HK1250164B - Aniline pyrimidine derivatives and uses thereof - Google Patents

Description

Aniline pyrimidine derivatives and uses thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of Chinese Patent Application No. 201510419018.X filed with the State Intellectual Property Office of China on July 16, 2015, the disclosure of which is incorporated herein by reference in its entirety.

Technical Field

The present application relates to anilinopyrimidine derivatives as EGFR inhibitors, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods or uses thereof for treating EGFR-mediated diseases.

Background Art

EGFR (Epidermal Growth Factor Receptor) is a receptor for epidermal growth factor (EGF) cell proliferation and signaling, also known as HER1 and ErbB1. EGFR belongs to the ErbB receptor family, which includes EGFR (ErbB-1), HER2/c-neu (ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4). EGFR is a glycoprotein, a tyrosine kinase receptor that penetrates the cell membrane and has a molecular weight of 170 kDa.

EGFR is located on the cell membrane surface and is activated by binding to ligands, including EGF and TGFα. Upon activation, EGFR converts from a monomer to a dimer. The dimerization involves both the binding of two receptor molecules of the same species (homodimerization) and the binding of different members of the human EGF-related receptor (HER) tyrosine kinase family (heterodimerization). EGFR dimerization activates its intracellular kinase pathways, including phosphorylation of key tyrosine residues in the intracellular domain, and stimulates numerous intracellular signaling pathways involved in cell proliferation and survival.

EGFR is overexpressed or aberrantly expressed in many solid tumors. EGFR is associated with tumor cell proliferation, angiogenesis, tumor invasion, metastasis, and inhibition of apoptosis. Possible mechanisms include: elevated EGFR expression leading to enhanced downstream signaling; increased expression of mutant EGFR receptors or ligands leading to sustained EGFR activation; enhanced autocrine loops; disruption of receptor downregulation mechanisms; and activation of aberrant signaling pathways. EGFR overexpression plays a crucial role in the progression of malignant tumors. For example, EGFR overexpression has been found in glial cells, renal cancer, lung cancer, prostate cancer, pancreatic cancer, and breast cancer.

Aberrant expression of EGFR and Erb-B2 plays a key role in tumor transformation and growth. Taking lung cancer as an example, EGFR is expressed in 50% of non-small cell lung cancer (NSCLC) cases, and its expression is correlated with poor prognosis. These two factors make EGFR and its family members prime candidates for targeted therapies. Two small molecule inhibitors targeting EGFR, gefitinib and erlotinib, received fast-track approval from the US FDA for the treatment of patients with advanced NSCLC who have failed to respond to conventional chemotherapy.

Early clinical data suggest that 10% of NSCLC patients respond to gefitinib and erlotinib. Molecular biological analysis has shown that, in most cases, patients who respond to the drugs harbor specific mutations in the gene encoding EGFR: deletions of amino acids 747–750 in exon 19 account for 45% of mutations, and another 10% occur in exons 18 and 20. The most common activating EGFR mutations (L858R and delE746_A750) result in increased affinity for small-molecule tyrosine kinase inhibitors (TKIs) and decreased affinity for adenosine triphosphate (ATP) relative to wild-type (WT) EGFR. The T790M mutation is a point mutation in EGFR exon 20 that confers acquired resistance to treatment with gefitinib or erlotinib. The latest research shows that the affinity of L858R combined with T790M mutation for ATP is stronger than that of L858R alone. TKI is an ATP-competitive kinase inhibitor, which leads to a lower binding rate of TKI to the kinase region.

Summary of the Invention

The first aspect of the present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

in:

X is selected from NR ⁶ or O;

R ¹ and R ² are independently selected from hydrogen, halogen, C _1-4 alkyl and cyano;

R ³ is selected from C _1-4 alkyl and C _1-4 alkoxy;

^R4 is selected from [2-(dimethylamino)ethyl](methyl)amino, (2-hydroxyethyl)(methyl)amino and morpholin-4-yl;

^R5 is selected from hydrogen, _C1-4 alkyl and _C1-3 alkoxy _C1-3 alkyl;

^R6 is selected from hydrogen and _C1-4 alkyl.

In one embodiment of the present application, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

X is selected from NR ⁶ or O;

R ¹ and R ² are independently selected from hydrogen, halogen and C _1-4 alkyl;

R ³ is selected from C _1-4 alkoxy;

^R4 is selected from [2-(dimethylamino)ethyl](methyl)amino, (2-hydroxyethyl)(methyl)amino and morpholin-4-yl;

^R5 is selected from hydrogen, _C1-4 alkyl and _C1-3 alkoxy _C1-3 alkyl;

^R6 is selected from hydrogen and _C1-4 alkyl.

In one embodiment of the present application, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

X is selected from NR ⁶ or O;

R ¹ and R ² are independently selected from hydrogen, chlorine, bromine, fluorine and methyl;

^R3 is methoxy;

^R4 is selected from [2-(dimethylamino)ethyl](methyl)amino, (2-hydroxyethyl)(methyl)amino and morpholin-4-yl;

^R5 is selected from hydrogen and methoxymethyl;

^R6 is selected from hydrogen and methyl.

In one embodiment of the present application, the compound of formula (I) described herein includes the following compounds or pharmaceutically acceptable salts thereof:

Another aspect of the present application provides a pharmaceutical composition comprising a compound of formula (I) disclosed herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients. Optionally, the pharmaceutical composition of the present application may further contain one or more additional therapeutic agents.

Another aspect of the present application provides a method for treating EGFR-mediated diseases, comprising administering to an individual in need thereof the compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Another aspect of the present application provides use of the compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating EGFR-mediated diseases.

In some embodiments of the present application, the EGFR-mediated disease is selected from a disease mediated by an EGFR-L858R activating mutation.

In some embodiments of the present application, the EGFR-mediated disease is selected from a disease mediated by the EGFR-T790M activating mutation. In some embodiments, the EGFR-mediated disease is selected from a disease mediated by the EGFR-L858R combined with the EGFR-T790M double mutation.

Detailed description of embodiments

definition:

Unless otherwise indicated, the following terms and phrases used herein have the following meanings. A specific term or phrase should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

As used herein, _Cmn means that there are mn carbon atoms in the moiety. For example, " _C1-4 alkyl" means that the alkyl group has 1 to 4 carbon atoms.

Numeric ranges herein refer to each integer in the given range. For example, "C _1-4 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "cyano" refers to a -CN group.

The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. Non-limiting examples of alkyl include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl.

The term "alkoxy" refers to a "-O-alkyl" group.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.

Examples of pharmaceutically acceptable salts include salts with inorganic acids, salts with organic acids, and salts with acidic amino acids.

The pharmaceutically acceptable salts of the present application can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, the compounds of the free base form are reacted with a stoichiometric amount of an appropriate acid to prepare.

Certain compounds of the present application may exist in unsolvated or solvated forms, including hydrate forms. Generally speaking, solvated forms are equivalent to unsolvated forms and are both included in the scope of the present application. Certain compounds of the present application may exist in polycrystalline or amorphous forms.

Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

The diagrammatic representations of racemic, ambiscalemic, scalemic, or enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise indicated, wedge-shaped and dashed bonds are used to represent the absolute configuration at a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are intended to be encompassed within the scope of this application.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are within the scope of the present invention.

Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereoisomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound, such as deuterium (D), tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

The term "pharmaceutically acceptable carrier" refers to carriers that have no significant irritating effect on organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carrier" refers to an inert substance that is administered together with the active ingredient and facilitates the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the State Food and Drug Administration for use in humans or animals (e.g., livestock). Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol. For further information on carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

The term "excipient" generally refers to a carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.

With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For oral dosage forms herein, an "effective amount" of an active substance in a composition refers to the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

The term "patient" or "individual" includes humans and animals, for example, mammals (eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, and birds, etc.).

DETAILED DESCRIPTION

In the first aspect of the present application, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is provided:

in:

X is selected from NR ⁶ or O;

R ¹ and R ² are independently selected from hydrogen, halogen, C _1-4 alkyl and cyano;

R ³ is selected from C _1-4 alkyl and C _1-4 alkoxy;

^R4 is selected from [2-(dimethylamino)ethyl](methyl)amino, (2-hydroxyethyl)(methyl)amino and morpholin-4-yl;

^R5 is selected from hydrogen, _C1-4 alkyl and _C1-3 alkoxy _C1-3 alkyl;

^R6 is selected from hydrogen and _C1-4 alkyl.

In one embodiment of the present application, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

X is selected from NR ⁶ or O;

R ¹ and R ² are independently selected from hydrogen, halogen and C _1-4 alkyl;

R ³ is selected from C _1-4 alkoxy;

^R4 is selected from [2-(dimethylamino)ethyl](methyl)amino, (2-hydroxyethyl)(methyl)amino and morpholin-4-yl;

^R5 is selected from hydrogen, _C1-4 alkyl and _C1-3 alkoxy _C1-3 alkyl;

^R6 is selected from hydrogen and _C1-4 alkyl.

In one embodiment of the present application, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

X is selected from NR ⁶ or O;

R ¹ and R ² are independently selected from hydrogen, chlorine, bromine, fluorine and methyl;

^R3 is methoxy;

^R4 is selected from [2-(dimethylamino)ethyl](methyl)amino, (2-hydroxyethyl)(methyl)amino and morpholin-4-yl;

^R5 is selected from hydrogen and methoxymethyl;

^R6 is selected from hydrogen and methyl.

In some embodiments of the present application, the compound of formula (I) described herein includes the following compounds or pharmaceutically acceptable salts thereof:

In some embodiments of the present application, the pharmaceutically acceptable salts of the compounds of formula (I) described herein include the hydrochloride salts of the following compounds:

Another aspect of the present application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition of the present application may further contain one or more additional therapeutic agents.

Another aspect of the present application provides a method for treating EGFR-mediated diseases, comprising administering to an individual in need thereof the compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Another aspect of the present application provides use of the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as described herein in the preparation of a medicament for treating EGFR-mediated diseases.

In some embodiments of the present application, the EGFR-mediated disease is selected from a disease mediated by an EGFR-L858R activating mutation.

In some embodiments of the present application, the EGFR-mediated disease is selected from a disease mediated by the EGFR-T790M activating mutation.

In some embodiments of the present application, the EGFR-mediated disease is selected from diseases mediated by activation of EGFR-L858R combined with EGFR-T790M double mutations.

In some embodiments of the present application, the EGFR-mediated disease is cancer; the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma; the lung cancer can be selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma.

The pharmaceutical composition of the present application can be prepared by combining the compound of the present application or its salt with a suitable pharmaceutically acceptable carrier, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels or microspheres and aerosols, etc.

Typical routes of administration of the compounds of the present invention, or their pharmaceutically acceptable salts, or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous or intravenous administration.

The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods and freeze-drying methods.

For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable carriers well known in the art. These carriers enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries or suspensions, etc., for oral administration to patients.

Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules to obtain a tablet or sugar-coated core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners and/or flavoring agents. Examples include microcrystalline cellulose, glucose solution, acacia mucilage, gelatin solution, sucrose and/or starch paste; talc, starch, magnesium stearate, calcium stearate and/or stearic acid; lactose, sucrose, starch, mannitol, sorbitol and/or dicalcium phosphate; silicon dioxide; cross-linked sodium carboxymethylcellulose, pre-coated starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose and/or cross-linked polyvinyl pyrrolidone, etc. Dragee cores may optionally be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

In some embodiments, the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof can be administered by any suitable route and method, such as orally or parenterally (e.g., intravenously). The therapeutically effective amount of the compound of formula (I) is from about 0.0001 to 20 mg/Kg body weight/day, for example, from 0.001 to 10 mg/Kg body weight/day.

In some embodiments, the dosage frequency of the compound of formula (I) is determined by the needs of the individual patient, for example, once or twice a day, or more times a day. Administration can be intermittent, for example, wherein the patient receives a daily dose of the compound of formula (I) over a period of several days, followed by a period of several days in which the patient does not receive a daily dose of the compound of formula (I).

The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Specific embodiments include but are not limited to the examples of the present application.

The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

In a specific embodiment, some of the compounds represented by formula (I) of the present application can be prepared by those skilled in the art of organic synthesis using standard methods in the art via Route 1:

Starting from the compound of formula (II) and the compound of formula (III), a substitution reaction first occurs between the amino group on the phenyl ring of the compound of formula (II) and the pyrimidine chlorine atom of the compound of formula (III), then the compound of formula (IV) constructs a carbonyl group and forms a ring structure to obtain the compound of formula (V), the compound of formula (V) is connected with R ⁶ to obtain the compound of formula (VI), the pyrimidine ring chlorine atom of the compound of formula (VI) reacts with the amino group on the phenyl ring of the compound of formula (VII) to obtain the compound of formula (VIII), the compound of formula (VIII) is connected with the side chain R ⁴ to obtain the compound of formula (IX), the nitro group of the compound of formula (IX) is reduced to obtain the amino group, which then forms an amide bond with the compound of formula (XI) to obtain the final product, the compound of formula (Ia).

Some of the compounds represented by formula (I) of the present application can also be prepared by those skilled in the art of organic synthesis using standard methods in the art via Route 2:

Starting from the compound of formula (XII) and the compound of formula (III), a substitution reaction first occurs between the amino group on the phenyl ring of the compound of formula (XII) and the pyrimidine chlorine atom of the compound of formula (III), then the methyl group of the compound of formula (XIII) is removed to obtain the compound of formula (XIV), the compound of formula (XIV) constructs a carbonyl group and forms a ring structure to obtain the compound of formula (XV), the pyrimidine ring chlorine atom of the compound of formula (XV) undergoes a substitution reaction with the amino group on the phenyl ring of the compound of formula (VII) to obtain the compound of formula (XVI), the compound of formula (XVI) is connected to the side chain ^R4 to obtain the compound of formula (XVII), the nitro group of the compound of formula (XVII) is reduced to obtain the amino group, which then forms an amide bond with the compound of formula (XI) to obtain the final product, the compound of formula (Ib).

In some embodiments of the present application, those skilled in the art may prepare according to the steps of Route 1 or Route 2 rather than strictly following them. Depending on the structure of the final product, they may add, subtract or change the order of the steps in Route 1 or Route 2, which also falls within the scope of the present application.

For the sake of clarity, the present application is further described with reference to examples, which, however, are not intended to limit or specify the scope of the invention.

All solvents used in this application are commercially available and can be used without further purification. All operations involving experiments sensitive to water and/or oxygen were carried out in pre-dried glassware under a nitrogen atmosphere. Unless otherwise stated, all raw materials are commercial raw materials and were not further purified before use. The column chromatography used in this application uses silica gel (200-300 mesh) produced by Qingdao Ocean Chemical Industry. Thin layer chromatography uses Merck (E.Merck) pre-coated chromatography plates (silica gel 60PF254, 0.25 mm). The instrument used for nuclear magnetic resonance spectroscopy analysis is a Varian VNMRS-400 resonance spectrometer, and the chemical shift is based on tetramethylsilane (TMS = δ 0.00) as the internal standard. The recording format of the nuclear magnetic resonance hydrogen spectrum data is: number of protons, peak type (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant (in Hertz Hz).

The following abbreviations are used herein: DMF stands for N,N-dimethylformamide; NMP stands for N-methylpyrrolidone; DCM stands for dichloromethane; PE stands for petroleum ether; EA stands for ethyl acetate; MeOH stands for methanol; _Pd2 (dba) ₃ stands for tris(dibenzylideneacetone)dipalladium; TsOH stands for p-toluenesulfonic acid; and BINAP stands for (±)-2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl.

The compounds were named manually or by software, and commercially available compounds used the supplier's catalog names.

Example

The following specific embodiments are intended to enable those skilled in the art to more clearly understand and implement the present application. They should not be considered as limiting the scope of the present application, but are merely exemplary and representative of the present application.

Example 1 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)acrylamide hydrochloride.

Step 1: N ¹ -(2-chloropyrimidin-4-yl)benzene-1,2-diamine

Disperse o-phenylenediamine (3.24 g, 30 mmol) and 2,4-dichloropyrimidine (4.47 g, 30 mmol) in anhydrous ethanol (60 mL). Add diisopropylethylamine (7.74 g, 60 mmol) and heat under reflux for 3 hours. Concentrate under vacuum to remove the solvent. The residue is dissolved in dichloromethane (100 mL), washed with water and saturated brine, and concentrated under vacuum to remove the solvent. The residue is separated by column chromatography (EA:PE = 1:2) to obtain the title compound (5.32 g, 80%).

¹ H NMR (CDCl ₃ ): δ 8.08 (1H, d, J = 5.6Hz), 7.20-7.12 (2H, m), 6.85-6.78 (2H, m), 6.74 (1H, s), 6.24 (1H, d, J = 5.6Hz), 3.82 (2H, br).

Step 2: 1-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

Dissolve N ¹ -(2-chloropyrimidin-4-yl)phenyl-1,2-diamine (2.21 g, 10 mmol) in DMF (15 mL), add carbonyldiimidazole (2.43 g, 15 mmol), stir at room temperature for 1 hour, pour into water (50 mL), continue stirring for 10 minutes, filter, wash with water (30 mL x 3), and dry to obtain the title compound (2.23 g, 90%).

¹ H NMR (DMSO-d ₆ ): δ 11.64 (1H, br), 8.78 (1H, d, J = 5.6Hz), 8.43 (1H, d, J = 5.6Hz), 8.26 (1H, d, J = 7.6Hz), 7.22-7.10 (3H, m).

Step 3: 1-(2-chloropyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

Disperse 1-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (600 mg, 2.43 mmol) in anhydrous DMF (10 mL) and cool in an ice-water bath. Add sodium hydride (116 mg, 60%, 2.90 mmol) and stir for 1 hour. Add iodomethane (345 mg, 2.43 mmol) dropwise and continue stirring for 1 hour. Pour the reaction mixture into water (50 mL), stir for 30 minutes, filter, wash with water (30 mL x 3), and dry to obtain the title compound (459 mg, 72%).

¹ H NMR (DMSO-d ₆ ): δ 8.79 (1H, d, J = 5.6Hz), 8.44 (1H, d, J = 6.0Hz), 8.29 (1H, d, J = 8.0Hz), 7.30-7.28 (2H, m), 7.24-7.19 (1H, m), 3.39 (3H, s).

Step 4: 1-(2-(4-Fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one p-toluenesulfonate

1-(2-Chloropyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (459 mg, 1.76 mmol), 4-fluoro-2-methoxy-5-nitroaniline (360 mg, 1.93 mmol), and p-toluenesulfonic acid monohydrate (551 mg, 2.89 mmol) were dispersed in 2-pentanol (10 mL) and stirred at 105°C overnight. After cooling, the mixture was filtered and the filter cake was washed three times with a small amount of 2-pentanol and dried to give the title compound (440 mg, 43%).

¹ H NMR (CDCl ₃ ): δ10.95 (1H, br), 8.49 (1H, d, J = 7.6Hz), 8.39 (1H, d, J = 7.2Hz), 8.21 (1H, d, J = 7.2Hz), 7.87 (2H, d, J = 8.4Hz), 7.68 ( 1H, d, J=8.4Hz), 7.28-7.23 (2H, m), 7.04 (2H, d, J=7.6Hz), 6.91-6.85 (2H, m), 3.92 (3H, s), 3.46 (3H, s), 2.38 (3H, s).

Step 5: 1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

1-(2-(4-Fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one p-toluenesulfonate (440 mg, 0.76 mmol) was dissolved in NMP (5 mL). Diisopropylethylamine (206 mg, 1.59 mmol) and ^N₁ , ^N₁ , ^N₂ -trimethylethane-1,2-diamine (116 mg, 1.14 mmol) were added. The reaction mixture was stirred at 85°C overnight. After cooling, the reaction solution was poured into water (50 mL), filtered, rinsed with a small amount of methanol, and dried to obtain the title compound (326 mg, 88%).

¹ H NMR (CDCl ₃ ): δ8.92 (1H, s), 8.51 (1H, d, J = 5.6Hz), 8.27 (1H, d, J = 7.6Hz), 7.82 (1H, d, J = 5.6Hz), 7.47 (1H, s), 7.29-7.19 (1H, m), 7.17-7.13 (1H, m) , 7.04 (1H, d, J = 7.6Hz), 6.69 (1H, s), 3.98 (3H, s), 3.47 (3H, s), 3.27 (2H, t, J = 7.2Hz), 2.89 (3H, s), 2.88 (2H, t, J = 7.2Hz), 2.26 (6H, s).

Step 6: 1-(2-(5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (326 mg, 0.66 mmol) was dissolved in methanol (10 mL), Pd/C (10%, 30 mg) was added, and the hydrogen atmosphere was replaced three times. The system was stirred under a hydrogen atmosphere overnight and filtered. The product was easily oxidized. The filtrate was quickly concentrated in vacuo and directly used for the next reaction.

Step 7: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)acrylamide hydrochloride

Dissolve 1-(2-(5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one, obtained in the previous step, in anhydrous dichloromethane (10 mL). Add diisopropylethylamine (129 mg, 1.00 mmol) and cool in an ice-water bath. Slowly add a solution of acryloyl chloride (60 mg, 0.66 mmol) in anhydrous dichloromethane (2 mL) dropwise to the system over 15 minutes. After stirring for 15 minutes, the reaction mixture was poured into petroleum ether (50 mL) and stirred for 10 minutes. Filter with suction, and rinse the filter cake with petroleum ether. The resulting crude product was isolated by column chromatography (DCM:MeOH = 20:1) to afford the title compound (164 mg, 45% yield for both steps).

¹ H NMR (DMSO-d ₆ ): δ10.15 (1H, br), 9.72 (1H, br), 8.70 (1H, s), 8.41 (1H, d, J = 5.6Hz), 8.16-8.12 (2H, m), 7.67 (1H, d, J = 5.6Hz), 7.22-712 (2H, m), 6.99-6.92 (3H, m), 6.19 (1H, dd, J = 2.0Hz, 17.2Hz), 5.68 (1H, dd, J = 2.0Hz, 10.4Hz), 3.77 (3H, s), 3.34 (3H, s), 3.28 (4H, br), 2.72 (6H, s), 2.60 (3H, s).

Example 2 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)acrylamide hydrochloride

Step 1: 1-(2-(4-Fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one p-toluenesulfonate

The title compound was synthesized in a manner analogous to that described in Step 4 of Example 1 from 1-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one and 4-fluoro-2-methoxy-5-nitroaniline.

¹ H NMR (DMSO-d ₆ ): δ11.47 (1H, s), 9.12 (1H, s), 8.62 (1H, d, J = 8.4Hz), 8.50 (1H, d, J = 5.6Hz), 8.16-8.14 (1H, m), 7.82 (1H, d, J = 5. 6Hz), 7.47-7.40 (3H, m), 7.15-7.09 (3H, m), 7.04 (1H, d, J=7.6Hz), 6.95-6.91 (1H, m), 3.96 (3H, s), 2.27 (3H, s).

Step 2: 1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized from 1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one p-toluenesulfonate in a manner similar to that described in Step 5 of Example 1.

¹ H NMR (DMSO-d ₆ ): δ11.39 (1H, s), 8.72 (1H, s), 8.42 (1H, d, J = 5.6Hz), 8.12-8.03 (2H, m), 7.68 (1H, d, J = 5.6Hz), 7.11-7.07 (1H, m), 7.02-7.00 (1H, m), 6.88-6.84 (1H, m), 6.81 (1H, s), 3.87 (3H, s), 3.28 (2H, t, J = 6.8Hz), 2.85 (3H, s), 2.46 (2H, t, J = 6.8Hz), 2.15 (6H, s).

Step 3: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)acrylamide hydrochloride

The title compound was synthesized from 1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one in a manner similar to that described in Steps 6 and 7 of Example 1.

¹ H NMR (MeOD): δ 8.46 (1H, d, J = 5.6Hz), 8.28 (1H, s), 8.14 (1H, d, J = 8.4Hz), 7.70 (1H, d, J = 5.6Hz), 7.12-7.06 (2H, m), 7.03-7.99 ( 1H, m), 6.97 (1H, s), 6.51-6.38 (2H, m), 5.83-5.80 (1H, m), 3.97 (3H, s), 3.45 (2H, br), 3.21 (2H, br), 2.81 (6H, s), 2.71 (3H, s).

Example 3 N-(5-(5-chloro-4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide hydrochloride

Step 1: N ¹ -(2,5-dichloropyrimidin-4-yl)benzene-1,2-diamine

The title compound was synthesized from 2,4,5-trichloropyrimidine and o-phenylenediamine in a manner similar to that described in Example 1, Step 1.

¹ H NMR (CDCl ₃ ): δ 8.18 (1H, s), 7.46 (1H, dd, J=1.6Hz, 7.2Hz), 7.15-7.11 (2H, m), 6.91-6.86 (2H, m), 3.67 (2H, br).

Step 2: 1-(2,5-Dichloropyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

Dissolve ^N- (2,5-dichloropyrimidin-4-yl)benzene-1,2-diamine (100 mg, 0.39 mmol) in ethyl acetate (5 mL), add diisopropylethylamine (151 mg, 1.17 mmol), and cool in an ice-water bath. Add triphosgene (71 mg, 0.24 mmol) portionwise, warm to room temperature, and continue stirring for 1 hour. Add saturated sodium bicarbonate solution (10 mL), continue stirring for 10 minutes, and extract with ethyl acetate (20 mL x 2). Combine the organic phases, wash with saturated brine, and concentrate in vacuo to remove the solvent to obtain the title compound (105 mg, 95%).

¹ H NMR (DMSO-d ₆ ): δ 11.44 (1H, br), 9.16 (1H, s), 7.20-7.04 (4H, m).

Step 3: 1-(2,5-dichloropyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized from 1-(2,5-dichloropyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one in a manner similar to that described in Step 3 of Example 1.

¹ H NMR (CDCl ₃ ): δ 8.80 (1H, s), 7.27-7.23 (2H, m), 7.18-7.16 (1H, m), 7.06 (1H, d, J=8.0Hz), 3.48 (3H, s).

Step 4: 1-(5-chloro-2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

1-(2,5-Dichloropyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (50 mg, 0.17 mmol), 4-fluoro-2-methoxy-5-nitroaniline (63 mg, 0.34 mmol), BINAP (11 mg, 0.017 mmol), and cesium carbonate (110 mg, 0.34 mmol) were dispersed in anhydrous toluene (5 mL). Nitrogen was bubbled through the mixture for 20 minutes, followed by the addition of _Pd2 (dba) ₃ (8 mg, 0.008 mmol). The reaction was carried out in a microwave reactor (100 W, 100°C) for 1 hour, followed by concentration in vacuo to remove the solvent. The residue was purified by column chromatography (DCM to DCM:EA = 20:1) to afford the title compound (54 mg, 72%).

¹ H NMR (CDCl ₃ ): 9.31 (1H, s), 8.02 (1H, s), 8.55 (1H, d, J = 8.2Hz), 7.33 (1H, d, J = 13.6Hz), 7.25 (1H , d, J = 7.2Hz), 7.21-7.16 (2H, m), 6.78 (1H, d, J = 12.0Hz), 3.97 (3H, s), 3.43 (3H, s).

Step 5: 1-(5-chloro-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized in a manner analogous to that described in Step 5 of Example 1 from 1-(5-chloro-2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one.

¹ H NMR (CDCl ₃ ): δ8.88 (1H, s), 8.59 (1H, s), 7.69 (1H, s), 7.25-7.19 (2H, m), 7.16-7.14 (1H, m), 7.05 (1H, d, J = 7.2Hz), 6. 65 (1H, s), 3.95 (3H, s), 3.49 (3H, s) 3.25 (2H, t, J = 7.2Hz), 2.56 (3H, s), 2.54 (2H, t, J = 7.2Hz), 2.25 (6H, s).

Step 6: 1-(2-(5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenylamino)-5-chloropyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

Disperse 1-(5-chloro-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (320 mg, 0.61 mmol), iron powder (139 mg, 2.48 mmol), and ammonium chloride (50 mg, 0.93 mmol) in a mixture of ethanol/water (8 mL/4 mL). The system was vigorously stirred at 80°C for 3 hours, cooled, filtered, and the organic solvent was removed in vacuo. Water (20 mL) was added to the resulting mixture, and the mixture was extracted with ethyl acetate (20 mL*3). The resulting organic phase was washed with saturated brine and concentrated in vacuo to remove the solvent to obtain the title compound, which was used directly in the next step.

Step 7: N-(5-(5-chloro-4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide hydrochloride

The title compound was synthesized from 1-(5-chloro-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one in a manner analogous to that described in Example 1, Step 7.

¹ H NMR (DMSO-d ₆ ): δ10.15 (1H, br), 9.68 (1H, br), 9.05 (1H, s), 8.66 (1H, s), 8.11 (1H, s), 7.23-7.20 (1H, m), 7.15-7.09 (2H, m), 7.05-6.99 (2H, m), 6.89 (1 H, s), 6.41 (1H, dd, J = 2.0Hz, 16.8Hz), 5.70 (1H, dd, J = 2.0Hz, 10.0Hz), 3.79 (3H, s), 3.35 (3H, s), 3.28 (2H, br), 2.65 (6H, s), 2.55 (5H, s).

Example 4 N-(5-(5-chloro-4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide hydrochloride

Step 1: 1-(5-chloro-2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized from 1-(2,5-dichloropyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one and 4-fluoro-2-methoxy-5-nitroaniline in a manner analogous to that described in Example 3, Step 4.

¹ H NMR (CDCl ₃ ): 9.24 (1H, d, J = 8.0Hz), 8.68 (1H, s), 8.45 (1H, s), 7.83 (1H, s), 7.34 (1H, s), 7.22-7.10 (3H, m), 6.78 (1H, d, J = 12.0Hz), 4.02 (3H, s).

Step 2: 1-(5-chloro-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

¹ H NMR (CDCl ₃ ): δ 8.94 (1H, s), 8.66 (1H, s), 8.38 (1H, br), 7.84 (1H, s), 7.23-7.13 (4H, m), 4.05 (3H, s), 3.56 (2H, br), 3.08 (2H, br), 2.89 (3H, s) 2.69 (6H, s).

The title compound was synthesized from 1-(5-chloro-2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one in a manner analogous to that described in Example 1, Step 5.

Step 3: N-(5-(5-chloro-4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-2-((2-(dimethylheptyl)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide hydrochloride

The title compound was synthesized from 1-(5-chloro-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one in a manner similar to that described in Steps 6 and 7 of Example 3.

¹ H NMR (CDCl ₃ ): δ12.20(1H, br), 9.35(1H, br), 9.17(1H, br), 8.64(1H, s), 8.41(1H, br), 7.69(1H, s), 7.21-7.16(1H, m), 7.13-7.07(3H, m) , 6.67 (1H, s), 6.42 (1H, dd, J = 1.6Hz, 16.8Hz), 5.71 (1H, d, J = 11.6Hz), 3.84 (3H, s), 3.24 (2H, br), 3.08 (2H, br), 2.72 (9H, br).

Example 5 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(2-oxobenzo[d]oxazol-3(2H)-yl)pyrimidin-2-ylamino)phenyl)acrylamide hydrochloride

Step 1: 2-Chloro-N-(2-methoxyphenyl)pyrimidin-4-amine

The title compound was synthesized from o-anisidine and 2,4-dichloropyrimidine in a manner similar to that described in Example 1, Step 1.

¹ H NMR (CDCl ₃ ): δ8.14 (1H, d, J = 5.6Hz), 7.83 (1H, br), 7.27 (1H, m), 7.17-7.13 (1H, m), 7.0 4-6.99 (1H, m), 6.96-6.94 (1H, m), 6.63-6.62 (1H, d, J=6.0Hz), 3.89 (3H, s).

Step 2: 2-(2-chloropyrimidin-4-ylamino)phenol

Dissolve 2-chloro-N-(2-methoxyphenyl)pyrimidin-4-amine (100 mg, 0.42 mmol) in anhydrous dichloromethane (3 mL) and cool in an ice-water bath. Slowly add a dichloromethane solution (2.5 mL, 2.12 mmol) dropwise, allow to warm to room temperature, and continue stirring for 2 hours. Add saturated ammonium chloride solution to quench the reaction, extract with dichloromethane (20 mL x 3), combine the organic phases, wash with saturated brine, and remove the solvent in vacuo to obtain the title compound (84 mg, 89%).

¹ H NMR (DMSO-d ₆ ): δ9.85 (1H, s), 9.31 (1H, s), 8.07 (1H, d, J = 6.0Hz), 7.57 (1H, br), 7.05-7.01 (1H, m), 6.93 (1H, d, J = 8.0Hz), 6.84-6.80 (1H, m), 6.66 (1H, br).

Step 3: 3-(2-chloropyrimidin-4-yl)benzo[d]oxazol-2(3H)-one

The title compound was synthesized from 2-(2-chloropyrimidin-4-ylamino)phenol in a manner similar to that described in Example 3, Step 2.

¹ H NMR (DMSO-d ₆ ): δ 8.87 (1H, d, J=5.6Hz), 8.25-8.19 (2H, m), 7.49 (1H, d, J=7.6Hz), 7.39-7.30 (2H, m).

Step 4: 3-(2-(4-Fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)benzo[d]oxazol-2(3H)-one p-toluenesulfonate

The title compound was synthesized in a manner similar to that described in Step 4 of Example 1 from 3-(2-chloropyrimidin-4-yl)benzo[d]oxazol-2(3H)-one.

¹ H NMR (DMSO-d ₆ ): δ10.83 (1H, br), 9.23 (1H, s), 8.59 (1H, d, J = 5.6Hz), 8.24 (1H, br), 7.64 (1H, d, J = 5.6Hz), 7.47-7 .43 (4H, m), 7.31-7.24 (1H, m), 7.19-7.14 (1H, m), 7.11 (2H, d, J = 8.0Hz), 3.97 (3H, s), 2.28 (3H, s).

Step 5: 3-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)benzo[d]oxazol-2(3H)-one

The title compound was synthesized in a manner similar to that described in Step 5 of Example 1 from 3-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)benzo[d]oxazol-2(3H)-one p-toluenesulfonate.

¹ H NMR (CDCl ₃ ): δ8.86 (1H, s), 9.23 (1H, s), 8.57 (1H, d, J = 5.6Hz), 8.24-8.22 (1H, m), 7.74 (1H, d, J = 5.6Hz), 7.48 (1H, s), 7.29 -7.25 (2H, m), 6.72 (1H, s), 4.01 (3H, s), 3.29 (2H, t, J = 7.2Hz), 2.89 (3H, s), 2.57 (2H, t, J = 7.2Hz), 2.27 (6H, s).

Step 6: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(2-oxobenzo[d]oxazol-3(2H)-yl)pyrimidin-2-ylamino)phenyl)acrylamide hydrochloride

The title compound was synthesized from 3-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)benzo[d]oxazol-2(3H)-one in a manner similar to that described in Steps 6 and 7 of Example 1.

¹ H NMR (CDCl ₃ ): δ12.21 (1H, br), 9.51 (1H, br), 9.22 (1H, s), 8.55 (1H, d, J = 5.6Hz), 8.25 (1H, d, J = 8.0Hz), 7.51 (1H, s), 7.26 (1H, s), 7.23-7.16 (4H, m) , 6.72 (1H, s), 6.31 (1H, dd, J = 2.0Hz, 16.8Hz), 5.67 (1H, dd, J = 2.0Hz, 10.4Hz,), 3.90 (3H, s), 3.29 (2H, br), 3.13 (2H, br), 2.76 (9H, br).

Example 6 N-(2-((2-hydroxyethyl)(methyl)amino)-4-methoxy-5-(4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)acrylamide

Step 1: 1-(2-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized from 2-(methylamino)ethanol in a manner similar to that described in Example 1, Step 5.

¹ H NMR (CDCl ₃ ): δ8.97 (1H, s), 8.52 (1H, d, J = 6.0Hz), 8.26 (1H, J = 7.2Hz), 7.83 (1H, d, J = 5.6Hz), 7.56 (1H, s), 7.27-7.23 (1H, m), 7.18-7.1 6 (1H, m), 7.04 (1H, J = 7.2Hz), 6.70 (1H, s), 4.00 (3H, s), 3.79-3.76 (2H, m), 3.48 (3H, s), 3.40 (2H, t, J = 7.2Hz), 2.84 (3H, s).

Step 2: N-(2-((2-hydroxyethyl)(methyl)amino)-4-methoxy-5-(4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)acrylamide

The title compound was synthesized from 1-(2-(4-((2-hydroxyethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one in a manner similar to that described in Steps 6 and 7 of Example 1.

¹ H NMR (CDCl ₃ ): δ9.30 (1H, s), 9.03 (1H, s), 8.52 (1H, d, J = 5.6Hz), 8.32 (1H, d, J = 8.0Hz), 7.80 (1H, d, J=5.6Hz), 7.46 (1H, s), 7.18-7.14 (1H, m), 7.08-7.03 (1H, m), 7 .01-6.95(1H,m), 6.77(1H,s), 6.34-6.32(2H,m), 5.65-5.63(1H,m), 3.87( 3H, s), 3.77-3.74 (2H, m), 3.45 (3H, s), 2.99 (2H, t, J=4.8Hz), 3.75 (3H, s).

Example 7 (E)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)-4-methoxybut-2-enamide

The title compound was synthesized from 1-(2-(5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one and (E)-4-methoxybut-2-enoyl chloride in a manner analogous to that described in Step 7 of Example 1.

¹ H NMR (CDCl ₃ ): δ12.32(1H, br), 9.24(1H, br), 9.17(1H, br), 8.52(1H, d, J=5.6Hz), 8.31(1H, d , J=8.0Hz), 7.80 (1H, d, J=5.6Hz), 7.49 (1H, br), 7.19-7.10 (2H, m), 6.99-6.96 (2H , m), 6.90-6.84 (1H, m), 6.72 (1H, s), 4.14 (2H, d, J = 3.2Hz), 3.90 (3H, s), 3.45 (3H , s), 3.40 (3H, s), 3.38-3.35 (2H, m), 3.12-3.08 (2H, m), 2.80 (6H, s), 2.74 (3H, s).

Example 8 N-(4-methoxy-5-(4-(3-methyl-2-oxo-2,3-dichlorobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-2-morpholinylphenyl)acrylamide

Step 1: 1-(2-(2-methoxy-4-morpholino-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized from 1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one p-toluenesulfonate and morpholine in a manner analogous to that described in Step 5 of Example 1.

¹ H NMR (CDCl ₃ ): δ9.10 (1H, s), 8.54 (1H, d, J = 5.6Hz), 8.27 (1H, d, J = 8.0Hz), 7.85 (1H, d, J = 5.6Hz), 7.59 (1H, s), 7.27-7.24 (1H, m), 7 .19-7.17(1H,m), 7.05(1H,d,J=8.0Hz), 6.65(1H,s), 4.04(3H,s), 3.91-3.89(4H,m), 3.49(3H,s), 3.10-3.08(4H,m).

Step 2: N-(4-methoxy-5-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-2-morpholinylphenyl)acrylamide

The title compound was synthesized from 1-(2-(2-methoxy-4-morpholin-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one in a manner similar to that described in Steps 6 and 7 of Example 1.

¹ H NMR (CDCl ₃ ): δ9.37 (1H, s), 8.55 (1H, d, J = 5.6Hz), 8.48 (1H, s), 8.34 (1H, d, J = 8.0Hz), 7.81 (1H, d, J = 5.6Hz), 7.46 (1H, s), 7.20-7.16 (1H, m), 7.10-7 .06 (1H, m), 7.01-6.99 (1H, m), 6.79 (1H, s), 6.36-6.22 (2H, m), 5.75-5.72 (1H, m), 3.91-3.88 (7H, m), 3.46 (3H, s), 2.90 (4H, t, J=4.8Hz).

Example 9 N-(2-((2-(dimethylamino)ethyl)(methyl)hexyl)-4-methoxy-5-(4-(5-methyl-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)acrylamide hydrochloride

Step 1: N ¹ -(2-chloropyrimidin-4-yl)-4-methylbenzene-1,2-diamine

The title compound was synthesized from 4-methylbenzene-1,2-diamine and 2,4-dichloropyrimidine in a manner similar to that described in Example 1, Step 1.

¹ H NMR (CDCl ₃ ): δ8.06 (1H, d, J = 6.0Hz), 7.00 (1H, d, J = 8.0Hz), 6.77 (1H, s), 6.66 (1H, s) , 6.62 (1H, d, J = 8.0Hz), 6.21 (1H, d, J = 6.0Hz), 3.79 (2H, br), 2.31 (3H, s).

Step 2: 1-(2-chloropyrimidin-4-yl)-5-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized in a manner similar to that described in Example 1, Step 2 from N ¹ -(2-chloropyrimidin-4-yl)-4-methylbenzene-1,2-diamine and carbonyldiimidazole.

¹ H NMR (CDCl ₃ ): δ 8.62 (1H, d, J = 5.6Hz), 8.47 (1H, d, J = 5.6Hz), 8.34 (1H, d, J = 8.4Hz), 7.97 (1H, s), 7.03 (1H, d, J = 8.4Hz), 6.91 (1H, s), 2.42 (3H, s).

Step 3: 1-(2-(4-Fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-5-methyl-1H-benzo[d]imidazol-2(3H)-one p-toluenesulfonate

The title compound was synthesized in a manner analogous to that described in Step 4 of Example 1 from 1-(2-chloropyrimidin-4-yl)-5-methyl-1H-benzo[d]imidazol-2(3H)-one and 4-fluoro-2-methoxy-5-nitroaniline.

¹ H NMR (DMSO-d ₆ ): δ11.39 (1H, s), 9.04 (1H, s), 8.61 (1H, d, J = 8.4Hz), 8.49 (1H, d, J = 5.6Hz), 8.04-8.02 (1H, m), 7.82 (1H, d, J = 5.6Hz), 7.4 9-7.41(3H,m), 7.11(2H,d,J=8.0Hz), 6.93(1H,s), 6.87(1H,s), 6.76-6.74(1H,m), 3.97(3H,s), 2.33(3H,s), 2.29(3H,s).

Step 4: 1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-5-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized in a manner analogous to that described in Step 5 of Example 1 from 1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-5-methyl-1H-benzo[d]imidazol-2(3H)-one p-toluenesulfonate and diisopropylethylamine.

¹ H NMR (CDCl ₃ ): δ 8.92 (1H, s), 8.50 (1H, d, J = 5.6Hz), 8.30 (1H, br), 8.11 (1H, d, J = 8.0Hz), 7.78 (1H, d, J = 5.6Hz), 7.45 (1H, s), 6.94 (1H, d, J = 8. 0Hz), 6.89 (1H, s), 6.70 (1H, s), 3.98 (3H, s), 3.31 (2H, t, J = 6.8Hz), 2.88 (3H, s), 2.61 (2H, t, J = 6.8Hz), 2.40 (3H, s), 2.31 (6H, s).

Step 5: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(5-methyl-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)acrylamide hydrochloride

The title compound was synthesized from 1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-5-methyl-1H-benzo[d]imidazol-2(3H)-one in a manner similar to that described in Steps 6 and 7 of Example 1.

¹ H NMR (MeOD): δ8.32 (1H, d, J = 6.0Hz), 7.91 (1H, d, J = 8.0Hz), 7.61 (1H, d, J = 5.6Hz), 6.87-6.84 (2H, m), 6.78 (1H, s), 6.70 (1H, d, J = 8.0Hz), 6.40-6.26(2H, m), 5.73-5.70(1H, m), 3.86(3H, s), 3.26(2H, br), 2.93(2H, br), 2.61(3H, s), 2.59(6H, s), 2.22(3H, s).

Example 10 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(5-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-4-methoxyphenyl)acrylamide hydrochloride

Step 1: N ¹ -(2-dichloropyrimidin-4-yl)-4-fluorobenzene-1,2-diamine

The title compound was synthesized from 2,4-dichloropyrimidine and 4-fluorobenzene-1,2-diamine in a manner similar to that described in Example 1, Step 1.

¹ H NMR (CDCl ₃ ): δ 8.06 (1H, d, J = 6.0Hz), 7.06-7.03 (1H, m), 6.71 (1H, s), 6.52-6.44 (2H, m), 6.14 (1H, d, J = 6.0Hz), 3.94 (2H, br).

Step 2: 1-(2-chloropyrimidin-4-yl)-5-fluoro-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized in a manner similar to that described in Example 1, Step 2, from N ¹ -(2-dichloropyrimidin-4-yl)-4-fluorobenzene-1,2-diamine and carbonyldiimidazole.

¹ H NMR (DMSO-d ₆ ): δ 11.81 (1H, s), 8.77 (1H, d, J = 6.0 Hz), 8.40 (1H, d, J = 6.0 Hz), 8.24-8.21 (1H, m), 7.03-6.96 (2H, m).

Step 3: 1-(2-chloropyrimidin-4-yl)-5-fluoro-3-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized in a manner similar to that described in Step 3 of Example 1 from 1-(2-chloropyrimidin-4-yl)-5-fluoro-1H-benzo[d]imidazol-2(3H)-one.

¹ H NMR (DMSO-d ₆ ): δ 8.77 (1H, d, J = 5.6Hz), 8.38 (1H, d, J = 5.6Hz), 8.23-8.19 (1H, m), 7.29 (1H, d, J = 8.8Hz), 7.04-7.00 (1H, m), 3.36 (3H, s).

Step 4: 5-Fluoro-1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one p-toluenesulfonate

The title compound was synthesized from 1-(2-chloropyrimidin-4-yl)-5-fluoro-3-methyl-1H-benzo[d]imidazol-2(3H)-one and 4-fluoro-2-methoxy-5-nitroaniline in a manner similar to that described in Step 4 of Example 1 and used directly in the next step.

Step 5: 1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-5-fluoro-3-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized from 5-fluoro-1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one p-toluenesulfonate in a manner similar to that described in Step 5 of Example 1.

¹ H NMR (CDCl ₃ ): δ8.86 (1H, s), 8.50 (1H, d, J = 5.6Hz), 8.24-8.21 (1H, m), 7.81 (1H, d, J = 5.6Hz), 7.42 (1H, s), 6.86-6.81 (1H, m), 6.76 (1H, dd, J =2.8Hz, 8.0Hz), 6.69 (1H, s), 3.98 (3H, s), 3.44 (3H, s), 3.29 (2H, t, J = 7.2Hz), 2.89 (3H, s), 2.57 (2H, t, J = 7.2Hz), 2.27 (6H, s).

Step 6: N-(2-((2-(dimethylamino)ethyl)(methyl)hexyl)-5-(4-(5-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-4-methoxyphenyl)acrylamide hydrochloride

The title compound was synthesized from 1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-5-fluoro-3-methyl-1H-benzo[d]imidazol-2(3H)-one in a manner similar to that described in Steps 6 and 7 of Example 1.

¹ H NMR (DMSO-d ₆ ): δ10.26 (1H, s), 9.78 (1H, s), 8.74 (1H, s), 8.43 (1H, d, J = 6.0Hz), 8.17 (2H, s), 7 .70 (1H, d, J = 6.0Hz), 7.22 (1H, dd, J = 2.4Hz, 8.8Hz), 7.06-6.99 (1H, m), 6.97 (1H, s ), 6.79-6.75 (1H, m), 6.21 (1H, dd, J = 2.0Hz, 16.8Hz), 5.71-5.68 (1H, m), 3.80 (3H , s), 3.63-3.57 (2H, m), 3.34 (3H, s), 3.16-3.09 (2H, m), 2.75 (6H, s), 2.63 (3H, s).

Example 11 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(5-fluoro-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-4-methoxyphenyl)acrylamide hydrochloride

Step 1: 5-Fluoro-1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one p-toluenesulfonate

The title compound was synthesized from 1-(2-aminopyrimidin-4-yl)-5-fluoro-1H-benzo[d]imidazol-2(3H)-one and 4-fluoro-2-methoxy-5-nitroaniline in a manner analogous to that described in Step 4 of Example 1.

¹ H NMR (DMSO-d ₆ ): δ11.68 (1H, s), 9.24 (1H, s), 8.64 (1H, d, J = 8.0Hz), 8.51 (1H, d, J = 6.0Hz), 8.23 (1H, br), 7.83 (1H, d, J = 6.0Hz), 7.48 (2H, d, J=8.0Hz), 7.43 (1H, d, J=8.0Hz), 7.12 (2H, d, J=8.0Hz), 6.94-6.91 (1H, m), 6.80-6.75 (1H, m), 3.98 (3H, s), 2.29 (3H, s).

Step 2: 1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-5-fluoro-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized from 5-fluoro-1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one p-toluenesulfonate in a manner similar to that described in Step 5 of Example 1.

¹ H NMR (DMSO-d ₆ ): δ8.83 (1H, s), 8.47 (1H, d, J = 5.6Hz), 8.26 (1H, s), 8.23-8.17 (1H, m), 7.77-7.68 (2H, m), 6.99-6.9 4(2H,m), 6.77-6.72(1H,m), 3.99(3H,s), 3.63(2H,m), 3.19-3.15(2H,m), 2.88(3H,s), 2.66(6H,s).

Step 3: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(5-fluoro-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-4-methoxyphenyl)acrylamide hydrochloride

The title compound was synthesized from 1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-5-fluoro-1H-benzo[d]imidazol-2(3H)-one in a manner similar to that described in Steps 6 and 7 of Example 1.

¹ H NMR (CD ₃ OD): δ8.45 (1H, dd, J=2.4Hz, 5.6Hz), 8.17-8.12 (1H, m), 7.73-7.69 (2H, m), 7.22 (1H, d, J=8.0Hz), 6.95 (1H, d, J=3.6Hz), 6.88-6.83 (1 H, m), 6.77-6.71 (1H, m), 6.44-6.42 (1H, m), 5.84-5.81 (1H, m), 3.97 (3H, s), 3.49-3.46 (2H, m), 3.23 (2H, m), 2.84 (6H, s), 2.71 (3H, s).

Example 12 N-(4-methoxy-2-(methyl(2-(methylamino)ethyl)amino)-5-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)acrylamide hydrochloride

Step 1: tert-Butyl 2-((5-methoxy-4-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-2-nitrophenyl)(methyl)amino)ethyl(methyl)carbamate

The title compound was synthesized in a manner analogous to that described in Step 5 of Example 1 from 1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one p-toluenesulfonate and tert-butyl 2-(methylamino)ethylcarbamate.

¹ H NMR (CDCl ₃ ): δ8.94 (1H, s), 8.51 (1H, d, J = 5.6Hz), 8.26 (1H, d, J = 7.2Hz), 7.80 (1H, d, J = 5.6Hz), 7.48 (1H, s), 7.24-7.22 (1H, m), 7.17-7.15 (1H , m), 7.03 (1H, d, J = 7.2Hz), 6.76 (1H, s), 4.01 (3H, s), 3.47-3.37 (5H, m), 3.31-3.23 (2H, m), 2.91 (3H, s), 2.83 (3H, s), 1.44 (9H, s).

Step 2: tert-Butyl 2-((2-acrylamido-5-methoxy-4-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)(methyl)amino)ethyl(methyl)carbamate

The title compound was synthesized from tert-butyl 2-((5-methoxy-4-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-2-nitrophenyl)(methyl)amino)ethyl(methyl)carbamate in a manner similar to that described in Steps 6 and 7 of Example 1.

¹ H NMR (CDCl ₃ ): δ9.37 (1H, br), 8.67 (1H, br), 8.54 (1H, d, J = 5.6Hz), 8.34 (1H, d, J = 7.6Hz), 7.79 (1H, d, J = 5.6Hz), 7.43 (1H, s), 7.19-7.15 (1H, m), 7.08-7.04 (1H, m), 6.98 (1H, d, J = 7.6Hz), 6.79 (1H, s), 6.35 (2H, d, J = 2.4Hz), 5.69-5.72 (1H, m), 3.89 (3H, s), 3.45 (3 H, s), 3.40-3.37 (2H, m), 3.00-2.85 (2H, m), 2.85 (3H, s), 2.70 (3H, s), 1.47 (9H, s).

Step 3: N-(4-methoxy-2-(methyl(2-(methylamino)ethyl)amino)-5-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)acrylamide hydrochloride

Acetyl chloride (0.3 mL, 1.7 mmol) was slowly added dropwise to anhydrous methanol (3 mL) cooled in an external ice-water bath and stirred for 1 hour. Tert-butyl 2-((2-acrylamido-5-methoxy-4-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)(methyl)amino)ethyl(methyl)carbamate (100 mg, 0.166 mmol) was dispersed in anhydrous methanol (2 mL) and then added to the aforementioned methanolic hydrogen chloride solution. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed by vacuum concentration, and the title compound (78 mg, 93%) was obtained by silica gel column chromatography (DCM:MeOH = 20:1).

¹ H NMR (CD ₃ OD): δ8.45 (1H, d, J = 5.6Hz), 8.19 (2H, d, J = 6.0Hz), 7.77 (1H, d, J = 5.6Hz), 7.21-7.16 (2H, m), 7.09-7.05 (1H, m), 6.95 (1H , s), 6.50-6.36 (2H, m), 5.80 (1H, dd, J = 2.0Hz, 6.0Hz), 3.96 (3H, s), 3.45 (3H, s), 3.35 (4H, br), 2.73 (3H, s), 2.72 (3H, s).

Example 13 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)phenyl)acrylamide

1-(2-(5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (82 g) obtained in Step 6 of Example 1 was added to THF (800 mL) and water (80 mL), stirred to dissolve, and 3-chloropropionyl chloride (24.8 g) was added dropwise. After TLC showed the disappearance of the starting material, triethylamine (358.2 g) was added and the temperature was raised to 65°C for reaction. After completion of the reaction, the reaction solution was concentrated to dryness, dissolved in 1 L of dichloromethane, and separated twice with water (500 mL). The organic phase was collected and concentrated to obtain 88 g of a crude product. The crude product was separated by column chromatography (DCM:MeOH=20:1) to obtain 62.5 g of the title compound.

ESI-MS [M+H] ⁺ : 517.2677.

¹ H NMR (DMSO-d ₆ ): δ10.05 (1H, s), 8.67 (1H, s), 8.5 (1H, s), 8.44 (1H, d, J = 5.6Hz), 8.12 (1H, d, J = 7.6Hz) , 7.13 (2H, m), 6.9 (1H, t, J = 6.4Hz), 7.7 (1H, d, J = 5.6Hz), 7.05 (1H, s), 6.4 (1H, dd, J = 10 .15Hz, 16.9Hz), 6.21 (1H, dd, J=1.6Hz, 16.9Hz), 5.72 (1H, brd, J=11.50Hz), 3.77 (3H, s ), 3.35 (3H, s), 2.91 (2H, t, J = 5.65Hz), 2.75 (3H, s), 2.34 (2H, t, J = 5.7Hz), 2.21 (6H, s).

Example 14 N-(5-(4-(5-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide hydrochloride

Step 1: 4-Chloro-N ¹ -(2-chloropyrimidin-4-yl)benzene-1,2-diamine

The title compound was synthesized from 2,4-dichloropyrimidine and 4-chloro-1,2-phenylenediamine in a manner similar to that described in Example 1, Step 1.

¹ H NMR (DMSO-d ₆ ): δ9.14 (1H, s), 8.05 (1H, d, J = 6.0Hz), 7.06 (1H, d, J = 8.4Hz), 6.80 (1H, s), 6.56 (1H, dd, J = 2.8Hz, 8.0Hz), 6.35 (1H, s), 5.32 (2H, br s).

Step 2: 5-Chloro-1-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized in a manner analogous to that described in Example 1, Step 2, from 4-chloro-N ¹ -(2-chloropyrimidin-4-yl)benzene-1,2-diamine and N,N′-carbonyldiimidazole.

¹ H NMR (DMSO-d ₆ ): δ 11.79 (1H, br s), 8.79 (1H, d, J = 5.6Hz), 8.39 (1H, d, J = 6.0Hz), 8.21 (1H, d, J = 8.8Hz), 7.23 (1H, dd, J = 2.0Hz, 8.4Hz), 7.12 (1H, s).

Step 3: 5-Chloro-1-(2-chloropyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized in a manner similar to that described in Example 1, Step 3, from 5-chloro-1-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one.

¹ H NMR (DMSO-d ₆ ): δ 8.78 (1H, d, J = 5.6Hz), 8.38 (1H, d, J = 5.6Hz), 8.19 (1H, d, J = 8.8Hz), 7.45 (1H, s), 7.23 (1H, d, J = 8.8Hz), 3.36 (3H, s).

Step 4: 5-Chloro-1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized from 5-chloro-1-(2-chloropyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one and 4-fluoro-2-methoxy-5-nitroaniline in a manner analogous to that described in Step 4 of Example 1.

¹ H NMR (DMSO-d ₆ ): 9.23 (1H, s), 8.61 (1H, d, J = 8.0Hz), 8.54 (1H, d, J = 5.6Hz), 8.22 (1H, d, J = 8.0Hz), 7.82 (1 H, d, J=5.6Hz), 7.44-7.41 (2H, m), 7.02 (1H, dd, J=2.0Hz, 8.4Hz), 3.97 (3H, s), 3.37 (3H, s).

Step 5: 5-Chloro-1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized in a manner analogous to that described in Step 5 of Example 1 from 5-chloro-1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one.

¹ H NMR (CDCl ₃ ): δ8.84 (1H, s), 8.49 (1H, d, J = 5.6Hz), 8.19 (1H, d, J = 8.4Hz), 7.79 (1H, d, J = 5.6Hz), 7.42 (1H, s), 7.09 (1H, dd, J = 2.4Hz, 8.8H z), 7.00 (1H, s), 6.69 (1H, s), 3.98 (3H, s), 3.43 (3H, s) 3.29 (2H, t, J = 7.2Hz), 2.89 (3H, s), 2.56 (2H, t, J = 7.2Hz), 2.27 (6H, s).

Step 6: 1-(2-(5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenylamino)pyrimidin-4-yl)-5-chloro-3-methyl-1H-benzo[d]imidazol-2(3H)-one

Disperse 5-chloro-1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (1.00 g) and zinc powder (1.24 g, 18.97 mmol) in a mixture of dichloromethane/methanol (15 mL/15 mL). Add 20 mL of saturated ammonium chloride solution dropwise at room temperature. Stir for 10 minutes, then filter. Add water (30 mL) to the filtrate, and extract with dichloromethane (30 mL x 3). Wash the resulting organic phase with saturated brine and concentrate in vacuo to remove the solvent to obtain the title compound, which is used directly in the next step.

Step 7: N-(5-(4-(5-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide hydrochloride

The title compound was synthesized from 1-(2-(5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenylamino)pyrimidin-4-yl)-5-chloro-3-methyl-1H-benzo[d]imidazol-2(3H)-one in a manner analogous to that described in Example 1, Step 7.

¹ H NMR (DMSO-d ₆ ): δ 10.42 (1H, br s), 9.82 (1H, s), 8.78 (1H, s), 8.44 (1H, d, J = 5.6Hz), 8.18 (1H, s), 8.13 (1H, s), 7.66 (1H, d, J = 5.6Hz), 7.38 (1H, d, J = 2.4Hz), 7.13-7.06 (1H, m) , 6.99-6.96 (2H, m), 6.20 (1H, dd, J = 2.0Hz, 16.8Hz), 5.69 (1H, dd, J = 2.0Hz, 10.0Hz), 3.80 (3H, s), 3.36-3.30 (7H, m), 2.75 (6H, s), 2.63 (3H, s).

Example 15 N-(5-(4-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide hydrochloride

Step 1: 4-Bromo-N ¹ -(2-chloropyrimidin-4-yl)benzene-1,2-diamine

The title compound was synthesized from 2,4-dichloropyrimidine and 4-bromo-1,2-phenylenediamine in a manner similar to that described in Example 1, Step 1.

¹ H NMR (DMSO-d ₆ ): δ9.13 (1H, s), 8.05 (1H, d, J = 6.0Hz), 7.01 (1H, d, J = 8.8Hz), 6.94 (1H, d, J = 2.4Hz), 6.69 (1H, dd, J = 2.0Hz, 8.4Hz), 6.38 (1H, s), 5.31 (2H, br s).

Step 2: 5-Bromo-1-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized in a manner analogous to that described in Example 1, Step 2, from 4-bromo-N ¹ -(2-chloropyrimidin-4-yl)benzene-1,2-diamine and N,N′-carbonyldiimidazole.

¹ H NMR (DMSO-d ₆ ): δ11.81 (1H, br s), 8.79 (1H, d, J = 5.6Hz), 8.40 (1H, d, J = 5.6Hz), 8.17 (1H, d, J = 8.8Hz), 7.37 (1H, dd, J = 2.0Hz, 8.8Hz), 7.26 (1H, d, J = 2.0Hz).

Step 3: 5-Bromo-1-(2-chloropyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized in a manner similar to that described in Example 1, Step 3, from 5-bromo-1-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one.

¹ H NMR (DMSO-d ₆ ): δ 8.81 (1H, d, J = 6.0Hz), 8.42 (1H, d, J = 8.0Hz), 8.19 (1H, d, J = 8.4Hz), 7.60 (1H, d, J = 2.0Hz), 7.41 (1H, dd, J = 2.0Hz, 8.4Hz), 3.40 (3H, s).

Step 4: 5-Bromo-1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized from 5-bromo-1-(2-chloropyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one and 4-fluoro-2-methoxy-5-nitroaniline in a manner analogous to that described in Step 4 of Example 1.

¹ H NMR (DMSO-d ₆ ): 9.22 (1H, s), 8.61 (1H, d, J = 8.4Hz), 8.54 (1H, d, J = 5.6Hz), 8.17 (1H, d, J = 8.0Hz), 7.82 (1H, d, J = 5.6Hz), 7.53 (1H , d, J=2.0Hz), 7.43 (1H, d, J=13.2Hz), 7.44-7.41 (2H, m), 7.14 (1H, dd, J=2.0Hz, 13.2Hz), 3.97 (3H, s), 3.37 (3H, s).

Step 5: 5-Bromo-1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

The title compound was synthesized in a manner analogous to that described in Step 5 of Example 1 from 5-bromo-1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one.

¹ H NMR (CDCl ₃ ): δ8.85 (1H, s), 8.50 (1H, d, J = 5.6Hz), 8.15 (1H, d, J = 8.4Hz), 7.79 (1H, d, J = 6.0Hz), 7.42 (1H, s), 7.24 (1H, dd, J = 2.0Hz, 8.4Hz), 7 .15 (1H, d, J = 2.0Hz), 6.69 (1H, s), 3.98 (3H, s), 3.44 (3H, s) 3.30 (2H, t, J = 6.8Hz), 2.90 (3H, s), 2.58 (2H, t, J = 7.2Hz), 2.28 (6H, s).

Step 6: 1-(2-(5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenylamino)pyrimidin-4-yl)-5-bromo-3-methyl-1H-benzo[d]imidazol-2(3H)-one

Disperse 5-bromo-1-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (1.00 g) and zinc powder (1.24 g, 18.97 mmol) in a mixture of dichloromethane/methanol (15 mL/15 mL). Add 20 mL of saturated ammonium chloride solution dropwise at room temperature. Stir for 10 minutes, then filter. Add water (30 mL) to the filtrate, and extract with dichloromethane (30 mL x 3). Wash the resulting organic phase with saturated brine and concentrate in vacuo to remove the solvent to obtain the title compound, which is used directly in the next step.

Step 7: N-(5-(4-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide hydrochloride

The title compound was synthesized from 1-(2-(5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenylamino)pyrimidin-4-yl)-5-bromo-3-methyl-1H-benzo[d]imidazol-2(3H)-one in a manner analogous to that described in Example 1, Step 7.

¹ H NMR (DMSO-d ₆ ): δ10.23 (1H, br s), 9.82 (1H, br s) s), 8.75 (1H, s), 8.44 (1H, d, J = 5.2Hz), 8.20 (1H, s), 8.05 (1H, s), 7.65 (1H, d , J=5.2Hz), 7.49 (1H, d, J=2.0Hz), 7.08 (1H, d, J=8.4Hz), 7.00-6.96 (2H, m), 6 .21 (1H, dd, J = 2.0Hz, 17.2Hz), 5.71 (1H, dd, J = 1.6Hz, 10.4Hz), 3.80 (3H, s), 3.36 (3H, s), 3.29-3.24 (2H, m), 3.16 (3H, s), 2.76-3.68 (2H, m), 2.65 (6H, s).

In vitro activity test

1. In vitro enzymatic detection method

EGFR and EGFR (T790M, L858R) kinases are expressed and purified through an insect expression system or purchased from commercial products.

A homogeneous time-resolved fluorescence (HTRF) assay platform for EGFR and EGFR (T790M, L858R) kinase activity was established using Cisbio's homogeneous time-resolved fluorescence (HTRF) method to determine compound activity. Compounds were serially diluted 10-fold starting at 1 μM in 100% DMSO. 4 μl of each dilution was added to 96 μl of reaction buffer (50 mM HEPES (pH 7.0), 0.02% _NaN₃ , 0.01% BSA, 0.1 mM Orthovanadate, 5 _mM MgCl₂, 50 nM SEB, 1 mM DTT). 2.5 μl of the diluted solution was then added to a 384-well plate (OptiPlate-384, PerkinElmer). 2.5 μl of kinase was then added, the mixture was centrifuged, and 5 μl of ATP and TK substrate-biotin were added to initiate the reaction. After incubating the 384-well plate in a 23°C incubator for a specified period of time, 5 μl of Eu ³⁺ -Cryptate-labeled TK-Antibody and 5 μl of streptavidin-XL665 were added to terminate the reaction. After incubation for 1 hour, fluorescence was read on an Envision (PerkinElmer) microscope. IC ₅₀ values for the compounds were calculated using GraphPad Prism 5.0 software.

2. Cell Proliferation Assay

Human non-small cell lung cancer cells NCI-H1975 were cultured in RPMI-1640 medium (supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin) in a cell culture incubator (37°C, 5% _CO₂ ). 2000 cells (195 μl) were seeded per well of a 96-well plate and cultured overnight. The following day, compounds were added in a three-fold serial dilution starting at 10 mM. 4 μl of each dilution was added to 96 μl of culture medium, and then 5 μl was added to the cell culture medium (final DMSO concentration of 0.1%, v/v). After 72 hours of treatment, the medium was aspirated and 30 μl of reagent (Promega) was added. Fluorescence signals were read on an Envison (Perkin Elmer) instrument, and _IC₅₀ values for cell proliferation inhibition were calculated using GraphPad Prism 5.0.

Human skin squamous cell carcinoma cell line A431 was cultured in a cell culture incubator (37°C, 5% _CO₂ ) using DMEM supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin. For compound testing, the substrate concentration was 0.6%. After reselection with 0.3% low-melting-point agar, 2,000 cells were plated per well (100 μl) in a 96-well plate. Compounds were serially diluted three-fold from 10 mM, with 2 μl of each concentration added to 98 μl of culture medium. Subsequently, 5.3 μl was added to the cell culture medium (final DMSO concentration of 0.1%, v/v). After one week (7 days), 20 μl of the reagent (Promega) was added, and the cells were incubated at 37°C for 4 hours. Fluorescence signals were read on an Envison (Perkin Elmer) and _IC₅₀ values for cell proliferation inhibition were calculated using GraphPad Prism 5.0.

Table 1: List of biological activities

NT: not tested; AZD9291 was prepared according to Example 28 of WO2013014448.

The above experimental results demonstrate that the compounds of the present application exhibit good inhibitory effects against EGFR, particularly the EGFR-L858R/T790M double mutant, in terms of enzyme activity. Furthermore, the WT/DM data demonstrate good selectivity. In terms of cellular activity, the compounds of the present application demonstrated good inhibitory effects against human non-small cell lung cancer cell line NCI-H1975 and human skin squamous cell carcinoma cell line A431.

Pharmacokinetic evaluation

The test compound was administered orally to healthy adult male rats using a single dose of 10 mg/kg adjuvanted with 20% sulfobutyl ether-β-cyclodextrin. Animals receiving oral administration were fasted overnight and from 10 hours before to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration. Approximately 0.3 mL of whole blood was collected from the orbital venous plexus into a heparinized tube. The sample was centrifuged at 4000 rpm for 5 minutes at 4°C. Plasma was transferred to a centrifuge tube and stored at -80°C until analysis. Plasma concentrations in the test compound samples were analyzed using a non-validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Plasma concentration-time data for individual animals were analyzed using WinNonlin (Professional Edition, Version 6.3; Pharsight). A non-compartmental model was used for concentration analysis. Pharmacokinetic parameters of the test compound were calculated.

Table 2.

Claims (8)

1. The hydrochloride salt of the compound represented by the following formula: 2. A pharmaceutical composition comprising a hydrochloride salt of the compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients. 3. The pharmaceutical composition of claim 2, further comprising one or more additional therapeutic agents. 4. Use of the hydrochloride salt of the compound of claim 1, or the pharmaceutical composition of claim 2 or 3, in the preparation of a medicament for treating EGFR-mediated diseases. 5. The use according to claim 4, wherein the EGFR-mediated disease is selected from diseases mediated by EGFR-L858R activating mutation, EGFR-T790M activating mutation, or EGFR-L858R combined with EGFR-T790M double mutation activation. 6. The use according to claim 4, wherein the EGFR-mediated disease includes cancer. 7. The use according to claim 6, wherein the cancer is selected from lung cancer. 8. The use according to claim 7, wherein the lung cancer includes non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, or lung squamous cell carcinoma.