits. The heterocyclic group can either be monocyclic ("monocyclic heterocyclic group") or a fused, bridged, or spiro ring system (such as a bicyclic system (also known as "bicyclic heterocyclic group")). Each instance of the heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituents can be at any available attachment point.

[0030] "Aryl" in the present invention refers to an aromatic system which may comprise a monocyclic or fused polycyclic ring, preferably an aromatic system comprising a monocyclic or fused bicyclic ring, containing 6 to 12 carbon atoms. The aryl may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available attachment point.

[0031] "Heteroaryl" in the present invention refers to an aryl in which at least one carbon atom is replaced by a heteroatom, preferably composed of 5 - 12 atoms. Preferably, the heteroatoms are selected from O, S, and N. The heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available attachment point.

[0032] "Pharmaceutically acceptable" in the present invention means that a carrier, vehicle, diluent, excipient, and / or the formed salt is generally chemically or physically compatible with the other components constituting a pharmaceutical dosage form and is physiologically compatible with the receptor.

[0033] "Salt" in the present invention refers to an acid salt and / or a base salt formed by reacting any compound described in the present invention with an inorganic and / or organic acid and / or base, including zwitterionic salts (inner salts) and also including quaternary ammonium salts.

[0034] "Solvate" in the present invention refers to a solvate formed by any compound described in the present invention and a solvent, where the solvent includes but is not limited to: water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, or dichloromethane, etc.

[0035] "Pharmaceutical composition" in the present invention refers to a mixture comprising at least one compound or its derivative (including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or their chemically protected forms) described in the present invention and one or more pharmaceutically acceptable carriers. Optionally, the mixture may further comprise one or more other drugs. One of the main purposes of the pharmaceutical composition is to facilitate the administration of the compounds of the present invention to an organism.

[0036] As described above, in the first aspect, the present invention provides a compound or its derivative, and the compound has a structure shown in the following formula Ⅰ:

[0037]

[0038] R1 is selected from hydrogen, unsubstituted or substituted alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl, aryl, and heteroaryl;

[0039] R2 is selected from hydrogen, unsubstituted or substituted alkyl, saturated or unsaturated cycloalkylmethylene, saturated or unsaturated heterocycloalkylmethylene, and benzyl;

[0040] R3 and R4 are independently selected from the structures represented by Formula II, III, IV and V:

[0041]

[0042] R5 and R6 are independently selected from hydrogen, alkyl, allyl, propargyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl;

[0043] R7 is selected from hydrogen, alkyl, allyl, propargyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl, alkoxyacyl, alkylaminoacyl, allylaminoacyl, propargylaminoacyl, haloalkylaminoacyl, saturated or unsaturated cycloalkylaminoacyl and saturated or unsaturated heterocycloalkylaminoacyl;

[0044] Y1, Y2 and Y3 are independently selected from CH and N, and more preferably, Y1, Y2 and Y3 are independently selected from CH;

[0045] Additionally preferably or further preferably, R1 is selected from hydrogen, C1-C6 alkyl (such as methyl, ethyl, propyl, butyl, pentyl or hexyl) substituted with 0-3 (e.g., 0, 1, 2 or 3) R8, C2-C6 alkenyl (such as vinyl, propenyl, butenyl, pentenyl or hexenyl), C2-C6 alkynyl (such as ethynyl, propynyl, butynyl, pentynyl or hexynyl), C3-C 10 (such as C3, C4, C5, C6, C7, C8, C9 or C 10 ) saturated or unsaturated cycloalkyl, C3-C 10 (such as C3, C4, C5, C6, C7, C8, C9 or C 10 ) saturated or unsaturated heterocycloalkyl, C 6-12 (such as C6, C7, C8, C9 C 10 、C 11 or C 12 ) aryl or heteroaryl, preferably C3-C 10 saturated or unsaturated heterocycloalkyl, more preferably tetrahydropyran. Wherein R8 is selected from C1-C6 alkyl (such as methyl, ethyl, propyl, butyl, pentyl or hexyl), C2-C6 alkenyl (such as vinyl, propenyl, butenyl, pentenyl or hexenyl), C2-C6 alkynyl (such as ethynyl, propynyl, butynyl, pentynyl or hexynyl), C3-C 10 (such as C3, C4, C5, C6, C7, C8, C9 or C 10 ) saturated or unsaturated cycloalkyl, C3-C 10 (such as C3, C4, C5, C6, C7, C8, C9 or C 10) saturated or unsaturated heterocycloalkyl, C1-C6 alkoxy (such as methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy), C1-C6 (such as C1, C2, C3, C4, C5 or C6) ester group, C1-C6 (such as C1, C2, C3, C4, C5 or C6) alkyl hydroxy, C1-C6 (such as C1, C2, C3, C4, C5 or C6) alkyl acyl, =O, =S, halogen (such as F, Cl, Br or I), cyano and hydroxy, preferably C1-C6 alkyl, more preferably methyl.

[0046] Also preferably or further preferably, R2 is selected from hydrogen, C1-C6 alkyl (such as methyl, ethyl, propyl, butyl, pentyl or hexyl) substituted by 0-3 (such as 0, 1, 2 or 3) R9, C3-C 10 (such as C3, C4, C5, C6, C7, C8, C9 or C 10 ) saturated or unsaturated cycloalkylmethylene, C3-C 10 (such as C3, C4, C5, C6, C7, C8, C9 or C 10 ) saturated or unsaturated heterocycloalkylmethylene and benzyl, preferably C1-C6 alkyl, more preferably ethyl. Wherein R9 is selected from trifluoromethoxy, methoxy, halogen (such as F, Cl, Br or I) and hydroxy, preferably methoxy or trifluoromethoxy, more preferably trifluoromethoxy.

[0047] R3 and R4 are independently selected from the structures of formulas II, III, IV and V as follows:

[0048]

[0049] Among them, preferably:

[0050] R5 and R6 are independently selected from hydrogen, C1-C6 alkyl (such as methyl, ethyl, propyl, butyl, pentyl or hexyl), C3-C6 (such as C3, C4, C5 or C6) allyl, C3-C6 (such as C3, C4, C5 or C6) propargyl, C3-C 10 (such as C3, C4, C5, C6, C7, C8, C9 or C 10 ) saturated or unsaturated cycloalkyl, C3-C 10 (such as C3, C4, C5, C6, C7, C8, C9 or C 10 ) saturated or unsaturated heterocycloalkyl; preferably, R5 and R6 are independently selected from hydrogen and C1-C6 alkyl; more preferably, R5 and R6 are independently hydrogen or methyl;

[0051] R7 is selected from hydrogen, C1-C6 alkyl (such as methyl, ethyl, propyl, butyl, pentyl or hexyl), C3-C6 alkenyl, C3-C6 (such as C3, C4, C5 or C6) propargyl, C3-C 10 (such as C3, C4, C5, C6, C7, C8, C9 or C 10 ) saturated or unsaturated cycloalkyl, C3-C 10 (such as C3, C4, C5, C6, C7, C8, C9 or C 10 ) saturated or unsaturated heterocycloalkyl, C1-C6 (such as C1, C2, C3, C4, C5 or C6) alkoxyacyl, C1-C6 (such as C1, C2, C3, C4, C5 or C6) alkylaminoacyl, C3-C6 (such as C3, C4, C5 or C6) alkenylaminoacyl, C3-C6 (such as C3, C4, C5 or C6) propargylaminoacyl, C2-C6 (such as C2, C3, C4, C5 or C6) haloalkylaminoacyl, C3-C 10 (such as C3, C4, C5, C6, C7, C8, C9 or C 10 ) saturated or unsaturated cycloalkylaminoacyl and C3-C 10 (such as C3, C4, C5, C6, C7, C8, C9 or C 10 ) saturated or unsaturated heterocycloalkylaminoacyl; preferably, R7 is selected from hydrogen, C1-C6 alkylaminoacyl and C3-C 10 saturated or unsaturated cycloalkylaminoacyl; more preferably, R7 is hydrogen;

[0052] Y1, Y2 and Y3 are independently CH or N, preferably CH.

[0053] Additionally preferably or further preferably, R1 is selected from one of the following groups:

[0054] Additionally preferably or further preferably, R2 is selected from one of the following groups:

[0055] Additionally preferably or further preferably, R3 and R4 are independently selected from one of the following groups:

[0056] Additionally preferably or further preferably, the compound is one of the following compounds:

[0057]

[0058]

[0059]

[0060] In a second aspect, the present invention provides a pharmaceutical composition, which comprises: (1) the compound or its derivative according to the first aspect of the present invention (such as the deuterated form, salt, isomer, crystal form or solvate of the compound) (as the active ingredient); and (2) a pharmaceutically acceptable carrier and / or excipient (as the auxiliary material).

[0061] In a third aspect, the present invention provides the use of the compound or its derivative according to the first aspect of the present invention (such as the deuterated form, salt, isomer, crystal form or solvate of the compound) as a BET / p300 bromodomain dual-target inhibitor.

[0062] Preferably or further preferably, the BET / p300 bromodomain dual-target inhibitor is used as a drug for preventing and / or treating tumors or myeloid hematopoietic stem cell malignant diseases, or as a drug for regulating regulatory T cells.

[0063] 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.

[0064] In a fourth aspect, the present invention provides a method for preparing the compound or its derivative according to the first aspect of the present invention, and the method is carried out according to the following synthetic route:

[0065]

[0066] And the method comprises the following steps:

[0067] 1) The compound of formula (1) and the compound of formula (2) undergo a nucleophilic attack reaction to generate the compound of formula (3);

[0068] 2) The compound of formula (3) is prepared into the compound of formula (4) through a reduction reaction;

[0069] 3) The compound of formula (4) and the compound of formula (5) undergo an acid amide condensation reaction to prepare the compound of formula (6);

[0070] 4) The compound of formula (6) undergoes a reaction under acidic conditions to prepare the compound of formula (7);

[0071] 5) The compound of formula (7) and the compound of formula (8) undergo a Suzuki reaction to prepare the compound of formula (I);

[0072] 6) The compound of formula (7) undergoes a Suzuki-Miyaura reaction to prepare the compound of formula (10);

[0073] 7) The compound of formula (10) and the compound of formula (11) are used to prepare the compound of formula (I) through the Suzuki reaction.

[0074] Example

[0075] The above content of the present invention will be further described in detail below in the form of examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technical solutions implemented based on the above content and inventive concept of the present invention fall within the scope of protection claimed by the present invention.

[0076] Example 1: 6-Methyl-4-(2-(tetrahydro-2H-pyran-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0077] Step 1: Synthesis of intermediate 1-2:

[0078]

[0079] The starting material 1-1 (5 g, 22.7 mmol), 2-(trifluoromethoxy)ethan-1-amine hydrochloride (4.0 g, 22.8 mmol) and N,N-diisopropylethylamine (9.9 mL, 56.8 mmol) were dissolved in 70 mL of dimethyl sulfoxide and reacted overnight at room temperature. After the reaction was completed, 150 mL of water was added to the reaction solution, and the precipitated solid was filtered, washed with water, and the filter cake was collected and dried at 50 °C to obtain intermediate 1-2 (6.5 g, yield 86.9%).

[0080] Step 2: Synthesis of intermediate 1-3:

[0081]

[0082] The intermediate 1-2 (6.5 g, 19.8 mmol) obtained in the previous step was dissolved in a 200 mL mixed solution of tetrahydrofuran and water in a ratio of 1:1. 10 mL of ammonia water was added dropwise to the solution, and then sodium dithionite (18.5 g, 106.3 mmol) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with ethyl acetate (2 × 100 mL). The organic phases were combined, washed with saturated sodium chloride solution (1 × 100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the product intermediate 1-3 (3.6 g, yield 60.9%).

[0083] Step 3: Synthesis of intermediate 1-4:

[0084]

[0085] Dissolve the intermediate 1-3 (1 g, 3.3 mmol) obtained in the previous step, tetrahydro-2H-pyran-4-carboxylic acid (478.6 mg, 3.7 mmol), HATU (CAS NO: 148893-10-1, 1.9 g, 5.01 mmol), and N,N-diisopropylethylamine (863.9 mg, 6.7 mmol) in 10 mL of N,N-dimethylformamide, and react at room temperature for 1 hour. After the reaction is completed, add 50 mL of water, extract with ethyl acetate (2×50 mL), combine the organic phases, wash with saturated sodium chloride solution (2×50 mL), dry over anhydrous sodium sulfate, concentrate, dissolve the obtained crude product (1.5 g) in 10 mL of acetic acid, and react at 100 °C overnight. After the reaction is completed, cool, rotary evaporate, add 50 mL of saturated sodium bicarbonate solution, extract with ethyl acetate (2×50 mL), combine the organic phases, wash with saturated sodium chloride solution (2×50 mL), dry over anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (dichloromethane:methanol = 50:1) to obtain intermediate 1-4 (700 mg, yield 53.6%).

[0086] Step 4: Synthesis of intermediate 1-5:

[0087]

[0088] Dissolve intermediate 1-4 (30 mg, 76.3 μmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (39.2 mg, 91.6 μmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (5.6 mg, 7.6 μmol), and potassium carbonate (15.8 mg, 114.4 μmol) in 2 mL of a 3:1 mixture of dioxane and water, displace with nitrogen three times, and react at 85 °C for 4 hours. After the reaction is completed, cool, add 25 mL of water, extract with ethyl acetate (2×25 mL), combine the organic phases, wash with saturated sodium chloride solution (1×25 mL), dry over anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 1-5 (29 mg, yield 61.8%).

[0089] Step 5: Synthesis of 6-methyl-4-(2-(tetrahydro-2H-pyran-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one:

[0090]

[0091] Intermediate 1-5 (29 mg, 47.2 μmol) was dissolved in 2 mL of dioxane, and 2 M sodium hydroxide solution (79.8 μL) was added dropwise thereto. The reaction was carried out at 90 °C for 4 hours. After the reaction was completed, it was cooled, 25 mL of water was added, and the mixture was extracted with ethyl acetate (2×25 mL). The organic phases were combined, washed with saturated sodium chloride solution (1×25 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (methylene chloride:methanol = 20:1) to obtain the target compound 1 (18 mg, yield 82.9%).

[0092] The following Examples 2 to 16 were synthesized by the method described in Example 1, or synthesized by a method similar to Example 1 using the corresponding intermediates.

[0093]

[0094]

[0095] The target compounds synthesized in Examples 1 to 10, their molecular structures and 1 1H NMR spectra are shown in the following table.

[0096]

[0097]

[0098] Example 11: 6-Methyl-4-(2-morpholin-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0099] Step 1: Synthesis of Intermediate 11-1:

[0100]

[0101] Intermediate 1-3 (1 g, 3.3 mmol) was dissolved in 50 mL of methylene chloride, and the solution was purged with nitrogen three times. Bis(trichloromethyl) carbonate (triphosgene, CO(OCCl3)2) (496.0 mg, 1.7 mmol) was added to the solution at 0 °C, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with methylene chloride (2×50 mL). The organic phases were combined, washed with saturated sodium chloride solution (1×50 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (methylene chloride:methanol = 50:1) to obtain Intermediate 17-1 (785 mg, yield 72.2%).

[0102] Step 2: Synthesis of Intermediate 11-2:

[0103]

[0104] Dissolve the intermediate 11-1 (785 mg, 2.4 mmol) obtained in the previous step in 10 mL of phosphorus oxychloride and react at 110 °C for 3 hours. After the reaction is completed, cool it. Add saturated sodium bicarbonate aqueous solution to the reaction solution at 0 °C to adjust the pH to 9. Extract with ethyl acetate (2×50 mL). Combine the organic phases, wash with saturated sodium chloride solution (1×50 mL), dry over anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 11-2 (560 mg, yield 67.5%).

[0105] Step 3: Synthesis of intermediate 11-3:

[0106]

[0107] Dissolve the intermediate 11-2 (560 mg, 1.6 mmol) obtained in the previous step, 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (837.9 mg, 2.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (124.8 mg, 0.16 mmol), and potassium carbonate (337.9 mg, 2.5 mmol) in 15 mL of a 3:1 mixture of dioxane and water. Replace the gas with nitrogen three times and react at 85 °C for 4 hours. After the reaction is completed, cool it. Add 50 mL of water, extract with ethyl acetate (2×50 mL). Combine the organic phases, wash with saturated sodium chloride solution (1×50 mL), dry over anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (methylene chloride:methanol = 20:1) to obtain intermediate 11-3 (682 mg, yield 74.0%).

[0108] Step 3: Synthesis of 6-methyl-4-(2-morpholino-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one:

[0109]

[0110] Dissolve the intermediate 11-3 (30 mg, 53.1 μmol) obtained in the previous step in 1 mL of morpholine and react at 100 °C for 6 hours. After the reaction is completed, cool it down, add 20 mL of water, extract with ethyl acetate (2 × 20 mL), combine the organic phases, wash with saturated sodium chloride solution (1 × 20 mL), dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. Dissolve the crude product in 2 mL of dioxane, add 57 μL of 2 M sodium hydroxide solution thereto, and react at 90 °C for 4 hours. After the reaction is completed, cool it down, add 25 mL of water, extract with ethyl acetate (2 × 25 mL), combine the organic phases, wash with saturated sodium chloride solution (1 × 25 mL), dry over anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (methylene chloride:methanol = 20:1) to obtain the target compound 1 (15 mg, yield 61.2%).

[0111] The following Examples 12 to 16 were synthesized by the method described in Example 11, or synthesized in a similar manner to Example 11 using the corresponding intermediates.

[0112]

[0113]

[0114] The target compounds synthesized in Examples 11 to 16, their molecular structures and 1 1H NMR spectra are shown in the following table.

[0115]

[0116]

[0117] The following Examples 17 to 29 were synthesized by the method described in Example 1, or synthesized in a similar manner to Example 1 using the corresponding intermediates.

[0118]

[0119]

[0120] The target compounds synthesized in Examples 17 to 29, their molecular structures and 1 1H NMR spectra are shown in the following table.

[0121]

[0122]

[0123]

[0124] Example 30: 6-Ethyl-4-(2-(tetrahydro-2H-pyran-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0125] Step 1: Synthesis of Intermediate 30-1:

[0126]

[0127] Dissolve Intermediate 1-4 (1 g, 2.5 mmol), bis(pinacolato)diboron (1.9 g, 7.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (156 mg, 0.2 mmol), and potassium acetate (998.4 mg, 10.2 mmol) in 20 mL of dioxane. Replace the air with nitrogen three times and react at 90 °C for 5 hours. After the reaction is completed, cool it down, add 50 mL of water, extract with ethyl acetate (2 × 50 mL), combine the organic phases, wash with saturated sodium chloride solution (1 × 50 mL), dry over anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (dichloromethane:methanol = 30:1) to obtain Intermediate 30-1 (800 mg, yield 71.5%).

[0128] Step 2: Synthesis of Intermediate 30-2:

[0129]

[0130] Dissolve Intermediate 30-1 (30 mg, 68.1 μmol), 4-bromo-6-ethyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (29.6 mg, 75.0 μmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (5.9 mg, 7.5 μmol), and potassium carbonate (14.1 mg, 102.2 μmol) in 2 mL of a 3:1 mixture of dioxane and, replace the air with nitrogen three times, and react at 90 °C for 5 hours. After the reaction is completed, cool it down, add 25 mL of water, extract with ethyl acetate (2 × 25 mL), combine the organic phases, wash with saturated sodium chloride solution (1 × 25 mL), dry over anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (dichloromethane:methanol = 30:1) to obtain Intermediate 30-1 (29 mg, yield 67.7%).

[0131] Step 3: Synthesis of 6-Ethyl-4-(2-(tetrahydro-2H-pyran-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one:

[0132]

[0133] Except for the differences shown in the above formula, it was carried out according to Step 5 of Example 1 to obtain the target compound 30 (18 mg, 82.2%).

[0134] The following Examples 31 to 38 were synthesized by the method described in Example 30 or were synthesized in a method similar to Example 30 using the corresponding intermediates.

[0135]

[0136]

[0137] The target compounds synthesized in Examples 30 to 38, their molecular structures and 1 1H NMR spectra are shown in the following table.

[0138]

[0139]

[0140] Example 39: N,6-Dimethyl-7-oxo-4-(2-(tetrahydro-2H-pyran-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0141] Step 1: Synthesis of Intermediate 39-1:

[0142]

[0143] Except for the differences shown in the above formula, it was carried out according to Step 2 of Example 30 to obtain Intermediate 39-1 (300 mg, 58.4%)

[0144] Step 2: Synthesis of Intermediate 39-2:

[0145]

[0146] Except for the differences shown in the above formula, it was carried out according to Step 3 of Example 30 to obtain Intermediate 39-2 (180 mg, 81.7%)

[0147] Step 3: Synthesis of N,6-Dimethyl-7-oxo-4-(2-(tetrahydro-2H-pyran-4-yl)-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazol-6-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide:

[0148]

[0149] The intermediate 39-2 (20 mg, 39.7 μmol) obtained in the previous step, methylamine hydrochloride (3.5 mg, 51.5 μmol), HATU (CAS NO: 148893-10-1, 22.6 mg, 59.5 μmol), and N,N-diisopropylethylamine (13.8 μL, 79.3 μmol) were dissolved in 2 mL of N,N-dimethylformamide and reacted at room temperature for 1 hour. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with dichloromethane (2×20 mL). The organic phases were combined, washed with saturated sodium chloride solution (1×20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (dichloromethane:methanol = 30:1) to obtain the target compound 39 (15 mg, 73.1%).

[0150] The following Examples 40 to 44 were synthesized by the method described in Example 39, or synthesized by a method similar to that of Example 39 using the corresponding intermediates.

[0151]

[0152] The target compounds synthesized in Examples 40 to 45, their molecular structures and 1 1H NMR spectra are shown in the following table.

[0153]

[0154]

[0155] Detection Example 1: In vitro inhibitory activity detection of the compound against histone acetyltransferase p300

[0156] The inhibitory activity of the compound against the bromodomain of p300 protein was detected by AlphaLISA technology, using NEO2734 (CAS No. 2081072-29-7) as a control.

[0157] 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. When there is no specific interaction between biomolecules, the singlet oxygen cannot diffuse to the acceptor beads, and no signal is generated. The specific experimental steps are as follows:

[0158] 1. Dilute Recombinant p300 protein, biotinylated histone peptide, inhibitor, Ni-Acceptor beads and Alpha Streptavidin Donor beads with reaction buffer;

[0159] 2. Add the following reagents to the white 384-well microplate in sequence:

[0160] -- 5 μL inhibitor (highest concentration 1 μM, 3-fold dilution) or epigenetic buffer,

[0161] -- 2.5 μL Recombinant p300 protein, bromodomain (aa1041 - 1161)

[0162] -- 2.5 μL biotinylated histone peptide;

[0163] 3. Seal the microplate and incubate at room temperature for 60 minutes;

[0164] 4. Add 10 μL of Ni-Acceptor beads, seal and incubate for 60 minutes

[0165] 5. Add 10 μL of Alpha Streptavidin Donor beads, seal and incubate for 30 minutes;

[0166] 6. Read with a Tecan microplate reader.

[0167] Set up two replicates for each group of experiments and a blank control group.

[0168] 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%

[0169] Using the inhibition rate (%) as the ordinate and the compound concentration as the abscissa, use Graphpad prism software to plot the competitive inhibition curve respectively, and calculate the concentration (IC 50 ) when the binding rate of the compound to p300 protein is 50% using the obtained regression equation. The experimental results are shown in Table 1.

[0170] Table 1: In vitro inhibitory activity of compounds against p300

[0171]

[0172]

[0173] ++++: represents IC 50 <20 nM

[0174] +++: represents 20 nM ≤ IC 50 <200 nM

[0175] Detection Example 2: Detection of the in vitro inhibitory activity of the compound against bromodomain protein BRD4

[0176] The HTRF technology was used to detect the inhibitory activity of the compound against the bromodomain of BRD4 protein.

[0177] Dilute the compound to be tested with Binding Domain diluent buffer to 10 times the final concentration for standby. Transfer 2 μL of 10x compound (4 μL Binding Domain diluent buffer: Positive control, 6 μL Enzymatic buffer: Negative control) to a 384-well ProxiPlate reaction plate. Add 4 μL of 5x BRD4(1) protein (BRD4(1) is 10 nM in the final system) to the above reaction plate, and add 4 μL of 5x [Lys(5,8,12,16)Ac]H4(1-21)-biotin with a final concentration of 40 nM. Stick on the film and incubate at 37 °C for 1 h.

[0178] Prepare a detection mixture with a final concentration of 5 nM SA-XL665(2x) and anti-His-Eu(K)(2x) using Detection buffer. Add 10 μL of the detection mixture (2x) to each well, incubate at room temperature for 3 h, and read the values using a multi-functional microplate reader Envision.

[0179] HTRF Ratio = Acceptor signal (665 nm) / Donor Signal (620 nm) x 10 4

[0180] 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%

[0181] IC 50 The value was obtained by regression using the four-parameter method in GraphPad software.

[0182] Table 2: In vitro inhibitory activity of the compound against BRD4

[0183]

[0184]

[0185] ++++: represents IC 50 <10nM

[0186] +++: represents 10nM ≤ IC 50 <100nM

[0187] As can be seen from the results of Table 1 and Table 2 above, the compounds of the present invention can strongly inhibit the activities of histone acetyltransferase p300 and bromodomain protein BRD4, and the inhibitory activities of some compounds are even better than those of the same type of drugs under clinical research, NEO2734. Therefore, they can be used as BET / p300 bromodomain dual-target inhibitors.

[0188] Detection Example 3: Detection of the inhibitory effect on the proliferation of sensitive cells by CCK8 method

[0189] To detect the inhibitory effect of the compounds of the present invention on the proliferation of tumor cells, the cell growth inhibitory activity of the compounds of the present invention was tested on the sensitive cell line (OPM-2 cells purchased from the German Collection of Microorganisms and Cell Cultures) obtained in the previous work. Cells in the logarithmic growth phase were seeded into 96-well plates at a concentration of 2.5×10 3 cells per well. After 24 hours, gradient-diluted compounds (10 μM three-fold dilution, 8 concentrations) were added. After inoculation, the cells were cultured in suspension for 5 days, and then 10 μL of CCK-8 reagent (Cell Counting Kit-8 cell counting reagent, purchased from Meilun Biology) was added to each well and cultured at 37 °C for 2 - 6 hours. The absorbance of each well at a wavelength of 450 nm was read using a microplate reader, and analysis was performed using SoftMax Pro 5.4.1 software. The IC 50 value (concentration-response curve fitting) was calculated using GraphPad Prism 5 statistical software. The experimental results are shown in Table 3.

[0190] Table 3: Inhibitory activity of compounds on the proliferation of tumor cells

[0191]

[0192] Note: ++++: represents IC 50 <10nM; +++: represents 10nM ≤ IC 50 <100nM

[0193] As can be seen from the results of Table 3 above, the compounds of the present invention showed excellent anti-proliferation effects on multiple myeloma cells OPM-2. The inhibitory effects can be comparable to those of the same type of drugs under clinical research, NEO2734, and the inhibitory effects of some compounds are even better than NEO2734. They can be used for the prevention and / or treatment of myeloid hematopoietic stem cell malignancies.

[0194] Test Example 4: Pharmacokinetic Evaluation

[0195] Animal Information

[0196] Species / Strain: ICR (CD-1) mice; Gender / Number: male; Body weight (g): male (25 - 30 g).

[0197] Feeding Method: Standard rodent diet, with no restriction on drinking water. Fast for 12 h before dosing and keep fasting for 2 h after dosing.

[0198] Breeding Environment: Control the animal room environment (target conditions: temperature 18 to 29 °C, relative humidity 30 to 70%. Monitor the temperature and relative humidity daily and maintain them within the temperature and humidity ranges of the above target conditions. An electronic time-controlled lighting system is used to provide a 12-hour light / 12-hour dark cycle.

[0199] Dosing Information

[0200]

[0201] Sample Collection

[0202] Orally administer the test compound to ICR mice at a dose of 10 mg / kg, with a dosing volume of 10 mL / kg. After dosing, collect blood from the orbital venous plexus at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h into heparinized EP tubes and temporarily place them on ice.

[0203] Intravenously administer the test compound to ICR mice at a dose of 2 mg / kg, with a dosing volume of 5 mL / kg. After dosing, collect blood from the orbital venous plexus at 0.05 h, 0.25 h, 0.75 h, 2 h, 4 h, 8 h, and 24 h into heparinized EP tubes and temporarily place them on ice

[0204] Sample Processing and Analysis

[0205] Centrifuge at 8000 rpm for 5 min, transfer 15 μL of the upper plasma to a 96-well plate. Add 150 μL of methanol:acetonitrile (v / v = 1:1) (containing 20 ng / mL tolbutamide) to the 15 μL of plasma, shake for 3 min, centrifuge at 4500 rpm for 5 min, and take 100 μL of the supernatant to a 2 mL deep-well plate. Add 100 μL of diluent (pure water), shake for 3 min, centrifuge at 4500 rpm for 5 min. Transfer 180 μL of the supernatant to the sample injection plate, analyze the content of the compound in the supernatant sample by LC-MS / MS, and calculate various pharmacokinetic parameters using WinNonlin software. The pharmacokinetic parameters of the test compound are shown in Table 3.

[0206] Table 4: PK Properties of Some Inventive Compounds in Mice

[0207]

[0208] The experimental results show that the optimized compounds in the present invention have good bioavailability, good oral absorption exposure, and relatively high C max and AUC, and at the same time have a moderate half-life T 1 / 2 and residence time MRT. These data indicate that the compounds of the present invention can be used as anti-tumor drugs.

[0209] 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 them; 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 on 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 embodiments of the present invention.

Claims

1. A compound or its derivative, wherein the compound has the structure shown in Formula I below: R1 is selected from hydrogen, unsubstituted or substituted alkyl, alkenyl, alkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl, aryl, and heteroaryl; R2 is selected from hydrogen, unsubstituted or substituted alkyl, saturated or unsaturated cycloalkylmethylene, saturated or unsaturated heterocycloalkylmethylene, and benzyl; R3 and R4 are independently selected from the structures shown in Formula II, III, IV, and V below: R5 and R6 are independently selected from hydrogen, alkyl, allyl, propargyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl; R7 is selected from hydrogen, alkyl, allyl, propargyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl, alkoxyacyl, alkylaminoacyl, allylaminoacyl, propargylaminoacyl, haloalkylaminoacyl, saturated or unsaturated cycloalkylaminoacyl, saturated or unsaturated heterocycloalkylaminoacyl; Y1, Y2, and Y3 are independently selected from CH and N; The derivative is selected from deuterated compounds, salts, isomers, crystal forms, or solvates.

2. The compound or its derivative according to claim 1, wherein: R1 is selected from hydrogen, C1-C6 alkyl substituted with 0-3 R8, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 saturated or unsaturated cycloalkyl, C3-C 10 saturated or unsaturated heterocycloalkyl, C 6-12 aryl or heteroaryl; wherein R8 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 ester group, C1-C6 alkyl hydroxy, C1-C6 alkyl acyl, =O, =S, halogen, cyano and hydroxy.

3. The compound or its derivative according to claim 1 or 2, wherein: R2 is selected from hydrogen, a C1-C6 alkyl group substituted with 0-3 R9s, a C3-C 10 saturated or unsaturated cycloalkylmethylene, C3-C 10 saturated or unsaturated heterocycloalkylmethylene and benzyl; wherein R9 is selected from trifluoromethoxy, methoxy, halogen and hydroxy.

4. The compound or its derivative according to any one of claims 1 to 3, wherein: R3 and R4 are independently selected from the structures of Formula II, III, IV, and V; Wherein, R5 and R6 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 propargyl, C3-C 10 saturated or unsaturated cycloalkyl, C3-C 10 saturated or unsaturated heterocycloalkyl; R7 is selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C 10 saturated or unsaturated cycloalkyl, C3-C 10 saturated or unsaturated heterocycloalkyl, C1-C6 alkoxyacyl, C1-C6 alkylaminoacyl, C3-C6 alkenylaminoacyl, C3-C6 alkynylaminoacyl, C2-C6 haloalkylaminoacyl, C3-C 10 saturated or unsaturated cycloalkylaminoacyl and C3-C 10 saturated or unsaturated heterocycloalkylaminoacyl; Y1, Y2, and Y3 are independently selected from CH and N, and more preferably, Y1, Y2, and Y3 are independently selected from CH.

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: R2 is selected from one of the following groups: R3 and R4 are independently 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; (2) A pharmaceutically acceptable carrier and / or excipient.

8. Use of the compound or 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 BET / p300 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 preparing the compound or its derivative according to any one of claims 1 to 6, characterized in that, The method is carried out according to the following synthetic route: And the method comprises the following steps: 1) The compound of Formula (1) and the compound of Formula (2) undergo a nucleophilic attack reaction to form the compound of Formula (3); 2) The compound of Formula (3) is prepared into the compound of Formula (4) through a reduction reaction; 3) The compound of Formula (4) and the compound of Formula (5) undergo an acid amide condensation reaction to form the compound of Formula (6); 4) The compound of Formula (6) undergoes a reaction under acidic conditions to form the compound of Formula (7); 5) The compound of Formula (7) and the compound of Formula (8) undergo a Suzuki reaction to form the compound of Formula (I); 6) The compound of formula (7) is prepared into the compound of formula (10) through the Suzuki-Miyaura reaction; 7) The compound of formula (10) and the compound of formula (11) are prepared into the compound of formula (I) through the Suzuki reaction.

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