CN108239075B

CN108239075B - Quinazoline compound, preparation method, application and pharmaceutical composition thereof

Info

Publication number: CN108239075B
Application number: CN201611211589.5A
Authority: CN
Inventors: 许恒; 陈晓光; 林松文; 季鸣; 吴德雨; 王春阳; 吕元皓
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2016-12-26
Filing date: 2016-12-26
Publication date: 2021-07-02
Anticipated expiration: 2036-12-26
Also published as: CN108239075A

Abstract

The invention relates to a quinazoline compound, a preparation method, application and a pharmaceutical composition thereof. The quinazoline compound is shown as a formula (I), is a phosphatidylinositol 3-kinase (PI3K) inhibitor, and can be used for preventing and/or treating diseases related to PI3K activity, such as cancer, immune diseases, cardiovascular diseases, virus infection, inflammation, metabolism/endocrine dysfunction or neurological diseases.

Description

Quinazoline compound, preparation method, application and pharmaceutical composition thereof

Technical Field

The invention belongs to the technical field of pharmacy, and relates to a quinazoline compound, and a preparation method, application and a pharmaceutical composition thereof.

Background

Phosphatidylinositol 3-kinases (PI3K) belong to the lipid kinase family and are classified into three major groups (I, II and III) according to their structure, regulation and specificity of lipid substrates. The most intensively studied at present are class I PI3K, such PI3K being a heterodimer consisting of a regulatory subunit (p85) and a catalytic subunit (p 110). Class I PI3K contains 4 subtypes, two of which, PI 3K. alpha. and PI 3K. beta. are widely present in all cell types, while the other two subtypes, PI 3K. delta. and PI 3K. gamma. are mainly distributed in leukocytes (Vanhaaesebroeck et al, Trends Biochem Sci., 2005, 30 (4): 194. sub.204). As the major downstream effector of Receptor Tyrosine Kinases (RTKs) and G-protein coupled receptors (GPCRs), PI3K mediates the signaling of various growth factors and cytokines into cells by catalyzing the production of phosphatidylinositol-3, 4, 5-triphosphate (PIP3) from phosphatidylinositol-4, 5-diphosphate (PIP 2). PIP3 acts as a second messenger within the cell that activates serine/threonine protein kinase (AKT) and downstream effectors, including the mammalian target of rapamycin (mTOR), thereby regulating a variety of cellular functions.

The PI3K signal pathway is one of the most common abnormal signal pathways in tumor cells and has a critical influence on the generation and development processes of tumors. In particular, PIK3CA gene encoding p110 alpha has a large number of amplifications and variations in most tumors, such as breast, lung, intestine, ovary, head and neck, stomach, prostate, brain, liver, digestive tract, 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 popular targets for targeting antitumor drugs. Several structural backbone types of PI3K inhibitors have been reported in succession, which show superior antitumor effects in both cellular and animal models, and several compounds have been tested in clinical trials against solid and hematological tumors, such as BKM120(Novartis, phase III), BEZ235(Novartis, phase II), PF-05212384(Pfizer, phase II), BAY 80-6946(Bayer, phase III), XL147(Exelixis, phase I/II), etc., in single or combined administration. The first PI3K inhibitor Idelalisib (Gilead, PI3K δ selective inhibitor) received FDA approval in 2014 for the treatment of Chronic Lymphocytic Leukemia (CLL), relapsed follicular B cell non-hodgkin lymphoma (FL), and relapsed Small Lymphocytic Lymphoma (SLL). In addition to tumors, PI3K has important regulation effects on inflammation, immune diseases, cardiovascular diseases, viral infection, metabolism/endocrine dysfunction or neurological diseases, and some compounds such as GSK2269557 (chronic obstructive pulmonary disease, clinical stage II), GSK2126458 (idiopathic pulmonary fibrosis, clinical stage I), UCB-5857 (primary sicca syndrome, clinical stage II) and RV-1729 (chronic obstructive pulmonary disease, clinical stage I) enter clinical test stages aiming at the diseases.

PI3K has become a very attractive drug target, but there is also a need to develop safer and more effective PI3K inhibitors for the prevention and/or treatment of cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction or neurological diseases.

Disclosure of Invention

The invention aims to provide a novel PI3K inhibitor, which has strong inhibitory activity on class I PI3K, including PI3K alpha, PI3K beta, PI3K gamma and/or PI3K delta, and particularly on PI3K alpha, so that the novel PI3K inhibitor has better prevention and/or treatment effects on diseases mediated by PI3K, such as cancer, immune diseases, cardiovascular diseases, viral infection, inflammation, metabolism/endocrine dysfunction or neurological diseases.

In one aspect, the present invention provides a compound of formula (I), a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein

L is selected from a single bond or C_1-3Alkylene, wherein said C_1-3Alkylene is optionally substituted with one or more Ra;

ra is selected from halogen or C_1-3An alkyl group;

R₁selected from hydrogen, C_1-3Alkyl radical, C_1-3Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl wherein said C is_1-3Alkyl radical, C_1-3Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl optionally substituted with one or more Rb;

rb is selected from halogen, cyano, hydroxy, trifluoromethyl, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl radical, C_1-3Alkylamino or di (C)_1-3Alkyl) amino;

R₂is selected from C_1-3Alkoxy, halogen or C_1-3An alkyl group;

R₃is selected from C_1-3Alkyl, 3-7 membered cycloalkyl, aryl or heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more groups selected from: halogen, C_1-3Alkyl, amino, C_1-3Alkylamino radical, di (C)_1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C_1-3An alkoxy group.

Preferably, the present invention provides a compound represented by formula (II), a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein

ra is selected from halogen or C_1-3An alkyl group;

R₂selected from methoxy, chloro or methyl;

R₃is selected from C_1-3Alkyl, 3-7 membered cycloalkyl, phenyl or thienyl, wherein said phenyl and thienyl are optionally substituted with one or more groups selected from the group consisting of: halogen, C_1-3Alkyl, amino, C_1-3Alkylamino radical, di (C)_1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C_1-3An alkoxy group;

ring A is selected from 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

R₄is selected from C_1-3Alkyl, halogen, cyano, trifluoromethyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl radical, C_1-3Alkylamino or di (C)_1-3Alkyl) amino;

m is 0, 1,2,3 or 4; when m is 2,3 or 4, R₄May be the same or different groups.

Further preferably, the present invention provides a compound represented by formula (II), a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein

ra is selected from halogen or C_1-3An alkyl group;

R₂selected from methoxy, chloro or methyl;

R₃selected from phenyl or thienyl, wherein said phenyl and thienyl are optionally substituted with at least one group selected from: halogen, C_1-3Alkyl, amino, C_1-3Alkylamino radical, di (C)_1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C_1-3An alkoxy group;

ring A is 3-7 membered cycloalkyl;

wherein

ra is selected from halogen or C_1-3An alkyl group;

R₂selected from methoxy, chloro or methyl;

R₃selected from phenyl or thienyl, wherein said phenyl and thienyl are optionally substituted with one or more groups selected from: halogen, C_1-3Alkyl, amino, C_1-3Alkylamino radical, di (C)_1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C_1-3An alkoxy group;

ring A is 3-7 membered heterocycloalkyl;

wherein

L is selected from a single bond or C_1-3Alkyl radical, wherein C_1-3Alkyl is optionally substituted with one or more Ra;

ra is selected from halogen or C_1-3An alkyl group;

R₂is methoxy;

ring A is selected from:

In particular, preferred compounds according to the invention are the following:

in another aspect, the present invention also provides a method for preparing the compound, its stereoisomers, geometric isomers and tautomers, which comprises the following steps:

(1) taking the compound A as a starting material, and preparing a compound B through bromination reaction;

(2) reacting the compound B with triphosgene to obtain a compound C;

(3) reacting the compound C with N, O-dimethylhydroxylamine hydrochloride to prepare a compound D;

(4) attacking the compound D by methyl magnesium bromide to obtain a compound E;

(5) reacting the compound E with 50% amino nitrile aqueous solution to obtain a compound F with a quinazoline framework;

(6) performing cyclization protection on the compound F by 2, 5-hexanedione to obtain a compound G;

(7) the compound G reacts with aluminum trichloride to remove methyl, and a universal intermediate H is obtained;

(8) carrying out Mitsunobu reaction on the intermediate H and alcohol or reacting with a halide to obtain a compound I;

(9) deprotecting the compound I by hydroxylamine hydrochloride to obtain a compound J;

(10) under the Suzuki reaction condition, coupling a compound F and a compound J with substituted pyridine-3-boronic acid pinacol ester to obtain the compound, a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof; or reacting the compound J with the diboron pinacol ester to obtain the corresponding boronic acid pinacol ester, and coupling the boronic acid pinacol ester with substituted 3-bromopyridine to obtain the compound, the stereoisomer, the geometric isomer, the tautomer or the pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention also provides a pharmaceutical composition comprising the compound, a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and/or excipient; preferably, the pharmaceutical composition further comprises one or more pharmaceutically active ingredients for preventing and/or treating cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders or neurological diseases, other than the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt; preferably, the pharmaceutical composition is a pharmaceutically acceptable pharmaceutical preparation for preventing and/or treating cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders or neurological diseases.

In yet another aspect, the present invention also provides a pharmaceutical formulation comprising at least one of the compounds, stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier or excipient; preferably, the pharmaceutical formulation is selected from the following pharmaceutical dosage forms: parenteral formulations, such as injection solutions or suspensions; enterally, e.g., orally, such as tablets or capsules; formulations for topical administration, for example lotions, gels, ointments, creams, nasal preparations, suppositories, transdermal preparations or ophthalmic preparations.

In still another aspect, the present invention also provides a use of the compound, a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine dysfunction, or neurological diseases. In other words, the present invention provides a method for preventing and/or treating cancer, immune diseases, cardiovascular diseases, viral infections, inflammations, metabolism/endocrine dysfunctions or neurological diseases, which comprises administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of the compound, a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

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

Halogen means fluorine, chlorine, bromine or iodine.

C_1-3Alkylene means a saturated, linear or branched divalent hydrocarbon radical having from 1 to 3 carbon atoms. Examples of such groups include, but are not limited to: methylene (-CH)₂-) ethylene (-CH₂CH₂-) propylene (-CH)₂CH₂CH₂-)。

C_1-3Alkyl refers to straight and branched chain saturated aliphatic hydrocarbon groups having 1 to 3 carbon atoms. Examples of such groups include, but are not limited to: methyl, ethyl, propyl, isopropyl.

3-7 membered cycloalkyl refers to a saturated monocyclic, fused, spiro or polycyclic structure having 3 to 7 carbon ring atoms. Examples of such groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cycloheptyl.

3-7 membered heterocycloalkyl refers to a saturated or partially unsaturated (i.e., having one or more double and or triple bonds in the ring) carbocyclic group of 3 to 7 ring atoms in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, or S (O) m (where m is an integer from 0 to 2), but not including the ring portion of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Specific examples of 3-7 membered saturated heterocycloalkyl groups include, but are not limited to: an oxetanyl group, an aziridinyl group, an azetidinyl group, an oxetanyl group, a thietanyl group, a dihydrofuranyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, an oxazolidinyl group, an isoxazolidinyl group, a thiazolidinyl group, an isothiazolidinyl group, a 1, 4-dioxanyl group, a 1, 3-dithiinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a dihydropyranyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, or the like; preferred are oxetanyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl.

C_1-3Alkoxy means an-O-alkyl group, wherein the alkyl group contains 1 to 3 carbon atoms and is straight, branched or cyclic. Examples of such groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy or cyclopropoxy.

Aryl means a monocyclic or bicyclic aromatic carbocyclic group, typically having 6 to 10 carbon atoms; such as phenyl or naphthyl. Phenyl is preferred.

Heteroaryl refers to a monocyclic 5-or 6-membered aromatic heterocyclic group, including but not limited to: 5-membered heteroaryl: furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl (1,2, 4-triazolyl, 1,3, 4-triazolyl or 1,2, 3-triazolyl), thiadiazolyl (1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,2, 3-thiadiazolyl or 1,2, 4-thiadiazolyl), and oxadiazolyl (1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 3-oxadiazolyl or 1,2, 4-oxadiazolyl), and 6-membered heteroaryl: pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl groups, and bicyclic groups, such as benzofuranyl, benzothienyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, indolizinyl, indolyl, isoindolyl. Preferred heteroaryl groups are thienyl, thiazolyl, pyridyl, pyrimidinyl.

Single bond means that the two groups to which it is attached are directly connected, for example, L represents a single bond in O-L-R indicates that the structure is actually O-R.

"optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances 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 the case where alkyl is substituted with halogen and the case where alkyl is not substituted with halogen.

If radicals, e.g. "R₄"depicted as" floating "in formula" on ring a:

means "R₄"any atom that may be ascribed to a ring system, provided that a stable structure is formed, is considered to be substituted on one of the ring atoms by a hydrogen that is depicted, suggested, or explicitly defined.

The compounds of the 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 (e.g., racemic mixtures), are within the scope of the present invention.

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

The compounds of the present invention include tautomers thereof. Tautomers refer to structural isomers of different energies that interconvert via a low energy barrier, such as keto-enol and imine-enamine tautomerism.

The compounds of the present invention also include isotopically-labeled compounds thereof, in which one or more atoms are replaced by atoms naturally found to have the same atomic number, but a different atomic mass or mass number. Examples include, but are not limited to: hydrogen isotope²H and³h; carbon isotope¹¹C、¹³C and¹⁴c; isotope of chlorine³⁶Cl; isotopes of fluorine¹⁸F; iodine isotope¹²³I and¹²⁵i; isotope of nitrogen¹³N and¹⁵n; oxygen isotope¹⁵O、¹⁷O and¹⁸o; isotope of phosphorus³²Isotopes of P and sulfur³⁵S。

Various hydrates and solvates of the compound or salt thereof of the present invention and polymorphic forms thereof (polymorphisms) are also included in the scope of the present invention.

Prodrugs of the compounds described herein are also included within the scope of the invention. Some derivatives of the compounds described in the present invention have weak pharmacological activity or no pharmacological activity themselves, but when these derivatives are administered in vivo or administered to the body, they may be converted into the compounds described in the present invention having pharmacological activity by means of, for example, hydrolytic cleavage, and the like, and these derivatives are referred to as "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.e.b.roche, American Pharmaceutical Association).

The compounds of the present invention include pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts are salts that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts are described in detail in j.pharma.sci.,1977,66,1-19 by Berge et al, 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 accordingly react with some inorganic or organic bases, or inorganic and organic acids, to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, dihydrogenphosphate, metaphosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, caprylate, or a mixture thereof, Citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate.

When used as a medicament, the compounds of the present invention are generally administered in the form of a pharmaceutical composition. Accordingly, pharmaceutical compositions of the compounds of the present invention and a pharmaceutically acceptable carrier, diluent or excipient are also included within the scope of the present invention. As used herein, carriers, adjuvants, excipients include any and all solvents, diluents or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like as appropriate for the particular dosage form desired. In Remington: the Science and Practice of Pharmacy, 21^stedition，2005，ed.D.B.Troy，Lippincott Williams&Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. 1999, Marcel Dekker, New York, disclose methods for formulating pharmaceutically acceptable groupsVarious carriers for the compounds and known techniques for their preparation are incorporated herein by reference.

The compositions of the present invention may be administered by any route suitable for the condition to be treated. In particular by administration in the form: parenterally, e.g., in the form of injectable solutions or suspensions; enterally, e.g., orally, e.g., in tablet or capsule form; 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 to the eye.

The pharmaceutical compositions may be administered in solid, semi-solid, liquid or gaseous form, or may be in a dry powder, such as lyophilized form. Pharmaceutical compositions can be packaged in a form convenient for delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatin, paper, tablets, suppositories, pellets, pills, troches, and lozenges. The type of packaging will generally depend on the route of administration. Implantable sustained release formulations, as well as transdermal formulations, are also contemplated.

Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, aluminum oxide, 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 silica, 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 powder; 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; buffering agents 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 non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate. Coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and anti-oxidizing agents may also be present in the composition, according to the judgment of the person skilled in the art.

The compounds of the present invention may be used alone or in combination with other therapeutic agents for the treatment of the diseases or conditions described herein, such as cancer. In certain embodiments, the compounds of the present invention are combined in a pharmaceutical combination formulation, or as a combination therapy in a dosing regimen, with a second compound having anti-hyperproliferative properties or for the treatment of a hyperproliferative disease, such as cancer. The second compound of the pharmaceutical combination or dosing regimen preferably has complementary activities to the compounds of the present invention such that they do not adversely affect each other. Such compounds are suitably present in the combination in an amount effective for the intended purpose. In one embodiment, the compounds of the present invention are combined with other anti-tumor agents. The anti-tumor medicine comprises: alkylating agents including, but not limited to, cyclophosphamide, mechlorethamine, melphalan, cinchonine, carmustine; platinoids including but not limited to carboplatin, cisplatin, oxaliplatin; topoisomerase inhibitors including, but not limited to, topotecan, camptothecin, topotecan, irinotecan; antibiotics, including but not limited to, anthracyclines, actinomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and plicamycin; anti-microtubule or anti-mitotic agents including, but not limited to, paclitaxel, vinorelbine, docetaxel, doxorubicin; antimetabolites including, but not limited to, fluorouracil, methotrexate, cytarabine, mercaptopurine (mecaptoprine), thioguanine, and gemcitabine; antibodies, including but not limited to herceptin, bevacizumab; hormones, including but not limited to letrozole (letrozole), vorozole (vorazole), tamoxifen, toremifene, fulvestrant, flutamide, nilutamide, triptorelin; kinase inhibitors, EGFR kinase inhibitors, including but not limited to gefitinib (gefitinib), erlotinib (erlotinib), lapatinib (lapatinib), afatinib (afatinib); VEGFR inhibitors including, but not limited to, Sorafenib (Sorafenib), regrafenib (Regorafenib), Sunitinib (Sunitinib), Cabozantinib (Cabozantinib), Pazopanib (Pazopanib), vandetanib (vandetanib), axitinib (axitinib); ALK inhibitors including, but not limited to, Crizotinib (Crizotinib), ceritinib (ceritinib), Alectinib; Bcr-Abl inhibitors, including but not limited to Imatinib (Imatinib), panatinib (Ponatinib), Nilotinib (Nilotinib), Dasatinib (Dasatinib); BTK inhibitors, including but not limited to Ibrutinib (Ibrutinib); B-RAF inhibitors, including but not limited to Vemurafenib (Vemurafenib); cyclin-dependent kinase CDK4/6 inhibitors, Palbociclib (Palbociclib); mTOR inhibitors, including but not limited to rapamycin (rapamycin), everolimus (everolimus); sirtuin inhibitors, including but not limited to vorinostat (vorinostat); PD1/PDL1 antibody, Keytruda (Pembrolizumab), Opdivo (Nivolumab).

Drawings

FIG. 1 is a tumor growth curve showing the growth inhibitory effect of example 9 on human lung carcinoma NCI-H460 in subcutaneous xenograft tumors in nude mice.

Detailed Description

The following are specific examples of the present invention, which further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

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

Preparation method

The compounds of the present invention may be synthesized according to the synthetic schemes herein and/or by techniques well known in the art. For example, the compounds provided by the present invention can be prepared according to the following general synthetic methods.

General synthetic method

Specifically, in a general synthetic method, the quinazoline compound provided by the invention can be prepared through a 10-step reaction. For example, starting material A is converted to compound B via bromination, which reacts with triphosgene to give compound C. And reacting the compound C with N, O-dimethylhydroxylamine hydrochloride to obtain a compound D, and attacking the compound D by methyl magnesium bromide to generate a compound E. And reacting the compound E with 50% amino nitrile aqueous solution to obtain a compound F with a quinazoline framework, and cyclizing the compound F with 2, 5-hexanedione to protect the amino group of the compound F. And (3) reacting the obtained compound G with aluminum trichloride to remove methyl, thereby obtaining a universal intermediate H. And carrying out Mitsunobu reaction on the intermediate H and various alcohols or reacting with various halides to obtain a compound I, and carrying out deprotection on the compound I by using hydroxylamine hydrochloride to obtain a compound J. Coupling of compound F and compound J with substituted pyridine-3-boronic acid pinacol esters under Suzuki reaction conditions known to those skilled in the art affords compounds 1-28. Alternatively, compound J is reacted with a pinacol ester of diboronic acid to give the corresponding pinacol ester of boronic acid, which is then coupled with a substituted 3-bromopyridine to give the final products, compounds 1-28.

Examples

Preparation examples

The compounds of the present invention may be synthesized according to one or more of the synthetic schemes herein and/or by techniques well known in the art. One skilled in the art will recognize that the synthetic methods of certain embodiments described in detail herein can be readily adapted to synthesize other embodiments. In some embodiments, the compounds described herein may be prepared by an appropriate combination of synthetic methods well known in the art. Many starting materials and other reagents are available from commercial suppliers, such as alfa aesar (china) chemical limited, or are readily prepared using synthetic methods commonly used in the art.

¹H NMR spectra were recorded on instruments operated at 400MHz or 500 MHz. H NMR spectra were obtained as a solution (reported in ppm) using CDCl₃(7.26ppm) or DMSO-d₆(2.50ppm) or internal tetramethylsilane (0.00ppm) as reference standard. When peak multiplicities are reported, 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 given are in hertz (Hz).

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

In the following preparations and examples, "Me" means methyl, "Et" means ethyl, "Ph" means phenyl, "PE" means petroleum ether, "EtOAc" means ethyl acetate, "MeOH" means methanol, "DMF" means N, N-dimethylformamide, "CDCl₃"refers to deuterated chloroform," DMSO-d₆"refers to deuterated dimethylsulfoxide," NMP "refers to 1-methyl-2-pyrrolidone," DCM "refers to dichloromethane," DCE "refers to 1, 2-dichloroethane," THF "refers to tetrahydrofuran," HCl "refers to hydrochloric acid," TsOH "refers to p-toluenesulfonic acid," AlCl₃"means aluminum trichloride," TEA "means triethylamine," NBS "means N-bromobutaneImide, "Na₂SO₄"means sodium sulfate" K₂CO₃"means potassium carbonate," MeMgBr "means methylmagnesium bromide," DEAD "means diethyl azodicarboxylate," PPh₃"means triphenylphosphine" PdCl₂(dppf) "means [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, "Ar" means argon, "M" means molar by volume, "rt" means room temperature, "min" means minutes, "h" means hours, "mL" means milliliters, "mmol" means millimoles, "μ M" means micromoles, "nM" means nanomoles, "and" c "means degrees celsius.

Preparation of general intermediate (H)

Step 1: preparation of 2-amino-5-bromo-3-methoxybenzoic acid (B)

NBS (28.04g, 157.5mmol) was added in 5 portions to a solution of 2-amino-3-methoxybenzoic acid (A) (25.08g, 150mmol) in DMF (200mL) over 20 min. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (2L) and extracted with EtOAc (500 mL. times.4). The combined organic layers were washed with water (500 mL. times.3) and brine (500mL), and dried over anhydrous Na₂SO₄Drying, filtration and concentration gave the crude product (B) as a dark brown solid (35g, 95% yield) which was used in the next step without purification.

¹H NMR(400MHz,DMSO-d₆)δ7.42(d,J＝2.2Hz,1H),7.07(d,J＝2.2Hz,1H),3.84(s,3H)。

Step 2: preparation of 6-bromo-8-methoxy-2H-benzo [ d ] [1,3] oxazine-2, 4(1H) -dione (C)

A mixture of compound (B) (35g, 142.2mmol) and triphosgene (32mg, 107.8mmol) in dry THF (350mL) was refluxed for 3 h. After cooling to room temperature, the resulting solid was collected by filtration, washed with PE/EtOAc solution (1:1, v/v, 200mL) and dried to give product (C) as a pale yellow solid (30.78g, 80% yield).

¹H NMR(400MHz,DMSO-d₆)δ11.43(s,1H),7.56(d,J＝2.0Hz,1H),7.55(d,J＝2.0Hz,1H),3.92(s,3H)。

And step 3: preparation of 2-amino-5-bromo-N, 3-dimethoxy-N-methylbenzamide (D)

A mixture of compound (C) (30.78g, 113.12mmol), N, O-dimethylhydroxylamine hydrochloride (16.55g, 169.68mmol) and TEA (26.7mL, 192.3mmol) in dioxane (300mL) was refluxed overnight. The volatiles were evaporated under reduced pressure. The reaction mixture was diluted with water (500mL) and extracted with EtOAc (200 mL. times.3). The combined organic layers were washed with water (200 mL. times.2) and brine (200mL), and dried over anhydrous Na₂SO₄Drying, filtering and concentrating. The residue was purified by flash column chromatography (silica gel, PE/EtOAc ═ 4:1, v/v) to give product (D) as a yellow oil (29.73g, 91% yield).

¹H NMR(400MHz,DMSO-d₆)δ7.01(d,J＝2.0Hz,1H),6.97(d,J＝2.0Hz,1H),5.10(br s,2H),3.82(s,3H),3.53(s,3H),3.22(s,3H)。

And 4, step 4: preparation of 1- (2-amino-5-bromo-3-methoxyphenyl) ethanone (E)

To a solution of compound (D) (29.73g, 103mmol) in anhydrous tetrahydrofuran (300mL) at-20 ℃ under an argon atmosphere was slowly added dropwise methylmagnesium bromide (1M tetrahydrofuran solution, 206mL, 206mmol) over 30 min. The resulting reaction mixture was stirred at-20 ℃ for 30min and then quenched with saturated aqueous ammonium chloride. The reaction mixture was diluted with water (1L) and extracted with EtOAc (300 mL. times.3). The combined organic layers were washed with water (300 mL. times.2) and brine (300mL) and washed with brineWater Na₂SO₄Drying, filtering and concentrating. The residue was purified by flash column chromatography (silica gel, PE/EtOAc ═ 15:1, v/v) to give the product (E) as a yellow oil (6.5g, 26% yield).

¹H NMR(400MHz,DMSO-d₆)δ7.50(d,J＝2.0Hz,1H),7.08(d,J＝2.0Hz,1H),7.04(s,2H),3.84(s,3H),2.51(s,3H)。

And 5: preparation of 6-bromo-8-methoxy-4-methyl-quinazolin-2-amine (F)

A mixture of compound (E) (7.41g, 30.36mmol) and concentrated hydrochloric acid (10mL) in 50% aqueous aminonitrile solution (74mL) was stirred at 120 ℃ for 15 min. The reaction mixture was cooled to room temperature, diluted with water (300mL), and the resulting solid was collected by filtration, washed with water (100mL) and ethanol (30mL), and dried to give product (F) as a pale yellow solid (8.00g, 98% yield).

¹H NMR(400MHz,DMSO-d₆)δ7.67(d,J＝2.0Hz,1H),7.20(d,J＝2.0Hz,1H),6.90(br s,2H),3.88(s,3H),2.67(s,3H)。

Step 6: preparation of 6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -8-methoxy-4-methyl-quinazoline (G)

A mixture of compound (F) (8.00g, 29.84mmol), 2, 5-hexanedione (13.61g, 119.36mmol), and p-toluenesulfonic acid monohydrate (0.568g, 2.98mmol) in NMP (80mL) and toluene (80mL) was refluxed at 160 ℃ for 6 h. The reaction mixture was cooled to room temperature, the toluene was evaporated under reduced pressure, diluted with water (400mL) and extracted with EtOAc (100 mL. times.3). The combined organic layers were washed with water (100 mL. times.3) and brine (100mL), and dried over anhydrous Na₂SO₄Drying, filtering and concentrating. The residue was purified by flash column chromatography (silica gel, PE/EtOAc ═ 30:1, v/v) to give the product (G) as a yellow solid (8.95G, yield87% in this case).

¹H NMR(400MHz,DMSO-d₆)δ8.04(d,J＝1.8Hz,1H),7.57(d,J＝1.8Hz,1H),5.84(s,2H),4.01(s,3H),2.92(s,3H),2.30(s,6H)。

And 7: preparation of 6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methylquinazolin-8-ol (H)

To a solution of compound (G) (3.27G, 9.56mmol) in DCE (300mL) was added AlCl₃(3.83g, 28.68 mmol). The resulting reaction mixture was stirred at 80 ℃ for 1.5 h. The reaction mixture was cooled to room temperature, diluted with water (300mL) and extracted with DCM (300 mL. times.2). The combined organic layers were washed with water (200mL) and brine (100mL), and dried over anhydrous Na₂SO₄Drying, filtering and concentrating. The residue was purified by flash column chromatography (silica gel, PE/EtOAc ═ 50:1, v/v) to give the product (H) as a yellow solid (2.41g, 77% yield).

¹H NMR(400MHz,DMSO-d₆)δ10.64(s,1H),7.93(d,J＝2.0Hz,1H),7.44(d,J＝2.0Hz,1H),5.84(s,2H),2.91(s,3H),2.29(s,6H)。

Example 1: n- (5- (2-amino-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (1)

Step 1: preparation of 6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methyl-8- ((tetrahydro-2H-pyran-4-yl) oxy) quinazoline (I-1)

To a stirred solution of compound (H) (3.322g, 10mmol), triphenylphosphine (3.148g, 12mmol) and tetrahydro-2H-pyran-4-ol (1.226g, 12mmol) in anhydrous tetrahydrofuran (50mL) was added diethyl azodicarboxylate (2.09g, 12mmol) at room temperature under an argon atmosphere. The resulting reaction mixture was stirred at room temperature overnight. Silica gel (10g) was added to the reaction solution, and the resulting mixture was evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, PE/EtOAc ═ 10:1, v/v) to give the product (I-1) as a yellow oil (2.097g, 50% yield).

¹H NMR(400MHz,DMSO-d₆)δ8.04(d,J＝1.9Hz,1H),7.70(d,J＝1.8Hz,1H),5.86(s,2H),5.01–4.91(m,1H),3.94–3.80(m,2H),3.56(ddd,J＝11.2,8.0,3.2Hz,2H),2.92(s,3H),2.36(s,3H),2.09–1.94(m,2H),1.77–1.65(m,2H)。

Step 2: preparation of 6-bromo-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) oxy) quinazolin-2-amine (J-1)

A mixture of compound (I-1) (2.082g, 5.0mmol) and hydroxylamine hydrochloride (1.734g, 25mmol) in ethanol (40mL) and water (4mL) was refluxed overnight. The resulting mixture was evaporated to dryness under reduced pressure, diluted with water (100mL), neutralized with saturated aqueous sodium bicarbonate solution, and extracted with DCM (50mL × 3). The combined organic layers were washed with water (50mL) and brine (50mL), and dried over anhydrous Na₂SO₄Drying, filtering and concentrating. The residue was purified by flash chromatography (silica gel, DCM/MeOH ═ 50:1, v/v) to give the product (J-1) as a yellow oil (0.667g, 39% yield).

¹H NMR(400MHz,DMSO-d₆)δ7.68(d,J＝2.0Hz,1H),7.36(d,J＝2.0Hz,1H),6.85(s,2H),4.82–4.73(m,1H),3.94–3.87(m,2H),3.53–3.45(m,2H),2.65(s,3H),2.05–1.96(m,2H),1.68–1.58(m,2H)。

MS(ESI+)m/z 337.8,339.8[M+H]⁺。

And step 3: preparation of N- (5- (2-amino-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (1)

A mixture of compound (J-1) (538mg, 1.59mmol), N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide (814mg, 1.91mmol) and 2M aqueous potassium carbonate (2.40mL, 4.8mmol) in dioxane (15mL) was degassed and PdCl was added₂(dppf) (58mg, 0.08 mmol). The resulting reaction mixture was degassed and backfilled with argon (three cycles) and then stirred at 100 ℃ for 5h under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc (50mL) and water (50mL) and acidified to pH 5-6 with 2M hydrochloric acid. The phases were separated and the aqueous layer was extracted with EtOAc (30 mL. times.2). The combined organic layers were washed with water (50mL) and brine (50mL), and dried over anhydrous Na₂SO₄Drying, filtering and concentrating. The residue was purified by flash column chromatography (silica gel, DCM/MeOH ═ 50:1, v/v) to give product (1) as a yellow foamy solid (400mg, 45% yield).

¹H NMR(400MHz,DMSO-d₆)δ10.29(s,1H),8.44(d,J＝2.2Hz,1H),7.96(d,J＝2.2Hz,1H),7.76(dt,J＝8.4,2.4Hz,1H),7.66(d,J＝1.2Hz,1H),7.64–7.54(m,1H),7.46(d,J＝1.2Hz,1H),7.23(dt,J＝8.6,2.0Hz,1H),6.79(s,2H),4.97–4.82(m,1H),3.98–3.89(m,2H),3.64(s,3H),3.56–3.45(m,2H),2.75(s,3H),2.10–1.99(m,2H),1.75–1.58(m,2H)。

MS(ESI+)m/z 558.2[M+H]⁺。

Example 2: n- (5- (2-amino-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2-chloro-4-fluorobenzenesulfonamide (2)

Compound (2) was prepared from compound (J-1) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2-chloro-4-fluorobenzenesulfonamide according to the method of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.17(s,1H),8.42(d,J＝2.3Hz,1H),7.94(dd,J＝8.8,6.0Hz,1H),7.90(d,J＝2.4Hz,1H),7.76(dd,J＝8.8,2.4Hz,1H),7.62(d,J＝1.6Hz,1H),7.43(d,J＝1.4Hz,1H),7.40–7.33(m,1H),6.79(s,2H),4.94–4.81(m,1H),3.98–3.89(m,2H),3.66(s,3H),3.57–3.45(m,2H),2.75(s,3H),2.10–1.99(m,2H),1.74–1.58(m,2H)。

MS(ESI+)m/z 574.1[M+H]⁺。

Example 3: n- (5- (2-amino-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -4-fluorobenzenesulfonamide (3)

Compound (3) was prepared from compound (J-1) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -4-fluorobenzenesulfonamide according to the method of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.04(s,1H),8.39(d,J＝2.4Hz,1H),7.88(d,J＝2.4Hz,1H),7.86–7.79(m,2H),7.61(d,J＝1.8Hz,1H),7.47–7.39(m,3H),6.79(s,2H),4.95–4.82(m,1H),3.98–3.89(m,2H),3.65(s,3H),3.56–3.42(m,2H),2.75(s,3H),2.11–1.98(m,2H),1.74–1.59(m,2H)。

MS(ESI+)m/z 540.2[M+H]⁺。

Example 4: n- (5- (2-amino-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -5-chlorothiophene-2-sulfonamide (4)

Compound (4) was prepared from compound (J-1) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -5-chlorothiophene-2-sulfonamide according to the procedure in step 3 of example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.34(s,1H),8.46(d,J＝2.4Hz,1H),7.95(d,J＝2.4Hz,1H),7.67(d,J＝1.6Hz,1H),7.47(d,J＝1.6Hz,1H),7.39(d,J＝4.0Hz,1H),7.24(d,J＝4.0Hz,1H),6.80(s,2H),4.95–4.84(m,1H),4.00–3.86(m,2H),3.74(s,3H),3.58–3.45(m,2H),2.76(s,3H),2.11–2.00(m,2H),1.77–1.60(m,2H)。

MS(ESI+)m/z 562.1[M+H]⁺。

Example 5: n- (5- (2-amino-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) methanesulfonamide (5)

Compound (5) was prepared from compound (J-1) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) methanesulfonamide according to the procedure in step 3 of example 1.

¹H NMR(400MHz,DMSO-d₆)δ9.34(s,1H),8.43(d,J＝2.3Hz,1H),7.95(d,J＝2.3Hz,1H),7.70(d,J＝1.6Hz,1H),7.47(d,J＝1.6Hz,1H),6.77(s,2H),4.97–4.81(m,1H),3.98(s,3H),3.96–3.88(m,2H),3.55–3.44(m,2H),3.08(s,3H),2.75(s,3H),2.10–2.00(m,2H),1.76–1.57(m,2H)。

MS(ESI+)m/z 460.2[M+H]⁺。

Example 6: n- (5- (2-amino-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) cyclopropylsulfonamide (6)

Compound (6) was prepared from compound (J-1) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) cyclopropylsulfonamide according to the procedure in step 3 of example 1.

¹H NMR(400MHz,DMSO-d₆)δ9.37(s,1H),8.43(d,J＝2.3Hz,1H),7.97(d,J＝2.3Hz,1H),7.69(d,J＝1.8Hz,1H),7.47(d,J＝1.8Hz,1H),6.78(s,2H),4.97–4.80(m,1H),3.98(s,3H),3.96–3.88(m,2H),3.57–3.44(m,2H),2.83–2.70(m,4H),2.12–1.98(m,2H),1.74–1.61(m,2H),1.01–0.89(m,4H)。

MS(ESI+)m/z 486.2[M+H]⁺。

Example 7: n- (5- (2-amino-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) oxy) quinazolin-6-yl) -2-methylpyridin-3-yl) -2, 4-difluorobenzenesulfonamide (7)

A mixture of compound (J-1) (75mg, 0.22mmol), potassium acetate anhydrous (65mg, 0.66mmol) and pinacol ester diboron (64mg, 0.25mmol) in dioxane (8mL) was degassed and PdCl was added₂(dppf) (16mg, 0.022 mmol). The resulting reaction mixture was degassed and back-filled with argon (three cycles) and stirred at 100 ℃ for 4h under an argon atmosphere. After cooling to room temperature, N- (5-bromo-2-methylpyridin-3-yl) -2, 4-difluorobenzenesulfonamide (91mg, 0.25mmol) and 2M aqueous potassium carbonate (0.44mL, 0.88mmol) were added to the resulting mixture. The resulting mixture was degassed and then PdCl was added₂(dppf) (16mg, 0.022 mmol). The resulting reaction mixture was degassed and backfilled with argon (three cycles) and then stirred at 100 ℃ for 5h under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc (30mL) and water (30mL) and acidified with hydrochloric acid to a pH of 5-6. The phases were separated and the aqueous layer was extracted with EtOAc (30 mL. times.2). The combined organic layers were washed with water (50mL) and brine (50mL), and dried over anhydrous Na₂SO₄Drying, filtering and concentrating. The residue was purified by preparative thin layer chromatography (DCM/MeOH/ammonia 15:1:0.1, v/v) to give product (7) as a yellow foamy solid (35mg, 29% yield).

¹H NMR(400MHz,DMSO-d₆)δ10.45(s,1H),8.73(s,1H),7.80(dt,J＝8.4,6.4Hz,1H),7.72–7.54(m,3H),7.40(s,1H),7.27(dt,J＝8.4,2.0Hz,1H),6.84(s,2H),4.91–4.80(m,1H),3.98–3.88(m,2H),3.58–3.43(m,2H),2.73(s,3H),2.33(s,3H),2.08–1.98(m,2H),1.77–1.58(m,2H)。

MS(ESI+)m/z 542.2[M+H]⁺。

Example 8: n- (5- (2-amino-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) oxy) quinazolin-6-yl) -2-chloropyridin-3-yl) -4-fluorobenzenesulfonamide (8)

A mixture of compound (J-1) (75mg, 0.22mmol), potassium acetate anhydrous (65mg, 0.66mmol) and pinacol ester diboron (64mg, 0.25mmol) in dioxane (8mL) was degassed and PdCl was added₂(dppf) (16mg, 0.022 mmol). The resulting reaction mixture was degassed and back-filled with argon (three cycles) and stirred at 100 ℃ for 4h under an argon atmosphere. After cooling to room temperature, N- (5-bromo-2-chloropyridin-3-yl) -4-fluorobenzenesulfonamide (91mg, 0.25mmol) and 2M aqueous potassium carbonate (0.44mL, 0.88mmol) were added to the resulting mixture. The resulting mixture was degassed and then PdCl was added₂(dppf) (16mg, 0.022 mmol). The resulting reaction mixture was degassed and backfilled with argon (three cycles) and then stirred at 100 ℃ for 5h under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc (30mL) and water (30mL) and acidified with hydrochloric acid to a pH of 5-6. The phases were separated and the aqueous layer was extracted with EtOAc (30 mL. times.2). The combined organic layers were washed with water (50mL) and brine (50mL), and dried over anhydrous Na₂SO₄Drying, filtering and concentrating. The residue was purified by preparative thin layer chromatography (DCM/MeOH/ammonia 15:1:0.1, v/v) to give the product (8) as a yellow foamy solid (30mg, 25% yield).

¹H NMR(400MHz,DMSO-d₆)δ10.53(s,1H),8.67(d,J＝1.7Hz,1H),7.99(d,J＝2.3Hz,1H),7.87–7.77(m,2H),7.71(d,J＝1.7Hz,1H),7.51–7.40(m,3H),6.90(s,2H),4.95–4.82(m,1H),3.98–3.88(m,2H),3.57–3.44(m,2H),2.76(s,3H),2.12–1.95(m,2H),1.75–1.59(m,2H)。

MS(ESI+)m/z 544.1[M+H]⁺。

Example 9: (R) -N- (5- (2-amino-4-methyl-8- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (9)

Step 1: preparation of (R) -6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methyl-8- ((tetrahydrofuran-3-yl) oxy) quinazoline (I-9)

Compound (I-9) was prepared from compound (H) and (S) -tetrahydrofuran-3-ol according to the procedure of step 1 in example 1.

¹H NMR(400MHz,CDCl₃)δ7.82(d,J＝1.6Hz,1H),7.22(d,J＝1.6Hz,1H),5.91(s,2H),5.22–5.14(m,1H),4.18–3.94(m,4H),2.91(s,3H),2.45(s,6H),2.33–2.26(m,2H)。

Step 2: preparation of (R) -6-bromo-4-methyl-8- ((tetrahydrofuran-3-yl) oxy) quinazolin-2-amine (J-9)

Compound (J-9) is prepared from compound (I-9) according to the method of step 2 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ7.69(d,J＝2.0Hz,1H),7.21(d,J＝2.0Hz,1H),6.89(s,2H),5.25–5.18(m,1H),3.97–3.83(m,3H),3.80–3.72(m,1H),2.66(s,3H),2.33–2.21(m,1H),2.05–1.93(m,1H)。

And step 3: preparation of (R) -N- (5- (2-amino-4-methyl-8- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (9)

Compound (9) was prepared from compound (J-9) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.28(s,1H),8.44(d,J＝2.3Hz,1H),7.97(d,J＝2.3Hz,1H),7.82–7.72(m,1H),7.67(d,J＝1.5Hz,1H),7.64–7.53(m,1H),7.32(d,J＝1.5Hz,1H),7.22(dt,J＝8.4,2.0Hz,1H),6.83(s,2H),5.43–5.29(m,1H),4.02–3.85(m,3H),3.83–3.74(m,1H),3.65(s,3H),2.75(s,3H),2.35–2.22(m,1H),2.08–2.01(m,1H)。

MS(ESI+)m/z 544.1[M+H]⁺。

Example 10: (R) -N- (5- (2-amino-4-methyl-8- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) methanesulfonamide (10)

Compound (10) was prepared from compound (J-9) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) methanesulfonamide according to the procedure in step 3 of example 1.

¹H NMR(400MHz,DMSO-d₆)δ9.35(s,1H),8.44(d,J＝2.3Hz,1H),7.97(d,J＝2.3Hz,1H),7.71(d,J＝1.6Hz,1H),7.34(d,J＝1.6Hz,1H),6.83(s,2H),5.39–5.33(m,1H),3.98(s,3H),3.97–3.87(m,3H),3.82–3.74(m,1H),3.09(s,3H),2.75(s,3H),2.34–2.22(m,1H),2.12–2.00(m,1H)。

MS(ESI+)m/z 446.1[M+H]⁺。

Example 11: (S) -N- (5- (2-amino-4-methyl-8- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (11)

Step 1: preparation of (S) -6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methyl-8- ((tetrahydrofuran-3-yl) oxy) quinazoline (I-11)

Compound (I-11) was prepared from compound (H) and (R) -tetrahydrofuran-3-ol according to the procedure of step 1 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ8.05(d,J＝1.8Hz,1H),7.58(d,J＝1.8Hz,1H),5.85(s,2H),5.38–5.31(m,1H),4.06–3.75(m,4H),2.92(s,3H),2.34(s,6H),2.32–2.24(m,1H),2.13–2.02(m,1H)。

Step 2: preparation of (S) -6-bromo-4-methyl-8- ((tetrahydrofuran-3-yl) oxy) quinazolin-2-amine (J-11)

Compound (J-11) is prepared from compound (I-11) according to the method of step 2 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ7.69(d,J＝2.0Hz,1H),7.21(d,J＝2.0Hz,1H),6.90(s,2H),5.25–5.18(m,1H),3.97–3.82(m,3H),3.80–3.72(m,1H),2.66(s,3H),2.33–2.21(m,1H),2.05–1.95(m,1H)。

And step 3: preparation of (S) -N- (5- (2-amino-4-methyl-8- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (11)

Compound (11) was prepared from compound (J-11) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.28(s,1H),8.44(d,J＝2.3Hz,1H),7.97(d,J＝2.3Hz,1H),7.76(dt,J＝8.6,6.4Hz,1H),7.67(d,J＝1.6Hz,1H),7.64–7.53(m,1H),7.32(d,J＝1.6Hz,1H),7.22(dt,J＝8.6,2.3Hz,1H),6.84(s,2H),5.43–5.29(m,1H),4.00–3.85(m,3H),3.83–3.73(m,1H),3.65(s,3H),2.75(s,3H),2.35–2.22(m,1H),2.12–2.01(m,1H)。

MS(ESI+)m/z 544.1[M+H]⁺。

Example 12: (S) -N- (5- (2-amino-4-methyl-8- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) methanesulfonamide (12)

Compound (12) was prepared from compound (J-11) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) methanesulfonamide according to the procedure in step 3 of example 1.

¹H NMR(400MHz,DMSO-d₆)δ9.35(s,1H),8.44(d,J＝2.3Hz,1H),7.97(d,J＝2.3Hz,1H),7.71(d,J＝1.8Hz,1H),7.34(d,J＝1.8Hz,1H),6.83(s,2H),5.39–5.33(m,1H),3.98(s,3H),3.96–3.86(m,3H),3.83–3.74(m,1H),3.09(s,3H),2.75(s,3H),2.35–2.23(m,1H),2.12–2.02(m,1H)。

MS(ESI+)m/z 446.1[M+H]⁺。

Example 13: n- (5- (2-amino-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) methoxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (13)

Step 1: preparation of 6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methyl-8- ((tetrahydro-2H-pyran-4-yl) methoxy) quinazoline (I-13)

Compound (I-13) was prepared from compound (H) and (tetrahydro-2H-pyran-4-yl) methanol according to the procedure of step 1 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ8.02(d,J＝1.9Hz,1H),7.55(d,J＝1.9Hz,1H),5.85(s,2H),4.07(d,J＝6.2Hz,2H),3.94–3.86(m,2H),3.36(dt,J＝11.6,2.0Hz,2H),2.91(s,3H),2.35(s,6H),2.19–2.03(m,1H),1.78–1.69(m,2H),1.52–1.37(m,2H)。

Step 2: preparation of 6-bromo-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) methoxy) quinazolin-2-amine (J-13)

Compound (J-13) is prepared from compound (I-13) according to the procedure in step 2 of example 1.

¹H NMR(400MHz,DMSO-d₆)δ7.65(d,J＝2.0Hz,1H),7.22(d,J＝2.0Hz,1H),6.83(s,2H),3.95(d,J＝6.7Hz,2H),3.92–3.84(m,2H),3.40–3.32(m,2H),2.65(s,3H),2.14–1.99(m,1H),1.78–1.69(m,2H),1.43–1.28(m,2H)。

And step 3: preparation of N- (5- (2-amino-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) methoxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (13)

Compound (13) was prepared from compound (J-13) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.28(s,1H),8.45(d,J＝2.1Hz,1H),7.97(d,J＝2.2Hz,1H),7.76(dt,J＝8.6,6.4Hz,1H),7.64(s,1H),7.63–7.55(m,1H),7.34(s,1H),7.22(dt,J＝8.6,2.4Hz,1H),6.79(s,2H),4.05(d,J＝6.6Hz,2H),3.90(dd,J＝11.0,3.0Hz,2H),3.64(s,3H),3.37(t,J＝11.0Hz,2H),2.75(s,3H),2.20–2.05(m,1H),1.84–1.74(m,2H),1.38(qd,J＝12.2,4.2Hz,2H)。

MS(ESI+)m/z 572.2[M+H]⁺。

Example 14: n- (5- (2-amino-4-methyl-8- ((tetrahydro-2H-pyran-4-yl) methoxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) methanesulfonamide (14)

Compound (14) was prepared from compound (J-13) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) methanesulfonamide according to the procedure in step 3 of example 1.

¹H NMR(400MHz,DMSO-d₆)δ9.35(s,1H),8.44(d,J＝2.2Hz,1H),7.97(d,J＝2.2Hz,1H),7.67(d,J＝1.2Hz,1H),7.36(d,J＝1.2Hz,1H),6.77(s,2H),4.06(d,J＝6.6Hz,2H),3.98(s,3H),3.90(dd,J＝11.2,3.0Hz,2H),3.36(t,J＝10.9Hz,2H),3.08(s,3H),2.75(s,3H),2.20–2.04(m,1H),1.77(d,J＝12.4Hz,2H),1.38(qd,J＝12.4,4.4Hz,2H)。

MS(ESI+)m/z 474.2[M+H]⁺。

Example 15: n- (5- (2-amino-4-methyl-8- ((1-methylpiperidin-4-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (15)

Step 1: preparation of 6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methyl-8- ((1-methylpiperidin-4-yl) oxy) quinazoline (I-15)

Compound (I-15) is prepared from compound (H) and 1-methylpiperidin-4-ol according to the method of step 1 in example 1

¹H NMR(400MHz,CDCl₃)δ8.02(d,J＝2.0Hz,1H),7.64(d,J＝2.0Hz,1H),5.86(s,2H),4.88–4.73(m,1H),2.91(s,3H),2.64–2.54(m,2H),2.37(s,6H),2.35–2.25(m,2H),2.18(s,3H),2.04–1.89(m,2H),1.87–1.71(m,2H)。

Step 2: preparation of 6-bromo-4-methyl-8- ((1-methylpiperidin-4-yl) oxy) quinazolin-2-amine (J-15)

Compound (J-15) is prepared from compound (I-15) according to the method of step 2 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ7.66(d,J＝2.0Hz,1H),7.28(d,J＝2.0Hz,1H),6.83(s,2H),4.64–4.47(m,1H),2.78–2.69(m,2H),2.65(s,3H),2.19(s,3H),2.18–2.10(m,2H),2.04–1.93(m,2H),1.73–1.60(m,2H)。

And step 3: preparation of N- (5- (2-amino-4-methyl-8- ((1-methylpiperidin-4-yl) oxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (15)

Compound (15) was prepared from compound (J-15) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.56(br s,1H),8.40(d,J＝2.4Hz,1H),7.94(d,J＝2.4Hz,1H),7.76(dt,J＝8.6,6.4Hz,1H),7.71(d,J＝1.6Hz,1H),7.61–7.51(m,2H),7.22(dt,J＝8.4,2.1Hz,1H),6.84(s,2H),4.95–4.85(m,1H),3.64(s,3H),3.10–2.95(m,2H),2.76(s,3H),2.69(s,3H),2.25–2.13(m,2H),2.07–1.95(m,2H)。

MS(ESI+)m/z 571.18994[M+H]⁺。

Example 16: n- (5- (2-amino-4-methyl-8- ((2-morpholinoethoxy) quinazoline-6-

2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (16)

Step 1: preparation of 4- (2- ((6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methylquinazolin-8-yl) oxy) ethyl) morpholine (I-16)

Compound (I-16) is produced from compound (H) and 2-morpholinoethanol by the method of step 1 in example 1.

¹H NMR(400MHz,CDCl₃)δ8.02(d,J＝2.0Hz,1H),7.64(d,J＝2.0Hz,1H),5.85(s,2H),4.33(t,J＝5.1Hz,2H),4.04(q,J＝7.0Hz,4H),3.64–3.46(m,4H),2.92(s,3H),2.81(t,J＝5.1Hz,2H),2.53(s,6H)。

Step 2: preparation of 6-bromo-4-methyl-8- (2-morpholinoethoxy) quinazolin-2-amine (J-16)

Compound (J-16) is prepared from compound (I-16) according to the procedure in step 2 of example 1.

¹H NMR(500MHz,DMSO-d₆)δ7.67(s,1H),7.28(s,1H),6.90(s,2H),4.21(t,J＝5.9Hz,2H),3.67–3.50(m,4H),2.74(t,J＝5.8Hz,2H),2.66(s,3H),2.51(br s,4H)。

And step 3: preparation of N- (5- (2-amino-4-methyl-8- ((2-morpholinoethoxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (16)

Compound (16) was prepared from compound (J-16) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ8.44(d,J＝2.2Hz,1H),7.97(d,J＝2.2Hz,1H),7.76(dt,J＝8.6,6.4Hz,1H),7.65(d,J＝1.6Hz,1H),7.58(ddd,J＝10.4,9.4,2.4Hz,1H),7.38(d,J＝1.6Hz,1H),7.26–7.17(m,1H),6.84(s,2H),4.31(t,J＝6.0Hz,2H),3.64(s,3H),3.61(t,J＝4.6Hz,4H),2.81(t,J＝6.0Hz,2H),2.75(s,3H),2.61–2.52(m,4H)。

MS(ESI+)m/z 587.2[M+H]⁺。

Example 17: n- (5- (2-amino-8- ((4, 4-difluorocyclohexyl) oxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (17)

Step 1: preparation of 6-bromo-8- ((4, 4-difluorocyclohexyl) oxy) -2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methylquinazoline (I-17)

Compound (I-17) was prepared from compound (H) and 4, 4-difluorocyclohexanol according to the procedure in step 1 of example 1.

¹H NMR(400MHz,CDCl₃)δ7.82(d,J＝1.8Hz,1H),7.31(d,J＝1.8Hz,1H),5.92(s,2H),4.85–4.77(m,1H),2.91(s,3H),2.45(s,6H),2.28–2.14(m,4H),2.07–1.92(m,4H)。

Step 2: preparation of 6-bromo-8- ((4, 4-difluorocyclohexyl) oxy) -4-methylquinazolin-2-amine (J-17)

Compound (J-17) is prepared from compound (I-17) according to the procedure in step 2 of example 1.

¹H NMR(400MHz,CDCl₃)δ7.65(d,J＝1.6Hz,1H),7.20(d,J＝

1.6Hz,1H),5.28(br s,2H),4.71–4.62(m,1H),2.74(s,3H),2.41–2.23(m,2H),2.23–2.10(m,2H),2.07–1.86(m,4H).

And step 3: preparation of N- (5- (2-amino-8- ((4, 4-difluorocyclohexyl) oxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (17)

Compound (17) was prepared from compound (J-17) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.28(s,1H),8.43(d,J＝2.2Hz,1H),7.96(d,J＝2.2Hz,1H),7.76(dt,J＝8.4,6.6Hz,1H),7.69(d,J＝1.4Hz,1H),7.63–7.54(m,1H),7.50(d,J＝1.4Hz,1H),7.22(dt,J＝8.4,2.0Hz,1H),6.76(s,2H),4.97–4.88(m,1H),3.64(s,3H),2.76(s,3H),2.28–2.11(m,2H),2.08–1.81(m,6H)。

MS(ESI+)m/z 592.2[M+H]⁺。

Example 18: n- (5- (2-amino-8- ((4-methoxycyclohexyl) oxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (18)

Step 1: preparation of 6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -8- ((4-methoxycyclohexyl) oxy) -4-methylquinazoline (I-18)

Compound (I-18) is prepared from compound (H) and 4-methoxycyclohexan-1-ol according to the procedure of step 1 in example 1.

¹H NMR(400MHz,CDCl₃)δ8.01(d,J＝1.9Hz,1H),8.00(d,J＝1.9Hz,1H),7.64(d,J＝1.9Hz,1H),7.62(d,J＝1.8Hz,1H),5.85(s,2H),4.86–4.74(m,2H),3.36–3.26(m,2H),3.25(s,3H),3.24(s,3H),2.91(s,6H),2.36(s,6H),2.35(s,6H),2.08–1.84(m,6H),1.76–1.68(m,6H),1.65–1.54(m,2H),1.53–1.42(m,2H)。

Step 2: 6-bromo-8- ((4-methoxycyclohexyl) oxy) -4-methylquinazolin-2-amine (J-18)

Compound (J-18) is prepared from compound (I-18) according to the procedure in step 2 of example 1. Two new spots of similar polarity are obtained.

The point where the polarity is smaller:

¹H NMR(400MHz,DMSO-d₆)δ7.65(d,J＝1.8Hz,1H),7.29(d,J＝1.8Hz,1H),6.82(s,2H),4.62–4.52(m,1H),3.29–3.20(m,4H),2.65(s,3H),2.08–1.95(m,4H),1.57–1.30(m,4H)。

MS(ESI+)m/z 366.1[M+H]⁺。

the more polar point:

¹H NMR(400MHz,DMSO-d₆)δ7.65(d,J＝2.0Hz,1H),7.27(d,J＝2.0Hz,1H),6.80(s,2H),4.71–4.54(m,1H),3.36–3.32(m,1H),3.24(s,3H),2.65(s,3H),1.86–1.54(m,8H)。

MS(ESI+)m/z 366.1[M+H]⁺。

and step 3: n- (5- (2-amino-8- ((4-methoxycyclohexyl) oxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (18)

Compound 18-1: prepared from the less polar product spot in step 2, following the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.28(s,1H),8.43(d,J＝2.2Hz,1H),7.95(d,J＝2.2Hz,1H),7.75(dt,J＝8.6,6.4Hz,1H),7.64(s,1H),7.62–7.55(m,1H),7.41(s,1H),7.22(dt,J＝8.4,2.4Hz,1H),6.77(s,2H),4.76–4.65(m,1H),3.64(s,3H),3.28–3.22(m,4H),2.75(s,3H),2.12–1.30(m,4H),1.60–1.30(m,4H)。

MS(ESI+)m/z 586.2[M+H]⁺. Compound 18-2: prepared from the more polar product site of step 2, following the procedure of step 3 of example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.28(s,1H),8.42(d,J＝2.2Hz,1H),7.93(d,J＝2.2Hz,1H),7.76(dt,J＝8.4,6.4Hz,1H),7.64(s,1H),7.63–7.54(m,1H),7.38(s,1H),7.22(dt,J＝8.4,2.4Hz,1H),6.74(s,2H),4.83–4.67(m,1H),3.65(s,3H),3.38–3.28(m,1H),3.25(s,3H),2.75(s,3H),1.88–1.70(m,6H),1.69–1.55(m,2H)。

MS(ESI+)m/z 586.2[M+H]⁺。

Example 19: n- (5- (2-amino-8- ((2, 2-dimethyltetrahydro-2H-pyran-4-yl) oxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (19)

Step 1: preparation of 6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -8- ((2, 2-dimethyltetrahydro-2H-pyran-4-yl) oxy) -4-methylquinazoline (I-19)

Compound (I-19) was prepared from compound (H) and 2, 2-dimethyltetrahydro-2H-pyran-4-ol according to the procedure in step 1 of example 1.

¹H NMR(400MHz,CDCl₃)δ7.81(d,J＝1.9Hz,1H),7.29(d,J＝1.9Hz,1H),4.85–4.76(m,1H),4.03–3.95(m,1H),3.80–3.70(m,1H),2.91(s,3H),2.44(s,6H),2.17–2.08(m,1H),2.08–1.99(m,1H) 1.92-1.75 (m,2H),1.34(s,3H),1.28(s, 3H). Step 2: preparation of 6-bromo-8- ((2, 2-dimethyltetrahydro-2H-pyran-4-yl) oxy) -4-methylquinazolin-2-amine (J-19)

Compound (J-19) is prepared from compound (I-19) according to the procedure in step 2 of example 1.

¹H NMR(500MHz,DMSO-d₆)δ7.67(d,J＝1.5Hz,1H),7.36(d,J＝1.5Hz,1H),6.83(s,2H),4.95–4.84(m,1H),3.80–3.61(m,2H),2.66(s,3H),2.06–1.94(m,2H),1.54–1.39(m,2H),1.24(s,3H),1.21(s,3H)。

And step 3: preparation of N- (5- (2-amino-8- ((2, 2-dimethyltetrahydro-2H-pyran-4-yl) oxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (19)

Compound (19) was prepared from compound (J-19) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.29(s,1H),8.44(d,J＝2.3Hz,1H),7.96(d,J＝2.3Hz,1H),7.76(dt,J＝8.6,6.4Hz,1H),7.65(d,J＝1.6Hz,1H),7.63–7.54(m,1H),7.44(d,J＝1.6Hz,1H),7.22(dt,J＝8.4,2.4Hz,1H),6.78(s,2H),5.08–4.93(m,1H),3.82–3.66(m,2H),3.65(s,3H),2.75(s,3H),2.13–1.93(m,2H),1.59–1.41(m,2H),1.25(s,3H),1.22(s,3H)。

MS(ESI+)m/z 586.2[M+H]⁺。

Example 20: n- (5- (2-amino-4-methyl-8- ((tetrahydrofuran-2-yl) methoxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (20)

Step 1: preparation of 6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methyl-8- ((tetrahydrofuran-2-yl) methoxy) quinazoline (I-20)

Compound (I-20) was prepared from compound (H) and tetrahydrofurfuryl alcohol according to the method of step 1 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ8.03(d,J＝1.8Hz,1H),7.58(d,J＝1.8Hz,1H),5.85(s,2H),4.32–4.14(m,3H),3.86–3.77(m,1H),3.74–3.66(m,1H),2.92(s,3H),2.34(s,6H),2.10–1.91(m,2H),1.90–1.77(m,2H)。

Step 2: preparation of 6-bromo-4-methyl-8- ((tetrahydrofuran-2-yl) methoxy) quinazolin-2-amine (J-20)

Compound (J-20) is prepared from compound (I-20) according to the method of step 2 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ7.66(d,J＝2.0Hz,1H),7.24(d,J＝2.0Hz,1H),6.91(s,2H),4.28–4.18(m,1H),4.11–3.98(m,2H),3.87–3.75(m,1H),3.6673–3.66(m,1H),2.66(s,3H),2.08–1.97(m,1H),1.97–1.77(m,2H),1.74–1.62(m,1H)。

And step 3: preparation of N- (5- (2-amino-4-methyl-8- ((tetrahydrofuran-2-yl) methoxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (20)

Compound (20) was prepared from compound (J-20) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.28(s,1H),8.45(d,J＝2.3Hz,1H),7.97(d,J＝2.3Hz,1H),7.76(dt,J＝8.6,6.4Hz,1H),7.65(d,J＝1.6Hz,1H),7.63–7.55(m,1H),7.37(d,J＝1.6Hz,1H),7.22(dt,J＝8.4,2.0Hz,1H),6.85(s,2H),4.32–4.22(m,1H),4.20–4.08(m,2H),3.87–3.79(m,1H),3.71(dt,J＝7.6,6.4Hz,1H),3.64(s,3H),2.75(s,3H),2.11–2.00(m,1H),2.00–1.80(m,2H),1.78–1.67(m,1H)。

MS(ESI+)m/z 558.2[M+H]⁺。

Example 21: n- (5- (2-amino-4-methyl-8- ((tetrahydrofuran-3-yl) methoxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (21)

Step 1: preparation of 6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methyl-8- ((tetrahydrofuran-3-yl) methoxy) quinazoline (I-21)

Compound (I-21) was prepared from compound (H) and (tetrahydrofuran-3-yl) methanol according to the procedure of step 1 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ8.03(d,J＝1.6Hz,1H),7.58(d,J＝1.6Hz,1H),5.85(s,2H),4.23–4.08(m,2H),3.88–3.75(m,2H),3.69(dd,J＝14.8,7.6Hz,1H),3.62(dd,J＝8.6,5.6Hz,1H),2.92(s,3H),2.84–2.71(m,1H),2.35(s,6H),2.12–2.00(m,1H),1.81–1.70(m,1H)。

Step 2: preparation of 6-bromo-4-methyl-8- ((tetrahydrofuran-3-yl) methoxy) quinazolin-2-amine (J-21)

Compound (J-21) is prepared from compound (I-21) according to the method of step 2 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ7.67(d,J＝2.0Hz,1H),7.26(d,J＝2.0Hz,1H),6.86(s,2H),4.08–3.95(m,2H),3.84–3.74(m,2H),3.67(dt,J＝8.0,6.6Hz,1H),3.59(dd,J＝8.6,5.0Hz,1H),2.78–2.68(m,1H),2.66(s,3H),2.09–1.98(m,1H),1.75–1.65(m,1H)。

And step 3: preparation of N- (5- (2-amino-4-methyl-8- ((tetrahydrofuran-3-yl) methoxy) quinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (21)

Compound (21) was prepared from compound (J-21) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.27(s,1H),8.45(d,J＝2.2Hz,1H),7.97(d,J＝2.2Hz,1H),7.75(dt,J＝8.4,6.4Hz,1H),7.66(d,J＝1.2Hz,1H),7.63–7.54(m,1H),7.38(d,J＝1.2Hz,1H),7.21(dt,J＝8.4,2.2Hz,1H),6.80(s,2H),4.19–4.03(m,2H),3.85–3.77(m,2H),3.73–3.60(m,5H),2.85–2.70(m,4H),2.12–1.99(m,1H),1.79–1.69(m,1H)。

MS(ESI+)m/z 558.2[M+H]⁺。

Example 22: n- (5- (2-amino-8- (cyclohexyloxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (22)

Step 1: preparation of 6-bromo-8- (cyclohexyloxy) -2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methyl-quinazoline (I-22)

A reaction mixture of compound (H) (1.661g, 5mmol), cyclohexyl bromide (8.15g, 50mmol) and potassium carbonate (6.91g, 50mmol) in acetonitrile (40mL) was refluxed overnight in a sealed tube. The resulting mixture was cooled to room temperature and then filtered. Silica gel (5g) was added to the filtrate, and the resultant mixture was evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, PE/EtOAc ═ 100:1, v/v) to give the product (I-22) as a yellow oil (1.7g, 82% yield).

¹H NMR(500MHz,DMSO-d₆)δ8.00(d,J＝2.0Hz,1H),7.61(d,J＝2.0Hz,1H),5.85(s,2H),4.79–4.72(m,1H),2.91(s,3H),2.35(s,6H),1.95–1.86(m,2H),1.79–1.70(m,2H),1.69–1.57(m,2H),1.56–1.31(m,4H)。

Step 2: preparation of 6-bromo-8- (cyclohexyloxy) -4-methyl-quinazolin-2-amine (J-22)

Compound (J-22) is prepared from compound (I-22) according to the method of step 2 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ7.64(d,J＝2.0Hz,1H),7.25(d,J＝2.0Hz,1H),6.83(s,2H),4.58–4.45(m,1H),2.65(s,3H),2.04–1.95(m,2H),1.82–1.67(m,2H),1.65–1.27(m,6H)。

And step 3: preparation of N- (5- (2-amino-8- (cyclohexyloxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (22)

Compound (22) was prepared from compound (J-22) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.28(s,1H),8.42(d,J＝2.3Hz,1H),7.93(d,J＝2.3Hz,1H),7.76(dt,J＝8.4,6.4Hz,1H),7.63(d,J＝1.6Hz,1H),7.62–7.56(m,1H),7.36(d,J＝1.4Hz,1H),7.22(dt,J＝8.4,2.0Hz,1H),6.76(s,2H),4.70–4.60(m,1H),3.65(s,3H),2.74(s,3H),2.09–1.97(m,2H),1.85–1.71(m,2H),1.66–1.30(m,6H)。

MS(ESI+)m/z 556.2[M+H]⁺。

Example 23: n- (5- (2-amino-8- (cyclopentyloxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (23)

Step 1: preparation of 6-bromo-8- (cyclopentyloxy) -2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methyl-quinazoline (I-23)

Compound (I-23) was prepared from compound (H) and cyclopentyl bromide following the procedure of step 1 in example 22.

¹H NMR(500MHz,DMSO-d₆)δ8.00(d,J＝1.5Hz,1H),7.53(d,J＝1.5Hz,1H),5.85(s,2H),5.18–5.09(m,1H),2.91(s,3H),2.34(s,6H),2.03–1.92(m,2H),1.89–1.80(m,2H),1.80–1.70(m,2H),1.69–1.58(m,2H)。

Step 2: preparation of 6-bromo-8- (cyclopentyloxy) -4-methyl-quinazolin-2-amine (J-23)

Compound (J-23) is prepared from compound (I-23) according to the method of step 2 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ7.64(d,J＝2.0Hz,1H),7.16(d,J＝2.0Hz,1H),6.83(s,2H),5.00–4.94(m,1H),2.65(s,3H),2.04–1.91(m,2H),1.80–1.68(m,4H),1.66–1.53(m,2H)。

And step 3: preparation of N- (5- (2-amino-8- (cyclopentyloxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (23)

Compound (23) was prepared from compound (J-23) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.30(s,1H),8.43(d,J＝2.4Hz,1H),7.93(d,J＝2.4Hz,1H),7.77(dt,J＝8.4,6.4Hz,1H),7.63(d,J＝1.8Hz,1H),7.63–7.56(m,1H),7.27(d,J＝1.6Hz,1H),7.22(dt,J＝8.4,2.2Hz,1H),6.79(s,2H),5.14–5.08(m,1H),3.66(s,3H),2.75(s,3H),2.10–1.93(m,2H),1.88–1.69(m,4H),1.69–1.51(m,2H)。

MS(ESI+)m/z 542.2[M+H]⁺。

Example 24: n- (5- (2-amino-8-cyclobutoxy-4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (24)

Step 1: preparation of 6-bromo-8-cyclobutoxy-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methyl-quinazoline (I-24)

Compound (I-24) was prepared from compound (H) and cyclobutylbromide according to the procedure in step 1 of example 22.

¹H NMR(400MHz,DMSO-d₆)δ8.02(d,J＝1.9Hz,1H),7.35(d,J＝1.9Hz,1H),5.85(s,2H),4.98(p,J＝7.0Hz,1H),2.91(s,3H),2.60–2.51(m,2H),2.33(s,6H),2.19–2.05(m,2H),1.92–1.77(m,1H),1.77–1.64(m,1H)。

Step 2: preparation of 6-bromo-8-cyclobutoxy-4-methylquinazolin-2-amine (J-24)

Compound (J-24) is prepared from compound (I-24) according to the procedure in step 2 of example 1.

¹H NMR(400MHz,DMSO-d₆)δ7.65(d,J＝2.0Hz,1H),7.00(d,J＝2.0Hz,1H),6.89(s,2H),4.81(p,J＝7.0Hz,1H),2.65(s,3H),2.49–2.42(m,2H),2.16–2.00(m,2H),1.89–1.57(m,2H).

And step 3: preparation of N- (5- (2-amino-8-cyclobutoxy-4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (24)

Compound (24) was prepared from compound (J-24) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.30(s,1H),8.42(d,J＝2.3Hz,1H),7.92(d,J＝2.3Hz,1H),7.77(dt,J＝8.6,6.4Hz,1H),7.64(d,J＝1.6Hz,1H),7.63–7.55(m,1H),7.23(dt,J＝8.6,2.4Hz,1H),7.12(d,J＝1.6Hz,1H),6.84(s,2H),4.94(p,J＝7.2Hz,1H),3.66(s,3H),2.75(s,3H),2.55–2.46(m,2H),2.19–2.06(m,2H),1.89–1.62(m,2H)。

MS(ESI+)m/z 528.1[M+H]⁺。

Example 25: preparation of N- (5- (2-amino-8- (2-methoxyethoxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (25)

Step 1: preparation of 6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -8- (2-methoxyethoxy) -4-methyl-quinazoline (I-25)

Compound (I-25) is prepared from compound (H) and 2-chloroethylmethyl ether according to the procedure in step 1 of example 22.

¹H NMR(400MHz,DMSO-d₆)δ7.80(d,J＝1.9Hz,1H),7.31(d,J＝1.9Hz,1H),5.90(s,2H),4.33(t J＝4.8Hz,2H),3.90(t,J＝4.8Hz,3H),3.48(s,3H),2.91(s,3H),2.43(s,6H)。

Step 2: preparation of 6-bromo-8- (2-methoxyethoxy) -4-methyl quinazolin-2-amine (J-25)

Compound (J-25) is prepared from compound (I-25) according to the method of step 2 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ7.67(d,J＝1.8Hz,1H),7.23(d,J＝1.8Hz,1H),6.90(s,2H),4.21(t,J＝4.4Hz,2H),3.90(t,J＝4.4Hz,3H),3.32(s,3H),2.66(s,3H)。

And step 3: preparation of N- (5- (2-amino-8- (2-methoxyethoxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (25)

Compound (25) was prepared from compound (J-25) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.32(br s,1H),8.43(s,1H),7.95(s,1H),7.76(dt,J＝8.5,6.6Hz,1H),7.64(d,J＝1.4Hz,1H),7.63–7.55(m,1H),7.34(d,J＝1.4Hz,1H),7.22(dt,J＝8.4,2.4Hz,1H),6.87(s,2H),4.35–4.28(m,2H),3.79–3.73(m,2H),3.64(s,3H),3.35(s,3H),2.75(s,3H)。

MS(ESI+)m/z 532.1[M+H]⁺。

Example 26: n- (5- (2-amino-8-isopropoxy-4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (26)

Step 1: preparation of 6-bromo-2- (2, 5-dimethyl-1H-pyrrol-1-yl) -8-isopropoxy-4-methyl-quinazoline (I-26)

Compound (I-26) was prepared from compound (H) and isopropyl bromide according to the method of step 1 in example 22.

¹H NMR(400MHz,DMSO-d₆)δ8.02(d,J＝1.8Hz,1H),7.59(d,J＝1.8Hz,1H),5.85(s,2H),4.98–4.88(m,1H),2.92(s,3H),2.34(s,6H),1.36(d,J＝6.0Hz,6H)。

Step 2: preparation of 6-bromo-8-isopropoxy-4-methylquinazolin-2-amine (J-26)

Compound (J-26) is prepared from compound (I-26) according to the procedure in step 2 of example 22.

¹H NMR(400MHz,DMSO-d₆)δ7.64(d,J＝2.0Hz,1H),7.22(d,J＝2.0Hz,1H),6.84(s,2H),4.86–4.75(m,1H),2.65(s,3H),1.31(d,J＝6.0Hz,6H)。

And step 3: preparation of N- (5- (2-amino-8-isopropoxy-4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (26)

Compound (26) was prepared from compound (J-26) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.30(s,1H),8.44(d,J＝2.3Hz,1H),7.94(d,J＝2.3Hz,1H),7.76(dt,J＝8.6,6.4Hz,1H),7.64(d,J＝1.6Hz,1H),7.63–7.56(m,1H),7.33(s,1H),7.22(dt,J＝8.4,2.0Hz,1H),6.83(s,2H),5.00–4.89(m,1H),3.64(s,3H),2.75(s,3H),1.34(d,J＝6.0Hz,6H)。

MS(ESI+)m/z 516.1[M+H]⁺。

Example 27: n- (5- (2-amino-8- (cyclopropylmethoxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (27)

Step 1: preparation of 6-bromo-8- (cyclopropylmethoxy) -2- (2, 5-dimethyl-1H-pyrrol-1-yl) -4-methyl-quinazoline (I-27)

Compound (I-27) was prepared from compound (H) and cyclopropylmethyl bromide following the procedure of step 1 in example 22.

¹H NMR(400MHz,DMSO-d₆)δ7.64(d,J＝1.8Hz,1H),7.14(d,J＝1.8Hz,1H),6.91(s,2H),3.90(d,J＝7.2Hz,2H),2.65(s,3H),1.33–1.23(m,1H),0.65–0.55(m,2H),0.35(q,J＝4.8Hz,2H)。

Step 2: preparation of 6-bromo-8- (cyclopropylmethoxy) -4-methylquinazolin-2-amine (J-27)

Compound (J-27) is prepared from compound (I-27) according to the procedure in step 2 of example 22.

And step 3: preparation of N- (5- (2-amino-8- (cyclopropylmethoxy) -4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (27)

Compound (27) was prepared from compound (J-27) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the method of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.27(s,1H),8.43(d,J＝2.2Hz,1H),7.94(d,J＝2.2Hz,1H),7.75(dt,J＝8.6,6.4Hz,1H),7.63(d,J＝1.6Hz,1H),7.62–7.55(m,1H),7.27(d,J＝1.6Hz,1H),7.24–7.18(m,1H),6.85(br s,2H),4.00(d,J＝7.0Hz,2H),3.63(s,3H),2.75(s,3H),1.37–1.27(m,1H),0.67–0.57(m,2H),0.40–0.33(m,2H)。

MS(ESI+)m/z 528.1[M+H]⁺。

Example 28: preparation of N- (5- (2-amino-8-methoxy-4-methylquinazolin-6-yl) -2-methoxypyridin-3-yl) -2, 4-difluorobenzenesulfonamide (28)

Compound (28) was prepared from compound (F) and N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide according to the procedure of step 3 in example 1.

¹H NMR(400MHz,DMSO-d₆)δ10.28(s,1H),8.46(d,J＝2.4Hz,1H),7.97(d,J＝2.4Hz,1H),7.76(dt,J＝8.6,6.4Hz,1H),7.65(d,J＝1.7Hz,1H),7.63–7.55(m,1H),7.31(d,J＝1.7Hz,1H),7.26–7.18(m,1H),6.83(s,2H),3.95(s,3H),3.64(s,3H),2.76(s,3H)。

MS(ESI+)m/z 488.1[M+H]⁺。

Evaluation of pharmacological Activity

Example 29: biochemical detection of PI3K alpha Activity

The potency of the compounds of the invention against PI3K a was evaluated using an in vitro kinase assay. The kinase activity of PI3K- α was determined by measuring the level of ADP produced in the kinase reaction using luciferase-based luminescence assays. Kinase-Glo^TMThe kinase assay kit was purchased from Promega. All assays were performed at room temperature using OptiPlate^TM384 white 384 well plates. PI3K alpha kinase was from Invitrogen. The substrate was PIP2 (Invitrogen). The kinase buffer included 50mM Hepes (pH 7.5), 3mM MgCl₂100mM NaCl, 1mM EGTA, 0.03% CHAPS and 2mM DTT. PI3K α kinase solution was prepared by diluting PI3K α kinase to 6.6nM in kinase buffer. The substrate solution comprised 100 μ M PIP2 and 50 μ M ATP. Test compounds were diluted to 10mM in 100% DMSO and then serially diluted 3-fold in 100% DMSO to 10 different concentrations. Compounds diluted in 100% DMSO were then diluted 25-fold in 1 × kinase buffer. mu.L of the diluted compound solution and 2.5. mu.L of PI 3K. alpha. kinase solution were added to each well of a 384-well plate. The reaction was started by adding 5. mu.L of substrate solution per well, with a final reaction volume of 10. mu.L, an ATP concentration of 25. mu.M, a PIP2 concentration of 50. mu.M, and a PI 3K. alpha. kinase concentration of 1.65 nM. The plate was covered and the reaction was allowed to proceed at room temperature for 1 hour, followed by addition of 10. mu.L of Kinase Kinase-Glo per well^TMThe reagent terminates the reaction. The plates were incubated for 15 minutes and the luminescence was subsequently read on an EnVision 2104 multi-label microplate detector reader.

Percent inhibition was calculated based on the following equation:

inhibition [% 100- (max-sample RLU)/(max-min) [% 100 ].

Where sample RLU is the luminescence reading at a given compound concentration, min is the reading for the DMSO control, and max is the reading for the no enzyme live control. IC of compound was calculated by using XLFit program in Excel₅₀The results are shown in Table 1.

Table 1: PI3K alpha kinase inhibitory Activity

Example 30: determination of tumor cell survival by MTT method

Digesting human lung cancer cells NCI-H460 in logarithmic growth phase with 0.25% pancreatin-EDTA to prepare single cell suspension with a certain concentration, inoculating the single cell suspension into a 96-well plate according to 1200 cells/well, adding 100 mu L of each well, adding fresh culture medium with different concentrations of compounds to be detected and corresponding solvent control after 24 hours, and adding 100 mu L of each well (DMSO final concentration is 100 mu L)<0.2%) for each test compound, 6-9 concentration groups were set, each group having three parallel wells. At 5% CO₂Continuously culturing for 96h at 37 ℃, adding 20 mu L of freshly prepared PBS (phosphate buffer solution) containing 5mg/mL MTT into each hole, continuously culturing for 4h, removing supernatant, adding 150 mu L of DMSO into each hole to dissolve MTT formazan precipitate, uniformly shaking by a micro-oscillator, measuring Optical Density (OD) value under the condition of 570nm wavelength, taking tumor cells treated by the DMSO solvent as a control group, calculating the inhibition rate of the compound to be detected on the growth of the tumor cells by the following formula, and calculating IC (integrated Circuit) through SPSS16.0₅₀：

Inhibition ratio (%) ═ (OD)_Control－OD_{Compound (I)})/OD_Control×100％

Wherein, OD_ControlThe average OD value, OD, of the control group_ControlIs the average OD value at a given compound concentration.

The results are shown in Table 2.

Table 2: antiproliferative activity on human lung cancer cell NCI-H460

Example 31: study on xenograft efficacy of nude mice

Collecting human lung cancer NCI-H460 tumor cells under aseptic condition, adjusting cell density to 1 × 10 with sterilized normal saline⁶Taking 0.2ml per ml, inoculating to the subcutaneous layer of the axillary back of the nude mouse, taking out under aseptic condition when the tumor grows to the size of 1cm in diameter, cutting into tumor blocks of 1mm multiplied by 1mm, and uniformly inoculating to the subcutaneous layer of the axillary back of the nude mouse. 6 days later, the tumor grows to 100-300 mm³Thereafter, animals were randomized and dosing was initiated (day 1). The test compounds were administered orally daily. Body weights were weighed twice weekly and tumor lengths and widths were measured with a vernier caliper, nude mice were dislocated and sacrificed 16 days after dosing, tumor tissues were stripped, weighed and photographed. Finally, the tumor inhibition rate is calculated, and the anti-tumor effect strength is evaluated according to the tumor inhibition rate, and the result is shown in table 3 and fig. 1.

Tumor volume was calculated according to the following formula:

tumor volume ═ a × b²) And/2, a and b represent tumor body length and width, respectively.

The percent tumor growth inhibition was calculated according to the following formula:

tumor growth inhibition (%) - (1-T/C) × 100, T being the final tumor volume of the test compound group, C being the final tumor volume of the solvent control group.

TABLE 3 example 9 growth inhibition of human lung carcinoma NCI-H460 in nude mice subcutaneous xenograft tumors

Summary of pharmacological activity:

all examples showed strong inhibitory activity against PI3K alpha kinase, IC₅₀Values were all less than 6 nM. All examples show strong antiproliferative activity on human lung carcinoma cells NCI-H460, IC₅₀All values are less than 3. mu.M. Among them, example 9 has a significant inhibitory effect on the growth of human lung cancer NCI-H460 in nude mouse subcutaneous xenograft tumors.

Claims

1. A compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

wherein

L is selected from a single bond or C_1-3An alkylene group;

R₁is composed of

Ring A is selected from cyclobutyl, cyclopentyl, cyclohexyl or the following 4-6 membered oxacycloalkyl:

R₄is selected from C_1-3Alkyl, halogen or C_1-3An alkoxy group;

m is 0, 1,2,3 or 4; when m is 2,3 or 4, R₄May be the same or different groups;

R₂is OMe;

R₃selected from phenyl or thienyl, optionally substituted with one or more halogens.

2. A compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein L is selected from one single bond or methylene.

3. According to claim 1The compound, a stereoisomer or pharmaceutically acceptable salt thereof, wherein R₃Selected from phenyl or thienyl, wherein said phenyl and thienyl are optionally substituted with one or more fluoro or chloro.

4. A compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from:

5. a pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4, a stereoisomer or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and/or excipient.

6. The pharmaceutical composition of claim 5, further comprising a pharmaceutically active ingredient other than the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof.

7. Use of a compound according to any one of claims 1-4, a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5 or 6, for the manufacture of a medicament for the prevention and/or treatment of a PI 3K-mediated disease.

8. Use of a compound according to any one of claims 1-4, a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5 or 6, for the manufacture of a medicament for the prevention and/or treatment of cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders, or neurological disorders.