Polysubstituted quinazoline compound, and preparation method, application and pharmaceutical composition thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a polysubstituted quinazoline compound, a preparation method and application thereof and a pharmaceutical composition. The polysubstituted quinazoline compound is shown as a formula (I), is a PI3K inhibitor, and can be used for preparing medicines for preventing and / or treating diseases related to PI3K activity, such as tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic dysfunction, endocrine dysfunction or nerve diseases. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medical technology and relates to a polysubstituted quinazoline compound and a preparation method, use and pharmaceutical composition thereof. Background Art

[0002] Phosphatidylinositol 3-kinase (PI3K) belongs to the lipid kinase family and can be divided into three major categories (I, II and III) according to their structure, regulatory function and lipid substrate specificity. The most intensively studied is the class I PI3K, which is a heterodimer consisting of a regulatory subunit (p85) and a catalytic subunit (p110). Class I PI3K contains four subtypes, of which PI3Kα and PI3Kβ are widely present in various cells, while the other two subtypes PI3Kδ and PI3Kγ are mainly distributed in leukocytes (Vanhaesebroeck et al., Trends Biochem Sci., 2005, 30(4): 194-204). As the main downstream effector of receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR), PI3K catalyzes phosphatidylinositol-4,5-bisphosphate (PIP2) to produce phosphatidylinositol-3,4,5-triphosphate (PIP3), thereby transmitting the signals of various growth factors and cytokines into cells. PIP3, as the second messenger in cells, can activate serine / threonine protein kinase B (AKT) and downstream effectors, including mammalian target of rapamycin (mTOR), thereby regulating a variety of cellular functions.

[0003] The PI3K signaling pathway is one of the most common abnormal signaling pathways in tumor cells, and has a key impact on the occurrence and development of tumors. In particular, the gene PIK3CA encoding p110α is amplified and mutated in most tumors, such as breast cancer, lung cancer, intestinal cancer, ovarian cancer, head and neck cancer, gastric cancer, prostate cancer, brain cancer, liver cancer, digestive tract tumors, leukemia, etc. (Zhao et al., Nat. Drug Discov. Rev. 2009, 8: 627-644). In recent years, PI3K and other related nodes on its pathway, such as AKT and mTOR, have become hot targets for the development of targeted anti-tumor drugs. Various structural types of PI3K inhibitors have been reported, and they have shown significant anti-tumor effects in cell and animal models. In addition, several compounds have been tested in clinical trials for solid tumors and blood tumors as a single agent or in combination, such as BKM120 (Novartis, clinical phase III), BEZ235 (Novartis, clinical phase II), PF-05212384 (Pfizer, clinical phase II), XL147 (Exelixis, clinical phase I / II), etc.

[0004] PI3K has become a very attractive drug target, and the development of PI3K inhibitors for the prevention and / or treatment of PI3K-related diseases has always been a problem to be solved in the art. However, PI3K inhibitors still have the problem of large toxic side effects. Therefore, the art still needs to develop new PI3K inhibitors with high efficiency and low toxicity. Summary of the invention

[0005] The technical problem solved by the present invention is to provide a new PI3K inhibitor, a preparation method, a pharmaceutical composition and use thereof. Such PI3K inhibitor has a strong inhibitory activity on class I PI3K, including PI3Kα, PI3Kβ, PI3Kγ and / or PI3Kδ, especially PI3Kα, thereby having a better preventive and / or therapeutic effect on diseases mediated by PI3K such as cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic dysfunction, endocrine dysfunction or neurological diseases.

[0006] In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:

[0007] The first aspect of the technical solution of the present invention is to provide a compound represented by formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts:

[0008]

[0009] in

[0010] R 1is hydrogen, fluorine, methoxy, ethoxy;

[0011] R 2 O(CH 2 )nR 3 、O(CH 2 )nCOR 4 , COR 4 NR 5 R 6 , 5-8 membered heterocycloalkyl;

[0012] R 3 is H, OH or C1-C4 alkyl;

[0013] R 4 OH, NR 7 R 8 or a 5-8 membered heterocycloalkyl group;

[0014] R 5 and R 6 Each is independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkylsulfonyl, C3-C6 cycloalkylsulfonyl, C1-C4 alkylacyl, C3-C6 cycloalkylacyl; the alkyl and cycloalkyl are optionally substituted by hydroxy, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C4-C6 N-containing heterocycloalkyl;

[0015] R 7 and R 8 Each is independently selected from hydrogen, C1-C4 alkyl, and the C1-C4 alkyl may be substituted by di(C1-C4 alkyl)amino;

[0016] n is 0, 1, 2, 3 or 4;

[0017] The 5- to 8-membered heterocycloalkyl group may be substituted by a C1-C4 alkyl group.

[0018] Preferably, the present invention provides a compound represented by formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, wherein:

[0019] R 1 is hydrogen, fluorine, methoxy, ethoxy;

[0020] R 2 OCH 2 CH 2 OH、OCH 2 CH 2 CH 2 OH or O(CH 2 )nCOR 4 ;

[0021] n is 1, 2 or 3;

[0022] R 4 NR 7 R 8 or a 5-8 membered heterocycloalkyl group;

[0023] R 7 and R 8 are each independently selected from hydrogen, methyl, ethyl, propyl, and R 7 and R 8 May be substituted by dimethylamino;

[0024] The 5- to 8-membered heterocycloalkyl group is piperazine, methylpiperazine, ethylpiperazine, isopropylpiperazine, piperidine, morpholine, or thiomorpholine.

[0025] Further preferably, the present invention provides a compound represented by formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, wherein:

[0026] R 1 is hydrogen, fluorine, methoxy, ethoxy;

[0027] R 2 OCH 2 CH 2 OH、OCH 2 CH 2 CH 2 OH or OCH 2 COR 4 ,

[0028] R 4 NR 7 R 8 or a 5-8 membered heterocycloalkyl group;

[0029] R 7 and R 8 are each independently selected from hydrogen, methyl, ethyl, propyl, and R 7 and R 8 May be substituted by dimethylamino;

[0030] The 5- to 8-membered heterocycloalkyl group is piperazine, methylpiperazine, ethylpiperazine, isopropylpiperazine, piperidine, morpholine, or thiomorpholine.

[0031] In another preferred embodiment, the present invention provides a compound represented by formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, wherein:

[0032] R 1 is hydrogen, fluorine, methoxy, ethoxy;

[0033] R 2 COR4 ;

[0034] R 4 NR 7 R 8 or a 5-8 membered heterocycloalkyl group;

[0035] R 7 and R 8 are each independently selected from hydrogen, methyl, ethyl, propyl, and R 7 and R 8 may be optionally substituted with dimethylamino;

[0036] The 5- to 8-membered heterocycloalkyl group is piperazine, methylpiperazine, ethylpiperazine, isopropylpiperazine, piperidine, morpholine, or thiomorpholine.

[0037] In another preferred embodiment, the present invention provides a compound represented by formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, wherein:

[0038] R 1 is hydrogen, fluorine, methoxy, ethoxy;

[0039] R 2 NR 5 R 6 ;

[0040] R 5 and R 6 Each is independently selected from hydrogen, methylsulfonyl, ethylsulfonyl, cyclopropanesulfonyl, acetyl, propionyl, isobutyryl, cyclopropylcarbonyl, cyclobutylcarbonyl;

[0041] R 5 and R 6 Optionally, it may be substituted with hydroxy, methoxy, dimethylamino, or pyrrolidinyl.

[0042] Specifically, the preferred compounds according to the present invention are as follows:

[0043]

[0044]

[0045]

[0046] The second aspect of the technical solution of the present invention is to provide a method for preparing the compound, its stereoisomers, geometric isomers, and tautomers, which comprises the following steps:

[0047]

[0048] (1) Using compound A as a starting material, preparing compound B through Miyaura reaction;

[0049] (2) Compound B is reacted with substituted pyridine to prepare compound C through Suzuki reaction;

[0050] (3) reacting compound C with NBS to prepare compound D;

[0051] (4) reacting compound D with ammonium formate and formamide to prepare compound E;

[0052] (5) coupling compound E with an aryl borate ester to prepare a compound of formula (I), a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0053] The second aspect of the technical solution of the present invention also provides a second method for preparing the compound, its stereoisomers, geometric isomers, and tautomers, which comprises the following steps:

[0054] (1) Compound E is used as a starting material and compound F is obtained through SUZUKI reaction;

[0055] (2) Compound F is reacted with carboxylic acid through a condensation reaction, or with an acid chloride to prepare a compound of formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0056] The second aspect of the technical solution of the present invention also provides a third method for preparing the compound, its stereoisomers, geometric isomers, and tautomers, which comprises the following steps:

[0057]

[0058] (1) Compound G is used as a starting material, and subjected to a substitution reaction with tert-butyl bromoacetate to obtain Compound H;

[0059] (2) Compound H and compound E undergo SUZUKI reaction to obtain compound J;

[0060] (3) Compound K is prepared by hydrolysis of compound J;

[0061] (4) Compound K is subjected to a condensation reaction to prepare a compound of formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0062] The second aspect of the technical solution of the present invention also provides a fourth method for preparing the compound, its stereoisomers, geometric isomers, and tautomers, which comprises the following steps:

[0063]

[0064] (1) Compound L is used as a starting material and reacted with compound E to obtain compound M through a SUZUKI reaction;

[0065] (2) Compound M is hydrolyzed to obtain compound N;

[0066] (3) Compound N is subjected to a condensation reaction to prepare a compound of formula (I), a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0067] The second aspect of the technical solution of the present invention also provides a fifth method for preparing the compound of formula (I), its stereoisomers, geometric isomers, and tautomers, which comprises the following steps:

[0068]

[0069] (1) Using compound G as a starting material, a substitution reaction is performed to obtain compound O;

[0070] (2) Compound O and Compound E are reacted by Suzuki reaction to prepare the compound of formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0071] The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition, which comprises the compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, and optional pharmaceutically acceptable carriers and / or excipients; preferably, the pharmaceutical composition also comprises one or more active pharmaceutical ingredients for preventing and / or treating tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine dysfunction or neurological diseases other than the compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts; preferably, the pharmaceutical composition is a pharmaceutically acceptable pharmaceutical preparation for preventing and / or treating tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine dysfunction or neurological diseases.

[0072] On the other hand, the present invention also provides a pharmaceutical preparation, which comprises at least one of the compounds, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts and optional pharmaceutically acceptable carriers and / or excipients; preferably, the pharmaceutical preparation is selected from the following pharmaceutical dosage forms: parenteral preparations, such as injection solutions or suspensions; enteral preparations, such as oral preparations, such as tablets or capsules; topical preparations, such as lotions, gels, ointments, emulsions, nasal preparations, suppositories, transdermal preparations or ophthalmic preparations.

[0073] In another aspect, the present invention also provides the use of the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of a drug for preventing and / or treating tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine dysfunction or neurological diseases. In other words, the present invention provides a method for preventing and / or treating tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine dysfunction or neurological diseases, the method comprising administering to a subject in need thereof a preventive and / or therapeutically effective amount of the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition.

[0074] Some of the terms used in the present invention are defined below, and other undefined terms have meanings known to those skilled in the art.

[0075] C 1-3 Alkyl refers to a straight chain or branched chain saturated aliphatic hydrocarbon group having 1 to 3 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, propyl, isopropyl.

[0076] C 1-3 Alkoxy refers to -O-alkyl, wherein the alkyl contains 1 to 3 carbon atoms and is linear, branched or cyclic. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy or cyclopropoxy.

[0077] 5-8 membered heterocycloalkyl refers to a saturated monocyclic, fused, spirocyclic or polycyclic structure having 5 to 8 ring atoms. Examples of such groups include, but are not limited to, piperazine, methylpiperazine, ethylpiperazine, isopropylpiperazine, piperidine, morpholine, and thiomorpholine.

[0078] "Optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes occasions where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with halogen" means that halogen may but need not be present, and the description includes situations where alkyl is substituted with halogen and situations where alkyl is not substituted with halogen.

[0079] The compounds of the present invention may contain one or more chiral centers, which exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof (such as racemic mixtures) are within the scope of the present invention.

[0080] The compounds described in the present invention include their geometric isomers. For example, if the compounds described in the present invention contain double bonds or fused rings, these compounds may exist as geometric isomers, and their cis-forms, trans-forms, and mixtures of cis-trans are all included in the scope of the present invention.

[0081] The compounds described in the present invention include their tautomers. Tautomers refer to structural isomers of different energies that interconvert via a low energy barrier, such as keto-enol and imine-enamine tautomerization.

[0082] Various hydrates and solvates of the compounds or salts thereof described in the present invention and polymorphisms thereof are also included in the scope of the present invention.

[0083] Prodrugs of the compounds described in the present invention are also included in the scope of the present invention. Certain derivatives of the compounds described in the present invention have weak pharmacological activity or no pharmacological activity, but when these derivatives are administered into or onto the body, they can be converted into pharmacologically active compounds described in the present invention by means such as hydrolysis and cleavage, and these derivatives are called "prodrugs". Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association).

[0084] The compounds of the present invention include pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts refer to salts that are pharmaceutically acceptable and have the pharmacological activity required by the parent compound. Berge et al. describe pharmaceutically acceptable salts in detail in J.Pharma.Sci., 1977, 66, 1-19, which is incorporated herein by reference. The compounds of the present invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and react with some inorganic or organic bases, or inorganic and organic acids to form pharmaceutically acceptable salts accordingly. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromides, hydroiodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0085] When the compounds of the present invention are used as drugs, they are usually administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions of the compounds of the present invention and pharmaceutically acceptable carriers, diluents or excipients are also included in the scope of the present invention. The carriers, adjuvants, and excipients used herein include any and all solvents, diluents or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. suitable for the desired specific dosage form. In Remington: The Science and Practice of Pharmacy, 21 st Various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference.

[0086] The composition according to the invention can be administered by any route suitable for the condition to be treated. In particular, it can be administered parenterally, for example in the form of an injectable solution or suspension; enterally, for example orally, for example in the form of tablets or capsules; topically, for example in the form of a lotion, gel, ointment or cream or in the form of a nasal or suppository. Topical application is, for example, application to the skin. Another form of topical administration is administration to the eye.

[0087] The pharmaceutical composition can be administered in solid, semisolid, liquid or gaseous form, or can be in a dried powder, such as a lyophilized form. The pharmaceutical composition can be packaged in a form that is convenient for delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatin, paper, tablets, suppositories, pellets, pills, lozenges and pastilles. The type of packaging will generally depend on the route of administration. Implantable sustained-release formulations are also contemplated, as well as transdermal formulations.

[0088] Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffers, as well as other nontoxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate. Colorants, release agents, coating agents, sweeteners, flavoring and fragrance agents, preservatives and antioxidants may also be present in the composition according to the judgment of the formulator.

[0089] The compounds of the present invention can be used alone or in combination with other therapeutic agents for treating diseases or conditions (e.g., cancer) described in the present invention. In certain embodiments, the compounds of the present invention are combined in a pharmaceutical combination preparation with a second compound having anti-hyperproliferative properties or for treating hyperproliferative diseases (e.g., cancer), or combined in a dosing regimen as a combined therapy. The second compound of the pharmaceutical combination preparation or the quantitative dosing regimen preferably has an activity complementary to the compounds of the present invention so that they do not adversely affect each other. Such compounds are appropriately present in the combination in an amount effective for the planned purpose. In one embodiment, the compounds of the present invention are combined with other anti-tumor drugs.The anti-tumor drugs include: alkylating agents, including but not limited to cyclophosphamide, nitrogen mustard, melphalan, leuprorelin, and carmustine; metal platinums, including but not limited to carboplatin, cisplatin, and oxaliplatin; topoisomerase inhibitors, including but not limited to topotec, camptothecin, topotecan, and irinotecan; antibiotics, including but not limited to anisocycline, actinomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and plicamycin; anti-microtubule or anti-mitotic agents, including but not limited to paclitaxel, vinorelbine, docetaxel, and doxorubicin; antimetabolites, including but not limited to fluorouracil, methotrexate, cytarabine, and mecaptopurine. , thioguanine, and gemcitabine; antibodies, including but not limited to Herceptin and bevacizumab; hormones, including but not limited to letrazole, vorazole, tamoxifen, toremifene, fulvestrant, flutamide, nilutamide, triptorelin; kinase inhibitors, EGFR kinase inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib; VEGFR inhibitors, including but not limited to sorafenib, regorafenib, enib), sunitinib, cabozantinib, pazopanib, vandetanib, axitinib; ALK inhibitors, including but not limited to crizotinib, ceritinib, alectinib; Bcr-Abl inhibitors, including but not limited to imatinib, ponatinib, nilotinib, dasatinib; BTK inhibitors agents, including but not limited to ibrutinib; B-RAF inhibitors, including but not limited to vemurafenib; cyclin-dependent kinase CDK4 / 6 inhibitors, palbociclib; mTOR inhibitors, including but not limited to rapamycin and everolimus; deacetylase inhibitors, including but not limited to vorinostat; PD1 / PDL1 antibodies, Keytruda (Pembrolizumab) and Opdivo (Nivolumab).

[0090] The fourth aspect of the technical solution of the present invention provides the use of the compound described in the first aspect, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition described in the third aspect in the preparation of a drug for preventing and / or treating PI3K-mediated diseases, wherein the PI3K-mediated diseases include cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic dysfunction, endocrine dysfunction or neurological diseases.

[0091] Beneficial technical effects:

[0092] The compounds of the present invention have significant inhibitory activity against PI3Kα kinase and human HGC-27 gastric cancer cells, especially Examples 4, 6-10, 13, 14, 21-26, 29-33 have nanomolar IC values ​​against PI3Kα kinase. 50 value. DETAILED DESCRIPTION

[0093] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention, but the protection scope of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0094] In the following examples, unless otherwise noted by structural formula or chemical name, molecules with a single chiral center exist as racemic mixtures. Unless otherwise noted by structural formula or chemical name, those molecules with two or more chiral centers exist as racemic mixtures of diastereomers. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0095] Preparation method

[0096] The preparation methods of the compounds of the present invention, their stereoisomers, geometric isomers, and tautomers can be synthesized according to the synthesis schemes herein and / or techniques well known in the art. For example, the compounds provided by the present invention can be prepared according to the following general synthesis methods.

[0097] In a general synthetic method, the compound represented by formula (I), its stereoisomers, geometric isomers, and tautomers are prepared according to method-1.

[0098] Synthesis method-1

[0099]

[0100] Specifically, in method-1, the methylquinazoline compounds of the present invention can be prepared by 5 steps of reaction. For example, compound A (2-amino-5-bromoacetophenone) and diboronic acid pinacol ester are subjected to Miyaura reaction to prepare compound B; compound B and substituted pyridine are subjected to Suzuki reaction to obtain compound C; compound C is brominated with NBS to obtain compound D; compound D is reacted with ammonium formate / formamide to prepare compound E; compound E aryl borate is coupled to prepare the compound described in formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts. In the second general synthesis method, the compound shown in formula (I) is prepared according to method-2.

[0101] Synthesis Method-2

[0102]

[0103] Specifically, in method-2, the methylquinazoline compound of the present invention can be prepared by a two-step reaction. For example, compound E is used as a starting material, and compound F is obtained by SUZUKI reaction coupling; compound F is subjected to a condensation reaction or a reaction with an acyl chloride to prepare a compound described in formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0104] In the third general synthetic method, the compound represented by formula (I) was prepared according to Method-3.

[0105] Synthesis method-3

[0106]

[0107] Specifically, in method-3, the methylquinazoline compounds of the present invention can be prepared by 4 steps. Compound G is used as a starting material, and a substitution reaction is performed with tert-butyl bromoacetate to prepare compound H; compound H and compound E are subjected to a SUZUKI reaction to prepare compound J; compound J is hydrolyzed to prepare compound K; compound J is subjected to a condensation reaction to prepare the compound described in formula (I), its stereostructure, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0108] In the fourth general synthetic method, the compound represented by formula (I) is prepared according to method-4.

[0109] Synthesis Method-4

[0110]

[0111] Specifically, in method-4, the methylquinazoline compound of the present invention can be prepared by a three-step reaction. Compound L is used as a starting material, and compound E is subjected to a SUZUKI reaction to prepare compound M; compound M is hydrolyzed to prepare compound N; and compound N is subjected to a condensation reaction to prepare the compound described in formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0112] In the fifth general synthetic method, the compound represented by formula (I), its stereoisomers, geometric isomers, and tautomers are prepared according to method-5.

[0113] Synthesis Method-5

[0114]

[0115] Specifically, in method-5, the methylquinazoline compound of the present invention can be prepared by a two-step reaction. Compound G is used as a starting material to prepare compound O by a substitution reaction; compound O and compound E are subjected to a SUZUKI reaction to prepare the compound of formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0116] The compounds described herein can be synthesized according to one or more synthesis schemes and / or techniques well known in the art. It will be appreciated by those skilled in the art that the synthesis methods of certain embodiments described in detail in the present invention can be easily adapted to synthesize other embodiments. In some embodiments, the compounds described herein can be prepared by an appropriate combination of synthesis methods well known in the art. Many starting materials and other reagents can be purchased from commercial suppliers, such as Alfa Aesar (China) Chemical Co., Ltd., or easily prepared using synthesis methods commonly used in the art.

[0117] 1 H NMR spectra were recorded on an instrument operating at 400 MHz or 500 MHz. H NMR spectra were obtained as solutions (reported in ppm) using CDCl 3 (7.26ppm) or DMSO-d 6 (2.50 ppm) or internal tetramethylsilane (0.00 ppm) as reference standard. When reporting peak multiplicities, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are given in Hertz (Hz).

[0118] If desired, (R)- and (S)-isomers of the non-limiting exemplary compounds, if present, can be resolved by methods known to those skilled in the art, such as by forming diastereomeric salts or complexes, which can be separated by, for example, crystallization; by forming diastereomeric derivatives, which can be separated by, for example, crystallization or chromatography; by selectively reacting one enantiomer with an enantiomer-specific reagent, followed by separation of the modified and unmodified enantiomers; or by chromatographic separation in a chiral environment, such as a chiral chromatographic column. Alternatively, a specific enantiomer can be prepared by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[0119] In the following preparation methods and examples, "Me" refers to methyl, "Et" refers to ethyl, "PE" refers to petroleum ether, "EtOAc" refers to ethyl acetate, "MeOH" refers to methanol, and "DMSO-d 6 ” refers to deuterated dimethyl sulfoxide, “DCM” refers to dichloromethane, “PTLC” refers to preparative thin layer chromatography, “KSCN” refers to potassium thiocyanate, “PdCl 2 "(dppf)" refers to (1,1′-bis(diphenylphosphino)ferrocenepalladium chloride), "mL" refers to milliliter, "mmol" refers to millimolar, "μM" refers to micromolar, "nM" refers to nanomolar, and "°C" refers to degrees Celsius.

[0120] Example 1: 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl)-N,N-dimethylbenzamide

[0121]

[0122] Step 1: Synthesis of 1-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one

[0123]

[0124] A mixture of 2-amino-5-bromoacetophenone (4.28 g, 20 mmol), bis(pinacol) borate (6.1 g, 24 mmol) and KOAc (3.9 g, 40 mmol) in dioxane (50 mL) was degassed, and then [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (1.46 g, 2 mmol) was added. The resulting reaction mixture was degassed and backfilled with argon (three cycles), and then stirred at 100°C in an argon atmosphere for 5 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) and water (50 mL). The two phases were separated, and the aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1, v / v) to give the product as a solid (4.28 g, yield 82%).

[0125] 1 H NMR (400 MHz, DMSO-d 6 )δ8.01(d,J=1.5Hz,1H),7.54(br s,2H),7.48(dd,J=8.3,1.5Hz,1H),6.73(d,J=8.5Hz,1H),2.52(s,3H),1.27(s,12H).

[0126] Step 2: Synthesis of 1-(2-amino-5-(5,6-dimethoxypyridin-3-yl)phenyl)ethan-1-one

[0127]

[0128] A mixture of 5-bromo-2,3-dimethoxypyridine (4.167 g, 19 mmol), 1-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one (5.96 g, 22.8 mmol) and 2N aqueous potassium carbonate solution (29 mL, 57 mmol) in dioxane (100 mL) was degassed, and then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (1.39 g, 1.9 mmol) was added. The resulting reaction mixture was degassed and backfilled with argon (three cycles), and then stirred at 100° C. in an argon atmosphere for 5 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (80 mL) and water (80 mL). The two phases were separated and the aqueous layer was extracted with ethyl acetate (80 mL×2). The combined organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane / ethyl acetate = 100 / 1, v / v) to give the product as a solid (3.688 g, yield 71%).

[0129] 1 H NMR (400 MHz, DMSO-d 6 )δ7.96(d,J=2.1Hz,1H),7.60(dd,J=8.7,2.2Hz,1H),7.49(d,J=2.1Hz,1H) ,7.29(s,2H),6.86(d,J=8.7Hz,1H),3.88(s,3H),3.88(s,3H),2.62(s,3H).

[0130] Step 3: Synthesis of 1-(2-amino-3-bromo-5-(5,6-dimethoxypyridin-3-ylphenyl)ethan-1-one

[0131]

[0132] 1-(2-amino-5-(5,6-dimethoxypyridin-3-yl)phenyl)ethane-1-one (4.65g, 17mol) and N-bromosuccinimide (3.13g, 17.6mol) were added to DCM, and the resulting reaction mixture was stirred at room temperature for 1h. After the reaction was completed, water (100ml) was added to dilute, the two phases were separated, and the aqueous layer was extracted with dichloromethane (30mL×2). The combined organic layer was washed with water (50mL) and brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane / ethyl acetate=100 / 1, v / v) to obtain the product as a solid (2.72g, yield 62.3%).

[0133] 1H NMR (400 MHz, DMSO-d 6 )δ8.07(d,J=2.1Hz,1H),8.05(d,J=2.1Hz,1H),8.01(d,J=2.1Hz,1H),7.54(d,J=2.1Hz,1H),7.30(s,2H),3.89(s,3H),3.89(s,3H),2.69(s,3H).

[0134] Step 4: Synthesis of 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline

[0135]

[0136] 1-(2-Amino-3-bromo-5-(5,6-dimethoxypyridin-3-ylphenyl)ethane-1-one (1.08 g, 3 mol) and ammonium formate (378 mg, 6 mol) were dissolved in formamide solution at room temperature and transferred to 150°C for reaction for 6 h. After the reaction, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 mL) and water (30 mL). The two phases were separated and the aqueous layer was extracted with ethyl acetate (30 mL×2). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane / ethyl acetate = 1 / 3, v / v) to give the product as a solid (812 mg, yield 73%).

[0137] 1 H NMR (400 MHz, DMSO-d 6 )δ9.20(s,1H),8.74(d,J=1.9Hz,1H),8.50(d,J=1.9Hz,1H),8.27(d,J=2 .1Hz,1H),,7.78(d,J=2.1Hz,1H),3.95(s,3H),3.94(s,3H),3.04(s,3H).

[0138] Step 5: Synthesis of 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)-N,N-dimethylbenzamide

[0139]

[0140] A mixture of 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline (180 mg, 0.5 mmol), (4-(dimethylcarbamoyl)phenyl)boronic acid (116 mg, 0.6 mmol) and 2N aqueous potassium carbonate solution (0.585 mL, 1.17 mmol) in dioxane (10 mL) was degassed, and then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (36 mg, 0.05 mmol) was added. The resulting reaction mixture was degassed and backfilled with argon (three cycles), and then stirred at 100° C. in an argon atmosphere for 5 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 mL) and water (30 mL). The two phases were separated, and the aqueous layer was extracted with ethyl acetate (30 mL×2). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane / methanol=20 / 1, v / v) to give the product as a solid (113 mg, yield 53%).

[0141] 1 H NMR (500 MHz, DMSO-d 6 )δ9.11(s,1H),8.50(d,J=2.0Hz,1H),8.35(d,J=2.0Hz,1H),8.30(d,J=2.0Hz,1H),7.84 –7.80(m,3H),7.54(d,J=8.3Hz,2H),3.94(s,3H),3.93(s,3H),3.05(s,3H),3.02(s,6H).

[0142] Example 2: 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)benzamide

[0143]

[0144] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.

[0145] 1 H NMR (500 MHz, DMSO-d 6)δ9.10(s,1H),8.50(d,J=2.0Hz,1H),8.35(d,J=2.0Hz,1H),8.30(d,J=2.0Hz,1H),8.07(br s,1H),8.00(d,J=8.3Hz,2H),7.87–7.79(m,3H),7.43(br s,1H),3.94(s,3H),3.93(s,3H),3.05(s,3H).

[0146] Example 3: 6-(5,6-dimethoxypyridin-3-yl)-8-(4-(2-methoxyethoxy)phenyl)-4-methylquinazoline

[0147]

[0148] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and (4-(2-methoxyethoxy)phenyl)boronic acid.

[0149] 1 H NMR (500 MHz, DMSO-d 6 )δ9.09(s,1H),8.41(d,J=2.1Hz,1H),8.27(d,J=2.1Hz,1H),8.25(d,J=2.1Hz,1H),7.79(d,J=2.1Hz,1H),7.72(d,J=8.7H z,2H),7.08(d,J=8.8Hz,2H),4.21–4.16(m,2H),3.944(s,3H),3.937(s,3H),3.74–3.69(m,2H),3.35(s,3H),3.03(s,3H).

[0150] Example 4: 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenol

[0151]

[0152] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol.

[0153] 1 H NMR (400 MHz, DMSO-d 6)δ9.59(s,1H),9.09(s,1H),8.41(d,J=2.0Hz,1H),8.27(d,J=2.0Hz,1H),8.23(d,J=2.0Hz,1H),7.80 (d,J=2.1Hz,1H),7.62(d,J=8.6Hz,2H),6.90(d,J=8.4Hz,2H),3.94(s,3H),3.94(s,3H),3.04(s,3H).

[0154] Example 5: 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl)-N,N-dimethylaniline

[0155]

[0156] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

[0157] 1 H NMR (500 MHz, DMSO-d 6 )δ9.08(s,1H),8.35(d,J=1.7Hz,1H),8.26(d,J=1.8Hz,1H),8.21(d,J=1.8Hz,1H),7.79(d,J=1.7Hz,1 H),7.66(d,J=8.7Hz,2H),6.85(d,J=8.8Hz,2H),3.943(s,3H),3.938(s,3H),3.02(s,3H),2.98(s,6H).

[0158] Example 6: 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)-N-methylbenzamide

[0159]

[0160] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.

[0161] 1 H NMR (400 MHz, DMSO-d 6)δ9.11(s,1H),8.56–8.49(m,2H),8.36(d,J=2.0Hz,1H),8.31(d,J=2.0Hz,1H),7.96(d,J=8.3Hz,2H),7.88 -7.82(m,3H),3.95(s,3H),3.94(s,3H),3.06(s,3H),2.84(d,J=4.5Hz,3H).

[0162] Example 7: 6-(5,6-dimethoxypyridin-3-yl)-4-methyl-8-(4-(piperidin-1-yl)phenyl)quinazoline

[0163]

[0164] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and N 4-(piperidin-1-yl)phenylboronic acid.

[0165] 1 H NMR (500MHz, DMSO-d6) δ9.07(s,1H),8.36(d,J=2.1Hz,1H),8.25(d,J=2.1Hz,1H),8.22(d,J=2.0Hz,1H),7.78(d,J=2.0Hz,1H),7.65(d ,J=8.8Hz,2H),7.03(d,J=8.8Hz,2H),3.94(s,3H),3.93(s,3H),3.29–3.19(m,4H),3.02(s,3H),1.70–1.61(m,4H),1.60-1.52(m,2H).

[0166] Example 8: 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)aniline

[0167]

[0168] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

[0169] 1 H NMR (400 MHz, DMSO-d 6)δ9.08(s,1H),8.34(d,J=2.1Hz,1H), 8.26(d,J=2.1Hz,1H), 8.18(d,J=2.1Hz,1H), 7.79(d,J=2.1Hz,1 H), 7.51 (d, J = 8.6Hz, 2H), 6.69 (d, J = 8.5Hz, 2H), 5.28 (s, 2H), 3.943 (s, 3H), 3.939 (s, 3H), 3.02 (s, 3H).

[0170] Example 9: 6-(5,6-dimethoxypyridin-3-yl)-8-(4-methoxyphenyl)-4-methylquinazoline

[0171]

[0172] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0173] 1 H NMR (500 MHz, DMSO-d 6 )δ9.09(s,1H),8.42(d,J=2.1Hz,1H),8.27(d,J=2.0Hz,1H),8.26(d,J=2.1Hz,1H),7.80(d,J=2.1Hz,1 H),7.72(d,J=8.7Hz,2H),7.07(d,J=8.9Hz,2H),3.943(s,3H),3.937(s,3H),3.84(s,3H),3.04(s,3H).

[0174] Example 10: 6-(5,6-dimethoxypyridin-3-yl)-4-methyl-8-(4-methylpiperazin-1-yl)phenyl)quinazoline

[0175]

[0176] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine.

[0177] 1 H NMR (500 MHz, DMSO-d 6)δ9.08(s,1H),8.37(d,J=1.9Hz,1H),8.26(d,J=2.0Hz,1H),8.22(d,J=1.9Hz,1H),7.78(d,J=1.9Hz,1H),7.66(d,J=8.7 Hz,2H),7.05(d,J=8.8Hz,2H),3.94(s,3H),3.93(s,3H),3.25–3.20(m,4H),3.02(s,3H),2.50–2.47(m,4H),2.25(s,3H).

[0178] Example 11: 4-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenylmorpholine

[0179]

[0180] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)4-methylquinazoline and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylmorpholine.

[0181] 1 H NMR (400 MHz, DMSO-d 6 )δ9.09(s,1H),8.40(d,J=2.1Hz,1H),8.28(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),7.81(d,J=2.1Hz,1H),7.70(d, J=8.8Hz,2H),7.08(d,J=8.9Hz,2H),3.94(s,3H),3.94(s,3H),3.81–3.76(m,4H),3.23–3.18(m,4H),3.04(s,3H).

[0182] Example 12: 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)-N-methylaniline

[0183]

[0184] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

[0185] 1 H NMR (500 MHz, DMSO-d 6)δ9.07(s,1H),8.33(d,J=2.0Hz,1H),8.25(d,J=2.1Hz,1H),8.18(d,J=2.1Hz,1H),7.78(d,J=2.1Hz,1H),7.58(d,J=8 .6Hz,2H),6.66(d,J=8.6Hz,2H),5.84(q,J=5.0Hz,1H),3.94(s,3H),3.93(s,3H),3.01(s,3H),2.75(d,J=5.0Hz,3H).

[0186] Example 13: N-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)-2-methoxyacetamide

[0187]

[0188] DIPEA (53 mg) and DMAP (5 mg, 0.04 mmol) were added to a DCM solution of 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)aniline (74 mg, 0.2 mmol) and 2-methoxyacetyl chloride (33 mg, 0.2 mmol), and stirred overnight at room temperature. The aqueous layer was extracted with dichloromethane (10 mL × 2). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane / methanol = 15 / 1, v / v) to give the product as a solid (36 mg, 42% yield).

[0189] 1 H NMR (500 MHz, DMSO-d 6 )δ9.92(s,1H),9.10(s,1H),8.45(d,J=2.0Hz,1H),8.29(d,J=2.0Hz 1H),8.28(d,J=2.0Hz,1H),7.83-7.78(m,3H),7.73(d,J=8.7Hz,2H),4.06(s,2H),3.94(s,3H),3.94(s,3H),3.42(s,3H),3.04(s,3H).

[0190] Example 14: N-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)-2-dimethylaminoacetamide

[0191]

[0192] Triethylamine (0.105 ml, 0.75 mmol) and HATU (144 mg, 0.38 mmol) were added to a DCM solution of 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)aniline (93 mg, 0.25 mmol) and dimethylglycine (39 mg, 0.38 mmol), and stirred at room temperature overnight. The aqueous layer was extracted with dichloromethane (10 mL × 2). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane / methanol = 15 / 1, v / v) to give the product as a solid (55 mg, 49% yield).

[0193] 1 H NMR (400 MHz, DMSO-d 6 )δ9.86(s,1H),9.10(s,1H),8.46(d,J=2.1Hz,1H),8.31-8.27(m,2H),7.84–7.76(m,3H) ,7.73(d,J=8.7Hz,2H),3.95(s,3H),3.94(s,3H),3.13(s,2H),3.05(s,3H),2.32(s,6H).

[0194] Example 15: N-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)-2-hydroxyacetamide

[0195]

[0196] Step 1: Synthesis of 1-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)amino)-2-methyl-1-oxopropan-2-yl acetate

[0197]

[0198] The title compound was prepared according to the method of Example 14 from 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)aniline and 1-chloro-2-methyl-1-oxo-2-propyl acetate.

[0199] 1 H NMR (400 MHz, DMSO-d 6)δ10.23(s,1H),9.10(s,1H),8.46(d,J=2.1Hz,1H),8.30(d,J=1.9Hz,1H),8.29(d,J=1.9Hz,1H),7.81(d,J=2.1Hz, 1H),7.76(d,J=8.7Hz,2H),7.71(d,J=8.8Hz,2H),4.70(s,2H),3.95(s,3H),3.94(s,3H),3.05(s,3H),2.15(s,3H).

[0200] Step 2: Synthesis of N-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)-2-hydroxyacetamide

[0201]

[0202] The reaction mixture of 1-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)amino)-2-methyl-1-oxopropane-2-yl acetate (50 mg, 0.11 mmol), LiOH·H2O (44 mg, 1.1 mmol), THF (3 ml), MeOH (3 ml) and H2O (1 ml) was stirred at room temperature for 2 h. After the reaction was completed, citric acid was added to adjust the pH to acidic, and the solid produced was collected by filtration and dried in vacuo to obtain the product as a light yellow solid (15 mg, yield 33%).

[0203] 1 H NMR (400 MHz, DMSO-d 6 )δ9.81(s,1H),9.10(s,1H),8.46(d,J=2.0Hz,1H),8.30(d,J=1.8Hz,1H),8.29(d,J=1.8Hz,1H),7.87–7.79(m, 3H),7.73(d,J=8.7Hz,2H),5.75(t,J=6.0Hz,1H),4.04(d,J=6.0Hz,2H),3.95(s,3H),3.94(s,3H),3.05(s,3H).

[0204] Example 16: N-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)-1-hydroxycyclopropane-1-carboxamide

[0205]

[0206] According to the synthesis method of Example 14, the title compound was prepared from 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)aniline and 1-hydroxycyclopropane-1-carboxylic acid.

[0207] 1 H NMR (500 MHz, DMSO-d 6 )δ9.95(s,1H),9.10(s,1H),8.44(d,J=2.0Hz,1H),8.29(d,J=2.4Hz,1H),8.28(d,J=2.4Hz,1H),7.89(d,J=8.3Hz,2H),7.81(d ,J=2.1Hz,1H),7.73(d,J=8.3Hz,2H),6.63(s,1H),3.95(s,3H),3.94(s,3H),3.04(s,3H),1.21–1.19(m2H),1.04–0.97(m,2H).

[0208] Example 17: (R)-N-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)-2-hydroxypropanamide

[0209]

[0210] The title compound was prepared according to the method of Example 14 from 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)aniline and (R)-2-hydroxypropionic acid.

[0211] 1 H NMR (400 MHz, DMSO-d 6 )δ9.78(s,1H),9.10(s,1H),8.46(d,J=2.1Hz,1H),8.33–8.26(m,2H),7.85(d,J=8.5Hz,2H),7.82(d,J=2.1Hz,1H),7.73 (d,J=8.7Hz,2H),5.79(d,J=5.2Hz,1H),4.26-4.10(m,1H),3.95(s,3H),3.94(s,3H),3.05(s,3H),1.35(d,J=6.7Hz,3H).

[0212] Example 18: (S)-N-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)-2-hydroxypropanamide

[0213]

[0214] The title compound was prepared according to the method of Example 14 from 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)aniline and (S)-2-hydroxypropionic acid.

[0215] 1 H NMR (400 MHz, DMSO-d 6 )δ9.78(s,1H),9.10(s,1H),8.46(d,J=2.1Hz,1H),8.33–8.26(m,2H),7.85(d,J=8.6Hz,2H),7.82(d,J=2.1Hz,1H),7.73(d,J=8.7Hz,2H),5.79(br s,1H),4.25-4.15(m,1H),3.946(s,3H),3.943(s,3H),3.05(s,3H),1.35(d,J=6.7Hz,3H).

[0216] Example 19: N-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

[0217]

[0218] The title compound was prepared according to the method of Example 14 from 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)aniline and 2-(pyrrolidin-1-yl)acetic acid.

[0219] 1 H NMR (400 MHz, DMSO-d 6 )δ9.85(s,1H),9.10(s,1H),8.45(d,J=2.0Hz,1H),8.29(d,J=1.6Hz,1H),8.28(d,J=1.6Hz,1H),7.83–7.76(m,3H) ,7.73(d,J=8.7Hz,2H),3.95(s,3H),3.94(s,3H),3.31(s,2H),3.05(s,3H),2.68–2.59(m,4H),1.82–1.73(m,4H).

[0220] Example 20: N-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)methanesulfonamide

[0221]

[0222] Triethylamine (0.085 ml, 0.6 mmol) was added to a dichloromethane solution of 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)aniline (74 mg, 0.2 mmol) and methanesulfonic anhydride (70 mg, 0.4 mmol) and reacted overnight at room temperature. The aqueous layer was extracted with dichloromethane (10 mL × 2). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane / methanol = 15 / 1, v / v) to give the product as a solid (47 mg, yield 53%).

[0223] 1 H NMR (400 MHz, DMSO-d 6 )δ9.90(s,1H),9.10(s,1H),8.46(d,J=2.1Hz,1H),8.30(d,J=2.0Hz,1H),8.29(d,J=2.0Hz,1H),7.81(d,J=2. 1Hz,1H),7.76(d,J=8.7Hz,2H),7.35(d,J=8.7Hz,2H),3.945(s,3H),3.940(s,3H),3.08(s,3H),3.05(s,3H).

[0224] Example 21: N-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)-2-hydroxy-2-methylpropanamide

[0225]

[0226] DMAP (6 mg, 0.05 mol) was added to a solution of 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)aniline (93 mg, 0.25 mmol), 2-acetoxyisobutyryl chloride (0.053 ml, 0.375 mmol), and DIPEA (0.087 ml, 0.5 mmol) in dichloromethane (5 ml), and stirred overnight at room temperature. The reaction solution was spin dried, and then LiOH·H 2 O (42 mg, 1 mmol), THF (3 mL), MeOH (3 mL), H 2 O (1 mL) and stirred at room temperature for 2 h. After the reaction was completed, it was diluted with ethyl acetate (5 mL) and water (5 mL). The two phases were separated and the aqueous layer was extracted with ethyl acetate (10 ml × 2). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by p-HPLC to obtain the product as a solid (70 mg, yield 56%).

[0227] 1 H NMR (400 MHz, DMSO-d 6 )δ9.69(s,1H),9.10(s,1H),8.45(d,J=2.1Hz,1H),8.29(d,J=1.9Hz,1H), 8.28(d,J=1.9Hz,1H),7.87(d,J=8.7Hz, 2H),7.81(d,J=2.1Hz,1H),7.73(d,J=8.6Hz,2H),5.79(s,1H),3.95(s,3H),3.94(s,3H),3.05(s,3H),1.39(s,6H).

[0228] Example 22: 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)acetic acid

[0229]

[0230] Step 1: tert-Butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate

[0231]

[0232] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.3 g, 15 mmol) and tert-butyl bromoacetate (2.9 ml, 18 mmol) in acetonitrile (50 ml) was added K 2 CO 3 (4.15 g, 30 mmol), added to 70 ° C for 6 h, after the reaction, silica gel (7 g) was added, and the resulting mixture was evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, petroleum ether / dichloromethane = 1:1, v / v) to obtain the product as a solid (4.63 g, yield 92%).

[0233] 1 H NMR (400 MHz, CHLOROFORM-d 6 )δ7.75(d,J=8.7Hz,2H),6.88(d,J=8.8Hz,2H),4.53(s,2H),1.47(s,9H),1.32(s,12H).

[0234] Step 2: tert-Butyl 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)acetate

[0235]

[0236] A mixture of 6-bromo-4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline (720 mg, 2.5 mmol), tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate (1.0 g, 3.0 mmol) and 2N aqueous potassium carbonate solution (0.38 mL, 7.5 mmol) in dioxane (20 mL) was degassed, and then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (190 mg, 0.25 mmol) was added. The resulting reaction mixture was degassed and backfilled with argon (three cycles), and then stirred at 100° C. in an argon atmosphere for 5 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 mL) and water (30 mL). The two phases were separated and the aqueous layer was extracted with ethyl acetate (30 mL×2). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane / ethyl acetate=1 / 1, v / v) to give the product as a solid (500 mg, 41% yield).

[0237] 1 H NMR (400 MHz, DMSO-d 6 )δ9.09(s,1H),8.44(d,J=2.0Hz,1H),8.28(d,J=2.0Hz,1H),8.27(d,J=2.0Hz,1H),7.81(d,J=2.1Hz,1H),7. 72(d,J=8.9Hz,2H),7.04(d,J=8.8Hz,2H),4.74(s,2H),3.94(s,3H),3.94(s,3H),3.04(s,3H),1.47(s,9H).

[0238] Step 3: 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)acetic acid

[0239]

[0240] To a solution of tert-butyl 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)acetate (540 mg, 1.1 mmol) in DCM (4 ml) was added TFA (2 ml). After the reaction was completed, the mixture was dried under vacuum, diluted with DCM (5 ml) × 2, dried under vacuum, and ethyl acetate (3 ml) was added. 2 O (3 ml) to precipitate a solid, which was filtered and dried to obtain a solid (260 mg, yield 54.8%).

[0241] 1 H NMR (400 MHz, DMSO-d 6 )δ9.10(s,1H),8.45(d,J=2.0Hz,1H),8.29(d,J=2.0Hz,1H),8.28(d,J=2.0Hz,1H),7.81(d,J=2.0Hz, 1H),7.72(d,J=8.8Hz,2H),7.05(d,J=8.9Hz,2H),4.77(s,2H),3.94(s,3H),3.94(s,3H),3.05(s,3H).

[0242] Example 23: 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)-N-(2-(dimethylamino)ethyl)-N-methylacetamide

[0243]

[0244] To a solution of 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)acetic acid (86 mg, 0.2 mmol) and N1,N1,N2-trimethylethane-1,2-diamine (0.039 ml, 0.3 mmol) in DCM (7 ml) was added TEA (0.084 ml, 0.6 mmol) and HATU (114 mg, 0.3 mmol), and the mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was diluted with DCM (10 mL) and water (10 mL). The two phases were separated, and the aqueous layer was extracted with DCM (10 mL×2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, DCM / MeOH=10 / 1, v / v) to give the product as a solid (43 mg, 42% yield).

[0245] 1 H NMR (400 MHz, CHLOROFORM-d 6)δ9.19(s,1H),8.16(d,J=2.0Hz,1H),8.10(d,J=2.0Hz,1H),8.05(d,J=2 .0Hz,1H),7.67(d,J=8.7Hz,2H),7.35(d,J=2.0Hz,1H),7.17–7.09(m,2H) ,4.85(s,1H),4.79(s,1H),4.10(s,3H),4.00(s,3H),3.60–3.45(m,2H)3 .14(s,2H),3.05(s,3H),3.01(s,1H),2.54(t,J=6.8Hz,2H),2.31(s,6H).

[0246] Example 24: 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)-N-(2-(dimethylamino)ethyl)acetamide

[0247]

[0248] According to the synthesis method of Example 23, the title compound was prepared from 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)acetic acid and N1,N1-dimethylethane-1,2-diamine.

[0249] 1 H NMR (400 MHz, DMSO-d 6 )δ9.09(s,1H),8.45(d,J=2.0Hz,1H),8.29(d,J=2.0Hz,1H),8.27(d,J=2.0Hz,1H),8.04(t,J=5.7Hz,1H),7.81(d,J=2.1Hz,1H),7.74(d,J=8. 8Hz,2H),7.10(d,J=8.9Hz,2H),4.57(s,2H),3.943(s,3H),3.938(s,3 H),3.29–3.22(m,2H),3.04(s,3H),2.36(t,J=6.7Hz,2H),2.18(s,6H).

[0250] Example 25: 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethan-1-one

[0251]

[0252] The title compound was prepared according to the method of step 3 in example 26 from 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)acetic acid and 1-methylpiperazine.

[0253] 1 H NMR (400 MHz, DMSO-d 6 )δ9.09(s,1H),8.44(d,J=2.0Hz,1H),8.29(d,J=2.1Hz,1H),8.27(d,J=2.0Hz,1H),7.81(d,J=2.1Hz,1H),7.71(d,J=8.8Hz,2H),7.05(d,J =8.8Hz,2H),4.91(s,2H),3.944(s,3H),3.938(s,3H),3.52–3.44(m,4H),3.04(s,3H),2.41–2.33(m,2H),2.32–2.25(m,2H),2.20(s,3H).

[0254] Example 26: 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)-N-(2-(dimethylamino)ethyl)benzamide

[0255]

[0256] Step 1: Methyl 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)benzoate

[0257]

[0258] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.

[0259] 1 H NMR (400 MHz, DMSO-d 6 )δ9.11(s,1H),8.54(d,J=2.1Hz,1H),8.38(d,J=2.0Hz,1H),8.31(d,J=2.0Hz,1H),8.09(d,J=8.4Hz, 2H),7.92(d,J=8.3Hz,2H),7.83(d,J=2.1Hz,1H),3.95(s,3H),3.94(s,3H),3.91(s,3H),3.06(s,3H).

[0260] Step 2: 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)benzoic acid

[0261]

[0262] Methyl 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)benzoate (104 mg, 0.25 mmol), LiOH·H 2 O (105 mg, 2.5 mmol), THF (3 ml), MeOH (3 ml) and H 2 The reaction mixture of 1 ml of 2-nitropropene was stirred at room temperature for 2 h. After the reaction was completed, citric acid was added to adjust the pH to acidic, and the generated solid was collected by filtration and dried in vacuo to obtain the product as a light yellow solid (70 mg, yield 70%).

[0263] 1 H NMR (400 MHz, DMSO-d 6 )δ9.11(s,1H),8.52(d,J=2.0Hz,1H),8.36(d,J=2.1Hz,1H),8.30(d,J=2.0Hz,1H),8.07(d,J=8 .4Hz,2H),7.87(d,J=8.3Hz,2H),7.83(d,J=2.1Hz,1H),3.95(s,3H),3.94(s,3H),3.06(s,3H).

[0264] Step 3: 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)-N-(2-(dimethylamino)ethyl)benzamide

[0265]

[0266] HATU (170 mg, 0.45 mmol) and triethylamine (0.13 ml, 0.9 mmol) were added to a solution of 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)benzoic acid (120 mg, 0.3 mmol) and N1,N1-dimethylethane-1,2-diamine (0.05 ml, 0.45 mmol) in DCM (6 mL). The mixture was reacted overnight at room temperature. After the reaction was completed, the mixture was diluted with DCM (10 mL) and water (10 mL). The two phases were separated and the aqueous layer was extracted with DCM (10 mL × 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, DCM / MeOH=10 / 1, v / v) to give the product as a solid (58 mg, yield 41%).

[0267] 1 H NMR (400 MHz, DMSO-d 6 )δ9.10(s,1H),8.78–8.70(m,1H),8.54(d,J=2.0Hz,1H),8.35(d,J=2.0Hz,1H),8.31(d,J=2.0Hz,1H),8.00(d,J=8.1Hz,2H),7.89 (d,J=8.1Hz,2H),7.83(d,J=2.0Hz,1H),3.95(s,3H),3.94(s,3H),3.68–3.58(m,2H),3.28–3.10(m,2H),3.07(s,3H),2.80(s,6H).

[0268] Example 27: 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide

[0269]

[0270] According to the method of step 3 in Example 26, the title compound was prepared from 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)benzoic acid and N1,N1,N2-trimethylethane-1,2-diamine.

[0271] 1 H NMR (400 MHz, DMSO-d 6 )δ9.11(s,1H),8.51(d,J=2.1Hz,1H),8.35(d,J=2.0Hz,1H),8.31(d,J=2.0Hz,1H),7.86–7.81(m,3H),7.52(d,J=8.2Hz,2H),3.95 (s,3H),3.94(s,3H),3.70–3.53(m,2H),3.06(s,3H),3.02(s,3H),2.66–2.54(m,1H),2.48–2.38(m,1H),2.30(s,3H),2.06(s,3H).

[0272] Example 28: 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)-N,N-dimethylacetamide

[0273]

[0274] Step 1: Preparation of N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetamide

[0275]

[0276] The title compound was synthesized according to the method of step 1 in Example 22 using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and 2-bromo-N,N-dimethylacetamide.

[0277] 1 H NMR (400 MHz, DMSO-d 6 )δ7.58(d,J=8.7Hz,2H),6.90(d,J=8.6Hz,2H),4.84(s,2H),2.99(s,3H),2.84(s,3H),1.27(s,12H).

[0278] Step 2: Preparation of 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)-N,N-dimethylacetamide

[0279]

[0280] The title compound was synthesized according to the method of Step 2 in Example 22 using 6-bromo-4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline and N,N-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetamide.

[0281] 1 H NMR (400 MHz, DMSO-d 6 )δ9.09(s,1H),8.44(d,J=2.0Hz,1H),8.29(d,J=2.0Hz,1H),8.27(d,J=2.0Hz,1H),7.81(d,J=2.1Hz,1H),7.7 0(d,J=8.7Hz,2H),7.05(d,J=8.8Hz,2H),4.89(s,2H),3.945(s,3H),3.939(s,3H),3.04(s,6H),2.87(s,3H).

[0282] Example 29: 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)-N-methylacetamide

[0283]

[0284] Step 1: N-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetamide

[0285]

[0286] The title compound was synthesized according to the method of Step 1 in Example 22 using 6-bromo-4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline and 2-bromo-N-methylacetamide.

[0287] 1 H NMR (500 MHz, DMSO-d 6 )δ7.61(d,J=8.5Hz,2H),6.95(d,J=8.6Hz,2H),4.48(s,2H),2.65(d,J=4.7Hz,4H),1.28(s,12H).

[0288] Step 2: 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)-N-methylacetamide

[0289]

[0290] The title compound was synthesized according to the method of Step 2 in Example 22 using 6-bromo-4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline and N-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetamide.

[0291] 1 H NMR (500 MHz, DMSO-d 6 )δ9.09(s,1H),8.43(d,J=1.7Hz,1H),8.28(d,J=1.8Hz,1H),8.27(d,J=1.8Hz,1H),8.11(q,J=4.9Hz,1H),7.80(d,J=1.7Hz,1 H),7.73(d,J=8.6Hz,2H),7.10(d,J=8.7Hz,2H),4.56(s,2H),3.943(s,3H),3.938(s,3H),3.04(s,3H),2.69(d,J=4.6Hz,3H).

[0292] Example 30: 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-dimethoxypyridin-8-yl)phenoxy)acetamide

[0293]

[0294] Step 1: Synthesis of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetamide

[0295]

[0296] The title compound was synthesized according to the method of Step 1 in Example 22 using 6-bromo-4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline and 2-bromo-N-methylacetamide.

[0297] 1 H NMR (400 MHz, CHLOROFORM-d 6 )δ7.78(d,J=8.0Hz,2H),6.92(d,J=8.0Hz,2H),6.53(s,1H),5.98(s,1H),4.52(s,2H),1.34(s,12H).

[0298] Step 2: Synthesis of 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-dimethoxypyridin-8-yl)phenoxy)acetamide

[0299]

[0300] The title compound was synthesized according to the method of Step 2 in Example 22 using 6-bromo-4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetamide.

[0301] 1 H NMR (500 MHz, DMSO-d 6 )δ9.10(s,1H),8.44(d,J=1.8Hz,1H),8.28(d,J=1.9Hz,1H),8.27(d,J=1.8Hz,1H),7.81(d,J=1.8Hz,1H),7.73(d,J =8.6Hz,2H),7.59(s,1H),7.44(s,1H),7.09(d,J=8.7Hz,2H),4.53(s,2H),3.944(s,3H),3.940(s,3H),3.04(s,3H).

[0302] Example 31: N-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)acetamide

[0303]

[0304] According to the synthesis method of Example 20, the title compound was synthesized using 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)aniline and acetic anhydride.

[0305] 1 H NMR (500 MHz, DMSO-d 6 )δ10.09(s,1H),9.10(s,1H),8.43(d,J=1.9Hz,1H),8.28(d,J=1.8Hz,1H),8.27(d,J=1.8Hz,1H) ,7.80(d,J=1.9Hz,1H),7.74–7.68(m,4H),3.944(s,3H),3.939(s,3H),3.04(s,3H),2.10(s,3H).

[0306] Example 32: 6-(5,6-dimethoxypyridin-3-yl)-4-methyl-8-(4-(pyrrolidin-1-yl)phenyl)quinazoline

[0307]

[0308] According to the method of step 5 in Example 1, the title compound was prepared from 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine.

[0309] 1 H NMR (500 MHz, DMSO-d 6 )δ9.08(s,1H),8.33(d,J=1.8Hz,1H),8.25(d,J=1.9Hz,1H),8.19(d,J=1.8Hz,1H),7.78(d,J=1.8Hz,1H),7.66(d,J=8. 6Hz, 2H), 6.65 (d, J = 8.7Hz, 2H), 3.942 (s, 3H), 3.937 (s, 3H), 3.30 (t, J = 6.4Hz, 4H), 3.02 (s, 3H), 1.99 (t, J = 6.4Hz, 4H).

[0310] Example 33: N-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenyl)cyclopropanesulfonamide

[0311]

[0312] The title compound was synthesized using the procedure of Example 20, 4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)aniline and cyclopropanesulfonyl chloride.

[0313] 1 H NMR (400 MHz, DMSO-d 6 )δ9.89(s,1H),9.10(s,1H),8.47(d,J=2.0Hz,1H),8.30(d,J=1.0Hz,1H),8.29(d,J=0.9Hz,1H),7.82(d,J=2.0Hz,1H),7 .75(d,J=8.6Hz,2H),7.37(d,J=8.5Hz,2H),3.95(s,3H),3.94(s,3H),3.05(s,3H),2.76–2.67(m,1H),1.07–0.96(m,4H).

[0314] Example 34: 8-(4-methoxyphenyl)-6-(6-methoxypyridin-3-yl)-4-methylquinazoline

[0315]

[0316] Step 1: Synthesis of 1-(2-amino-5-(6-methoxypyridin-3-yl)phenyl)ethan-1-one

[0317]

[0318] According to the method of step 2 in Example 1, 1-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one and (6-methoxypyridin-3-yl)boronic acid were used to synthesize the title compound.

[0319] 1 H NMR (400 MHz, DMSO-d 6 )δ8.45(dd,J=2.7,0.5Hz,1H),7.98(dd,J=8.6,2.7Hz,1H),7.95(d,J=2.2Hz,1H),7. 58(dd,J=8.7,2.2Hz,1H),7.30(s,2H),6.89–6.84(m,2H),3.88(s,3H),2.61(s,3H).

[0320] Step 2: Synthesis of 1-(2-amino-3-bromo-5-(6-methoxypyridin-3-yl)phenyl)ethan-1-one

[0321]

[0322] According to the method of step 3 in Example 1, 1-(2-amino-5-(6-methoxypyridin-3-yl)phenyl)ethan-1-one and NBS were used to synthesize the title compound.

[0323] 1 H NMR (400 MHz, DMSO-d 6 )δ8.50(d,J=2.1Hz,1H),8.07(d,J=2.1Hz,1H),8.04(dd,J=8.6,2.6Hz,1H),8.01(d,J=2.1Hz,1H),7.31(br s,2H),6.88(dd,J=8.6,0.5Hz,1H),3.89(s,3H),2.68(s,3H).

[0324] Step 3: Synthesis of 8-bromo-6-(6-methoxypyridin-3-yl)-4-methylquinazoline

[0325]

[0326] According to the method of step 4 in Example 1, the title compound was synthesized from 1-(2-amino-3-bromo-5-(6-methoxypyridin-3-yl)phenyl)ethan-1-one and ammonium formate.

[0327] 1 H NMR (400 MHz, DMSO-d 6 )δ9.20(s,1H),8.76(dd,J=2.7,0.6Hz,1H),8.69(d,J=1.9Hz,1H),8.50(d,J=1.9Hz,1 H), 8.31 (dd, J=8.7, 2.7Hz, 1H), 6.99 (dd, J=8.7, 0.6Hz, 1H), 3.94 (s, 3H), 3.03 (s, 3H).

[0328] Step 4: Synthesis of 8-(4-methoxyphenyl)-6-(6-methoxypyridin-3-yl)-4-methylquinazoline

[0329]

[0330] According to the method of step 5 in Example 1, 8-bromo-6-(6-methoxypyridin-3-yl)-4-methylquinazoline and 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were synthesized into the title compound.

[0331] 1 H NMR (500 MHz, DMSO-d 6)δ9.09 (s, 1H), 8.78 (d, J = 2.6Hz, 1H), 8.43 (d, J = 2.1Hz, 1H), 8.33 (dd, J = 8.6, 2.6Hz, 1H), 8.23 ​​(d, J = 2.0Hz, 1H) ),7.74(d,J=8.7Hz,2H),7.07(d,J=8.9Hz,2H),6.99(d,J=8.6Hz,1H),3.94(s,3H),3.84(s,3H),3.03(s,3H).

[0332] Example 35: 6-(5-Fluoro-6-methoxypyridin-3-yl)-8-(4-methoxyphenyl)-4-methylquinazoline

[0333]

[0334] Step 1: Synthesis of 1-(2-amino-5-(5-fluoro-6-methoxypyridin-3-yl)phenyl)ethan-1-one

[0335]

[0336] According to the method of step 2 in Example 1, 1-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one and 5-bromo-3-fluoro-2-methoxypyridine were synthesized into the title compound.

[0337] 1 H NMR (400 MHz, DMSO-d 6 )δ8.29(d,J=1.8Hz,1H),8.04(dd,J=12.2,1.8Hz,1H),8.00(d,J=1.9Hz,1H),7.62( dd,J=8.7,1.9Hz,1H),7.35(s,2H),6.86(d,J=8.7Hz,1H),3.97(s,3H),2.62(s,3H).

[0338] Step 2: Synthesis of 1-(2-amino-3-bromo-5-(5-fluoro-6-methoxypyridin-3-yl)phenyl)ethan-1-one

[0339]

[0340] According to the method of step 3 in Example 1, 1-(2-amino-5-(5-fluoro-6-methoxypyridin-3-yl)phenyl)ethan-1-one and NBS were used to synthesize the title compound.

[0341] 1 H NMR (400 MHz, DMSO-d 6)δ8.35(d,J=2.1Hz,1H),8.16–8.10(m,2H),8.08–8.05(m,1H),7.36(s,2H),3.98(s,3H),2.69(s,3H).

[0342] Step 3: Synthesis of 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline

[0343]

[0344] According to the method of step 4 in Example 1, the title compound was synthesized from 1-(2-amino-3-bromo-5-(5-fluoro-6-methoxypyridin-3-yl)phenyl)ethan-1-one and ammonium formate.

[0345] 1 H NMR (400 MHz, DMSO-d 6 )δ9.21(s,1H),8.74(d,J=1.9Hz,1H),8.61(d,J=2.1Hz,1H),8.55(d,J=1.9Hz,1H),8.40(dd,J=12.0,2.1Hz,1H),4.03(s,3H),3.03(s,3H).

[0346] Step 4: 6-(5-fluoro-6-methoxypyridin-3-yl)-8-(4-methoxyphenyl)-4-methylquinazoline

[0347]

[0348] According to the method of step 5 in Example 1, 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline and 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were synthesized into the title compound.

[0349] 1 H NMR (500 MHz, DMSO-d 6 )δ9.09(s,1H),8.62(d,J=2.1Hz,1H),8.46(d,J=2.1Hz,1H),8.41(dd,J=11.9,2.1Hz,1H),8.26(d, J=2.0Hz,1H),7.74(d,J=8.8Hz,2H),7.07(d,J=8.7Hz,2H),4.03(s,3H),3.84(s,3H),3.03(s,3H).

[0350] Example 36: 2-(4-(6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)phenoxy)ethan-1-ol

[0351]

[0352] According to the method of step 5 in Example 1, 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1-ol were synthesized into the title compound.

[0353] 1 H NMR (400 MHz, DMSO-d 6 )δ9.10(s,1H),8.64(d,J=1.9Hz,1H),8.48(d,J=1.9Hz,1H),8.43(dd,J=12.0,2.0Hz,1H),8.28(d,J=1.9Hz,1H),7.74(d,J=8. 7Hz, 2H), 7.08 (d, J = 8.8Hz, 2H), 4.93 (t, J = 5.5Hz, 1H), 4.08 (t, J = 5.0Hz, 2H), 4.03 (s, 3H), 3.77 (q, J = 5.2Hz, 2H), 3.04 (s, 3H).

[0354] Pharmacological activity evaluation

[0355] Experimental Example 1: Kinase activity test of PI3Kα

[0356] In vitro kinase activity test was used to evaluate the inhibitory activity of the compounds of the present invention on PI3Kα kinase. ADP-Glo ​​kinase assay kit was purchased from Promega. PI3Kα kinase was purchased from Invitrogen. All assays were performed at room temperature. Briefly, the compound, PI3Kα kinase, PIP2 and ATP were dissolved in kinase buffer and then added to each well of a 384-well plate. The 384-well plate was incubated at room temperature for 1 hour, followed by the addition of ADP-Glo ​​reagent and incubation at room temperature for 2 hours. After the kinase detection reagent was added to each well, the 384-well plate was incubated at room temperature for 30 minutes, followed by reading the cold light on the EnVision plate reader.

[0357] The percentage inhibition was calculated based on the following formula:

[0358] Inhibition % = 100 – (max-sample RLU) / (max-min)*100.

[0359] Where sample RLU is the luminescence reading at a given compound concentration, max refers to the reading of the DMSO control, and min refers to the reading of the no enzyme activity control. The IC value of the compound was calculated using the XLfit program in Excel. 50 value.

[0360] Table 1: Inhibitory activity of the example compounds on PI3Kα kinase

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369] Experimental Example 2: MTT method to determine the survival rate of tumor cells

[0370] HGC-27 cells (human gastric cancer cells) in the logarithmic growth phase were digested with 0.25% trypsin-EDTA until the cells became round, and then terminated with complete medium and made into a single cell suspension. 2500 cells / 100 μL / well were seeded in a 96-well plate and placed at 37°C, 5% CO 2 Incubate overnight in a cell culture incubator. On the second day, add 100 μL of complete culture medium (DMSO final concentration is 0.1%) containing different concentrations of the test compound and the corresponding solvent control to the corresponding wells, and continue incubating in the cell culture incubator for 72 hours. Then add 20 μL of freshly prepared MTT solution (50 mg / ML, dissolved in PBS) to each well to make the final concentration of MTT 5 mg / mL. After the cells are placed in a cell culture incubator and incubated for 4 hours, the supernatant is carefully discarded, 180 μL of DMSO is added to each well to dissolve the MTT formazan precipitate and oscillate with a micro-oscillator to mix. The optical density (OD) is measured at a detection wavelength of 570 nm. Taking the tumor cells treated with 0.1% DMSO as the control group, the inhibition rate of the test compound on tumor cell growth is calculated using the following formula, and the IC is calculated according to the median effect equation 50 :

[0371] Inhibition rate (%) = (average OD value of the control group - average OD value of the drug-added group) / average OD value of the control group × 100%.

[0372] Table 2. Proliferation inhibitory activity on human gastric cancer HGC27 cells

[0373]

[0374]

[0375]

[0376]

[0377]

Claims

1. A compound represented by formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts: in, R1 is hydrogen, fluorine, methoxy, ethoxy; R2 is O(CH2)nR3, O(CH2)nCOR4, COR4, NR5R6, or 5-8 membered heterocycloalkyl; R3 is H, OH or C1-C4 alkyl; R4 is OH, NR7R8 or a 5-8 membered heterocycloalkyl group; R5 and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkylsulfonyl, C3-C6 cycloalkylsulfonyl, C1-C4 alkylacyl, C3-C6 cycloalkylacyl; the alkyl and cycloalkyl are optionally substituted with hydroxyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4 alkyl)amino, C4-C6 N-containing heterocycloalkyl; R7 and R8 are each independently selected from hydrogen, C1-C4 alkyl, and the C1-C4 alkyl may be substituted by di(C1-C4 alkyl)amino; n is 0, 1, 2, 3 or 4; The 5- to 8-membered heterocycloalkyl group may be substituted by a C1-C4 alkyl group.

2. The compound according to claim 1, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, characterized in that: The R2 is OCH2CH2OH, OCH2CH2CH2OH or O(CH2)nCOR4, wherein: n is 1, 2 or 3; R4 is NR7R8 or a 5-8 membered heterocycloalkyl; R7 and R8 are each independently selected from hydrogen, methyl, ethyl, propyl, and R7 and R8 may be substituted by dimethylamino; The 5- to 8-membered heterocycloalkyl group is piperazine, methylpiperazine, ethylpiperazine, isopropylpiperazine, piperidine, morpholine, or thiomorpholine.

3. The compound according to claim 1, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, characterized in that: The R2 is COR4, wherein: R4 is NR7R8 or a 5-8 membered heterocycloalkyl; R7 and R8 are each independently selected from hydrogen, methyl, ethyl, propyl, and R7 and R8 may be optionally substituted by dimethylamino; The 5- to 8-membered heterocycloalkyl group is piperazine, methylpiperazine, ethylpiperazine, isopropylpiperazine, piperidine, morpholine, or thiomorpholine.

4. The compound according to claim 1, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, characterized in that: The R2 is NR5R6, wherein: R5 and R6 are each independently selected from hydrogen, methylsulfonyl, ethylsulfonyl, cyclopropanesulfonyl, acetyl, propionyl, isobutyryl, cyclopropylcarbonyl, cyclobutylcarbonyl; R5 and R6 may be optionally substituted with hydroxy, methoxy, dimethylamino, pyrrolidinyl.

5. The compound according to claim 1, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, wherein the partial compound is selected from:

6. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises at least one compound according to any one of claims 1 to 5, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt and optionally a pharmaceutically acceptable carrier and / or excipient.

7. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition further comprises a pharmaceutically active ingredient other than the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt.

8. Use of the compound according to any one of claims 1 to 5, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to any one of claims 6 or 7 in the preparation of a medicament for preventing and / or treating a PI3K-mediated disease.

9. The method according to claim 8, characterized in that The PI3K-mediated diseases include tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic dysfunction, endocrine dysfunction or neurological diseases.

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