CN108239076A - Quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition - Google Patents

Abstract

The invention relates to quinazoline compounds, their preparation method, application and pharmaceutical composition. The quinazoline compound is represented by formula (I), which is a phosphatidylinositol 3-kinase (PI3K) inhibitor, and can be used to prevent and/or treat diseases related to PI3K activity, such as cancer, immune disease, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, or neurological disease.

Description

Quinazoline compounds and their preparation method, use and pharmaceutical composition

technical field

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

Background technique

Phosphatidylinositol 3-kinase (PI3K) belongs to the lipid kinase family and participates in various functions such as cell proliferation, differentiation, apoptosis and glucose transport. PI3Ks are classified into three major classes (I, II, and III) according to their structure, regulation, and lipid substrate specificity. At present, the most in-depth research is class I PI3K, which is composed of regulatory subunit (p85) and catalytic subunit (p110), and is a heterodimer. Class I PI3K includes four subtypes, of which two subtypes, PI3Kα and PI3Kβ, are widely present in various types of 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 activates serine/threonine protein kinase (protein kinase B, AKT) and other downstream effectors by generating Phospholipids that transduce signals from various growth factors and cytokines into cells. Abnormal/overactive signaling pathways mediated by PI3K are associated with various diseases. For example, PI3K plays a key role in the occurrence and development of tumors, especially the gene PIK3CA encoding p110α is found in most tumors such as breast cancer, lung cancer, colon cancer, ovarian cancer, head and neck cancer, gastric cancer, prostate cancer, Brain cancer, liver cancer, digestive tract tumors, and leukemia have a large number of amplifications and mutations (Zhao et al., Nat. Drug Discov. Rev. 2009, 8:627-644). In 2014, the FDA approved the PI3Kδ inhibitor Idelalisib (Gilead) for the treatment of chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL). Some PI3K inhibitors are undergoing anti-tumor clinical trials, such as BKM120 (Novartis, Phase III), BAY 80-6946 (Bayer, Phase III), PF-05212384 (Pfizer, Phase II) and so on. In addition to tumors, class I PI3Ks also play important regulatory roles in inflammation, immune diseases, cardiovascular diseases, viral infections, metabolic/endocrine dysfunction, and neurological diseases. Some compounds such as GSK2269557 (chronic obstructive pulmonary disease, clinical phase II), GSK2126458 (idiopathic pulmonary fibrosis, clinical phase I), UCB-5857 (primary Sjögren's syndrome, clinical phase II) and RV-1729 (chronic obstructive pulmonary disease, clinical phase I) have entered clinical trials for these diseases experimental stage.

PI3K has become a very attractive drug target, but there is still 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 disease.

Contents of the invention

The purpose of the present invention is to provide a new PI3K inhibitor, which has strong inhibitory activity on class I PI3K, including PI3Kα, PI3Kβ, PI3Kγ and/or PI3Kδ, especially PI3Kα, so as to treat diseases mediated by PI3K, Such as cancer, immune disease, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction or neurological disease have better preventive and/or therapeutic effects.

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

in

R ₁ is C _1-3 alkyl;

L is selected from a single bond or C _1-3 alkylene, wherein said C _1-3 alkylene is optionally substituted by one or more R;

Ra is selected from halogen or C _1-3 alkyl;

R ₂ is selected from hydrogen, C _1-3 alkyl, C _1-3 alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, wherein said C _1-3 alkyl, C _{1 -3} alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl are optionally substituted by one or more Rb;

Rb is selected from halogen, cyano, hydroxyl, trifluoromethyl, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _1-3 alkylamino or two (C _{1 -3} alkyl) amino;

R ₃ is selected from C _1-3 alkoxy, halogen or C _1-3 alkyl;

_R is selected from C _1-3 alkyl, 3-7 membered cycloalkyl, aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more groups selected from : Halogen, C _1-3 alkyl, amino, C _1-3 alkylamino, di(C _1-3 alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C _1-3 alkoxy base.

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

in

R ₁ is C _1-3 alkyl;

L is selected from a single bond or C _1-3 alkylene, wherein said C _1-3 alkylene is optionally substituted by one or more R;

Ra is selected from halogen or C _1-3 alkyl;

_R is selected from methoxy, chlorine or methyl;

_R is selected from C _1-3 alkyl, 3-7 membered cycloalkyl, phenyl or thienyl, wherein the phenyl and thienyl are optionally substituted by one or more groups selected from the group consisting of: halogen , C _1-3 alkyl, amino, C _1-3 alkylamino, di(C _1-3 alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C _1-3 alkoxy;

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

R ₅ is selected from C _1-3 alkyl, halogen, cyano, trifluoromethyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _1-3 alkylamino or two (C _{1-3 3} alkyl) amino;

m is 0, 1, 2, 3 or 4; when m is 2, 3 or 4, R ₅ may be the same or different groups.

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

in

R ₁ is methyl;

L is selected from a single bond or C _1-3 alkylene, wherein said C _1-3 alkylene is optionally substituted by one or more R;

Ra is selected from halogen or C _1-3 alkyl;

R ₃ is methoxy;

_R is selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally substituted by one or more groups selected from the group consisting of halogen, C _1-3 alkyl, amino, C _1-3 alkane Amino, two (C _1-3 alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C _1-3 alkoxy;

Ring A is a 3-7 membered cycloalkyl group;

R ₅ is selected from C _1-3 alkyl, halogen, cyano, trifluoromethyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _1-3 alkylamino or two (C _{1-3 3} alkyl) amino;

m is 0, 1, 2, 3 or 4; when m is 2, 3 or 4, R ₅ may be the same or different groups.

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

in

R ₁ is methyl;

L is selected from a single bond or C _1-3 alkylene, wherein said C _1-3 alkylene is optionally substituted by one or more R;

Ra is selected from halogen or C _1-3 alkyl;

R ₃ is methoxy;

_R is selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally substituted by one or more groups selected from the group consisting of halogen, C _1-3 alkyl, amino, C _1-3 alkane Amino, two (C _1-3 alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C _1-3 alkoxy;

Ring A is a 3-7 membered heterocycloalkyl group;

R ₅ is selected from C _1-3 alkyl, halogen, cyano, trifluoromethyl, C _1-3 alkoxy, C _1-3 alkylhydroxyl, C _1-3 alkylamino or two (C _{1-3 3} alkyl) amino;

m is 0, 1, 2, 3 or 4; when m is 2, 3 or 4, R ₅ may be the same or different groups.

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

in

R ₁ is methyl;

L is selected from a single bond or C _1-3 alkylene, wherein said C _1-3 alkylene is optionally substituted by one or more R;

Ra is selected from halogen or C _1-3 alkyl;

R ₃ is methoxy;

_R is selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally substituted by one or more groups selected from the group consisting of halogen, C _1-3 alkyl, amino, C _1-3 alkane Amino, two (C _1-3 alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C _1-3 alkoxy;

Ring A is selected from:

R ₅ is selected from C _1-3 alkyl, halogen, cyano, trifluoromethyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _1-3 alkylamino or two (C _{1-3 3} alkyl) amino;

m is 0, 1, 2, 3 or 4; when m is 2, 3 or 4, R ₅ may be the same or different groups.

Specifically, preferred compounds according to the invention are as follows:

On the other hand, the present invention also provides the preparation method of said compound, its stereoisomer, geometric isomer, tautomer, which comprises the following steps:

(1) Using compound A as the starting material, prepare compound B through bromination reaction;

(2) compound B reacts with triphosgene to obtain compound C;

(3) compound C was reacted with N,O-dimethylhydroxylamine hydrochloride to prepare compound D;

(4) Obtain compound E by attacking compound D by methylmagnesium bromide;

(5) Compound E reacts with ammonium formate and formamide to obtain compound F with quinazoline skeleton;

(6) Compound F reacts with aluminum trichloride to demethylate to obtain general intermediate G;

(7) Mitsunobu reaction between intermediate G and alcohol, or reaction with halogenated compound to obtain compound H;

(8) Under Suzuki reaction conditions, compound H is coupled with substituted pyridine-3-boronic acid pinacol ester to obtain the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically Acceptable salt; or compound H reacts with biboronic acid pinacol ester to obtain corresponding boric acid pinacol ester, which is then coupled with substituted 3-bromopyridine to obtain the compound, its stereoisomer, geometric isomer isomers, tautomers or pharmaceutically acceptable salts.

In another aspect, the present invention also provides a pharmaceutical composition, which comprises the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, and Optional pharmaceutically acceptable carrier and/or excipient; Preferably, the pharmaceutical composition also comprises the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically One or more pharmaceutical active ingredients for the prevention and/or treatment of cancer, immune disease, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction or neurological disease other than acceptable salts; preferably, the The pharmaceutical composition is a pharmaceutically acceptable pharmaceutical preparation for preventing and/or treating cancer, immune disease, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction or neurological disease.

In another aspect, the present invention also provides a pharmaceutical preparation, which comprises at least one of the compounds, stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof and optionally A pharmaceutically acceptable carrier or/or excipient; Preferably, the pharmaceutical preparation is selected from the following pharmaceutical dosage forms: parenteral administration preparations, such as injection solutions or suspensions; enteral administration preparations, such as Oral formulations such as tablets or capsules; topical formulations such as lotions, gels, ointments, creams, nasal formulations, suppositories, transdermal formulations or ophthalmic formulations.

In another aspect, the present invention also provides the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition used for preventing and/or Or use in drugs for the treatment of cancer, immune disease, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction or neurological disease. In other words, the present invention provides a method for preventing and/or treating cancer, immune disease, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction or neurological disease, the method comprising administering prophylaxis to a subject in need And/or a therapeutically effective amount of the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition.

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

Halogen means fluorine, chlorine, bromine or iodine.

C _1-3 alkylene refers to a saturated linear or branched divalent hydrocarbon group having 1 to 3 carbon atoms. Examples _of such _groups include, but _are not limited to: methylene ( _-CH2- ), ethylene ( _-CH2CH2- ), propylene ( _-CH2CH2CH2- ).

C _1-3 alkyl refers to straight-chain 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.

A 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 bonds and or triple bonds in the ring) carbocyclic group having 3 to 7 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms for carbon. Specific examples of 3-7 membered saturated heterocycloalkyl groups include, but are not limited to: oxirane group, aziridine group, azetidinyl group, oxetanyl group, thietanyl group, Dihydrofuryl, tetrahydrofuryl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,4- Dioxanyl, 1,3-dioxanyl, 1,3-dithianyl, piperidinyl, morpholinyl, piperazinyl, dihydropyranyl, Tetrahydropyranyl, tetrahydrothiopyranyl, etc.; preferably oxetanyl, tetrahydrofuryl, tetrahydropyranyl, piperidyl, morpholinyl, piperazinyl.

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.

Aryl refers to a monocyclic or bicyclic aromatic carbocyclic group, usually having 6-10 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), thiazolyl Oxadiazolyl (1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl or 1,2,4-thiadiazolyl) and oxa 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, and bicyclic groups such as benzofuryl, benzothienyl, indazolyl, purinyl, quinolinyl, isoquinyl Linyl, phthalazinyl, naphthyridyl, quinoxalinyl (chinocalinyl), quinazolinyl, cinnolinyl, pteridinyl, indolyl, indolyl, isoindolyl. Preferred heteroaryl groups are thienyl, thiazolyl, pyridyl, pyrimidinyl.

A single bond means that the two groups it connects are directly connected. For example, when L in O-L-R represents a single bond, it means that the structure is actually O-R.

"Optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes 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 both cases where the alkyl is substituted by halogen and cases where the alkyl is not substituted by halogen.

If a group such as " _R5 " is depicted as "floating" on ring system A in the formula:

It is meant that " _R5 " is attributable to any atom of the ring system, provided that a stable structure is formed where a depicted, implied or explicitly defined hydrogen on one of the ring atoms is considered to be substituted.

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

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

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 tautomerizations.

The compounds described herein also include isotopically labeled compounds wherein one or more atoms are replaced by atoms of the same atomic number but different atomic mass or mass number found in nature. Examples include, but are not limited to: hydrogen isotopes ² H and ³ H; carbon isotopes ¹¹ C, ¹³ C ^{, and 14} C; chlorine isotope ³⁶ Cl; fluorine isotope ¹⁸ F; iodine isotopes ¹²³ I and ¹²⁵ I; ; oxygen isotopes ¹⁵ O, ¹⁷ O and ¹⁸ O; phosphorus isotope ³² P and sulfur isotope ³⁵ S.

Various hydrates and solvates of the compounds described in the present invention or salts thereof and polymorphisms thereof 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. Certain derivatives of the compounds described in the present invention have weak or no pharmacological activity themselves, but when these derivatives are given to the body or to the body, they can be converted into pharmacologically active compounds by, for example, hydrolytic cleavage, etc. Of the compounds described herein, 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 ) found in .

The compounds described in the present invention include their pharmaceutically acceptable salts. A pharmaceutically acceptable salt refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts are described in detail by Berge et al. 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 correspondingly react with some inorganic or organic bases, or inorganic and organic acids to form pharmaceutical acceptable salt. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, Hydrochloride, Hydrobromide, Hydroiodide, Acetate, Propionate, Caprate, Octanoate, Acrylate, Formate, Isobutyrate, Hexanoate, Heptanoate, Propiolate, Oxalate, Malonate, Succinate, Suberate, Sebacate, Fumarate, Maleate, Butyne-1,4-dioate, Hexamate Alkyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate , phthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, hydroxyethyl salt, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate.

When the compounds of the present invention are used as medicines, they are usually administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions of the compounds described in the present invention and pharmaceutically acceptable carriers, diluents or excipients are also included in the scope of the present invention. As used herein, carriers, adjuvants, vehicles include any and all solvents, diluents or other liquid vehicles, dispersing or suspending agents, surfactants, isotonic agents, Thickener or emulsifier, preservative, solid binder, lubricant, etc. In Remington: The Science and Practice of Pharmacy, ^21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, Various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed, the contents of which are incorporated herein by reference.

The compositions described herein may be administered by any route appropriate for the condition to be treated. In particular by administration in the following forms: parenterally, e.g. in the form of injectable solutions or suspensions; enterally, e.g. orally, e.g. in the form of tablets or capsules; topically, e.g. in lotions, gels, ointments Or in emulsion form or in nasal or suppository form. Topical application is, for example, application to the skin. Another form of topical administration is administration to the eye.

The pharmaceutical composition may be administered in solid, semi-solid, liquid or gaseous form, or may be in 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, papers, tablets, suppositories, pellets, pills, lozenges, 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 (such as human serum albumin), buffer substances (such as phosphate), Glycine, sorbic acid or potassium sorbate, mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal dioxide Silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (such as lactose, glucose, and sucrose), starches (such as cornstarch, 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 for suppositories Waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn and soybean oils; 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; agents such as sodium lauryl sulfate and magnesium stearate. Coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions, according to the judgment of the formulator.

The compounds described herein may be used alone or in combination with other therapeutic agents for the treatment of diseases or conditions described herein (eg, cancer). In certain embodiments, a compound described herein is combined in a pharmaceutical combination formulation, or administered as a combination therapy, with a second compound that has anti-hyperproliferative properties or is useful in the treatment of a hyperproliferative disease such as cancer. combined in the program. The second compound of the pharmaceutical combination or dosing regimen preferably has complementary activities to the compounds of the invention so that they do not adversely affect each other. Such compounds are suitably present in combination in amounts effective for the intended purpose. In one embodiment, the compounds of the invention are combined with other antineoplastic agents. The antineoplastic drugs include: alkylating agents, including but not limited to cyclophosphamide, nitrogen mustard, melphalan, cyclonine, carmustine; metal platinums, including but not limited to carboplatin, cisplatin, oxalate Liplatin; topoisomerase inhibitors, including but not limited to topotecan, camptothecin, topotecan, irinotecan; antibiotics, including but not limited to anicycline, actinomycin D, daunorin Mycin, doxorubicin, mitoxantrone, bleomycin, plicamycin; antimicrotubule or antimitotic agents, including but not limited to paclitaxel, vinorelbine, docetaxel, doxorubicin; Anti-metabolites, including but not limited to fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine; antibodies, including but not limited to Herceptin, 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, Sunitinib, Cabozantinib, Pazopanib, Vandetanib ), axitinib; ALK inhibitors, including but not limited to crizotinib, ceritinib, alectinib; Bcr-Abl inhibitors, including but not limited to imatinib (Imatinib), Ponatinib, Nilotinib, Dasatinib; BTK inhibitors, including but not limited to Ibrutinib; B-RAF inhibitors, Including but not limited to Vemurafenib; cyclin-dependent kinase CDK4/6 inhibitor, Palbociclib; mTOR inhibitors, including but not limited to rapamycin, Evidence Everolimus; sirtuin inhibitors, including but not limited to vorinostat; PD1/PDL1 antibodies, Keytruda (Pembrolizumab), Opdivo (Nivolumab).

Description of drawings

Figure 1 is a tumor growth curve, which shows the inhibitory effect of Example 1 on the growth of human lung cancer NCI-H460 in subcutaneous xenograft tumors in nude mice.

Detailed ways

The following are specific examples 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 examples. All 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.

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 diastereoisomers. Individual enantiomers/diastereomers may be obtained by methods known to those skilled in the art.

Preparation

The compounds described in the present invention can be synthesized according to the synthetic 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 synthetic methods.

Specifically, in the general synthesis method, the quinazoline compounds described in the present invention can be prepared through 8-step reactions. For example, starting material A is converted to compound B by bromination, which reacts with triphosgene to give compound C. Compound C was reacted with N,O-dimethylhydroxylamine hydrochloride to obtain compound D, which was attacked by methylmagnesium bromide to generate compound E. Compound E is reacted with ammonium formate and formamide to obtain compound F with quinazoline skeleton, which is then reacted with aluminum chloride to demethylate to obtain general intermediate G. Compound H is obtained by Mitsunobu reaction of intermediate G with various alcohols or with various halides. Compounds F and H are coupled with substituted pyridine-3-boronic acid pinacol esters under Suzuki reaction conditions known to those skilled in the art to afford compounds 1-30. Alternatively, compound H is reacted with pinacol diborate to give the corresponding pinacol arylboronate, which is then coupled with a substituted 3-bromopyridine to give the final product compound 1-30.

General Synthetic Method

Example

Preparation Example

The compounds described herein can be synthesized according to one or more of the synthetic schemes herein and/or techniques well known in the art. Those skilled in the art will recognize that the synthetic methods detailed in this disclosure for certain embodiments can be readily adapted for the synthesis of other embodiments. In some embodiments, the compounds described herein can 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 Co., Ltd., or are readily prepared using synthetic methods commonly used in the art.

¹ H NMR spectra were recorded on instruments operating at 400 MHz or 500 MHz. H NMR spectra were obtained in solution (reported in ppm) using _CDCl3 (7.26 ppm) or DMSO- _d6 (2.50 ppm) or internal standard tetramethylsilane (0.00 ppm) as reference standards. When reporting peak multiplicity, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd ( double doublet), dt (double triplet). Coupling constants are given in Hertz (Hz).

When desired, (R)- and (S)-isomers of 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, for example, by crystallization; by formation of diastereoisomeric derivatives, which can be separated, for example, by crystallization or chromatography; selectivity of one enantiomer with an enantiomer-specific reagent reaction followed by separation of the modified and unmodified enantiomers; or chromatographic separation in a chiral environment such as a chiral chromatography column. Alternatively, a particular enantiomer can be prepared by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

In the following preparation methods and examples, "Me" refers to methyl, "Ph" refers to phenyl, "PE" refers to petroleum ether, "EtOAc" refers to ethyl acetate, "MeOH" refers to methanol, "EtOH " refers to ethanol, "DMF" refers to N,N-dimethylformamide, "CDCl ₃ " refers to deuterated chloroform, "DMSO-d ₆ " refers to deuterated dimethyl sulfoxide, "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, "AlCl ₃ " refers to trichloro aluminum oxide, "TEA" refers to triethylamine, "NBS" refers to N-bromosuccinimide, "Na ₂ SO ₄ " refers to sodium sulfate, "K ₂ CO ₃ " refers to potassium carbonate, ""MeMgBr" means methylmagnesium bromide, "DEAD" means diethyl azodicarboxylate, "PPh ₃ " means triphenylphosphine, "PdCl ₂ (dppf)" means [1,1'-bis (diphenylphosphino)ferrocene]palladium dichloride, "Ar" refers to argon, "M" refers to molar concentration, "rt" refers to room temperature, "min" refers to minutes, and "h" means hours, "mL" means milliliters, "mmol" means millimoles, "μM" 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 (28.04 g, 157.5 mmol) was added in 5 portions to a solution of 2-amino-3-methoxybenzoic acid (A) (25.08 g, 150 mmol) in DMF (200 mL) over 20 min. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (2 L), extracted with EtOAc (500 mL x 4). The combined organic layers were washed with water (500 mL×3) and brine (500 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product (B) as a dark brown solid (35 g, 95% yield), without Purified and used directly in the next step.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.42 (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) (35 g, 142.2 mmol) and triphosgene (32 mg, 107.8 mmol) in anhydrous THF (350 mL) 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, 200 mL), and dried to give product (C) as a pale yellow solid (30.78 g, 80% yield).

¹ H NMR (400MHz,DMSO-d ₆ )δ11.43(s,1H),7.56(d,J=2.0Hz,1H),7.55(d,J=2.0Hz,1H),3.92(s,3H) .

Step 3: Preparation of 2-amino-5-bromo-N,3-dimethoxy-N-methylbenzamide (D)

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

¹ H NMR (400MHz, DMSO-d ₆ )δ7.01(d, J=2.0Hz, 1H), 6.97(d, J=2.0Hz, 1H), 5.10(brs, 2H), 3.82(s, 3H) ,3.53(s,3H),3.22(s,3H).

Step 4: Preparation of 1-(2-amino-5-bromo-3-methoxyphenyl)ethanone (E)

To a solution of compound (D) (29.73 g, 103 mmol) in anhydrous tetrahydrofuran (300 mL) at -20°C in an argon atmosphere, methylmagnesium bromide (1M tetrahydrofuran solution, 206 mL) was slowly added dropwise within 30 min. 206 mmol). The resulting reaction mixture was stirred at -20 °C for 30 min, then quenched with saturated aqueous ammonium chloride. The reaction mixture was diluted with water (1 L), extracted with EtOAc (300 mL×3). The combined organic layers were washed with water (300 mL×2) and brine (300 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, PE/EtOAc=15:1, v/v) to obtain product (E) as a yellow oil (6.5 g, yield 26%).

¹ H NMR (400MHz, DMSO-d ₆ )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).

Step 5: Preparation of 6-bromo-8-methoxy-4-methylquinazoline (F)

A reaction mixture of compound (E) (3.328 g, 13.63 mmol) and ammonium formate (3.271 g, 54.52 mmol) in formamide (34 mL) was stirred at 150 °C for 7 h. The reaction mixture was cooled to room temperature, diluted with water (150 mL), extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate=10:1 then 4:1, v/v) to obtain product (F) as a yellow solid (2.492 g, yield 72.2%).

¹ H NMR (400MHz,DMSO-d ₆ )δ9.09(s,1H),8.00(d,J=1.9Hz,1H),7.54(d,J=1.9Hz,1H),4.00(s,3H) ,2.87(s,3H).

Step 6: Preparation of 6-bromo-4-methylquinazolin-8-ol (G)

To a solution of compound (F) (4.36 g, 17.23 mmol) in 1,2-dichloroethane (390 mL) was added aluminum trichloride (6.90 g, 51.69 mmol). The resulting reaction mixture was stirred at 80 °C for 1.5 h. The reaction mixture was cooled to room temperature, diluted with water (400 mL), extracted with dichloromethane (300 mL×2). The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, DCM/MeOH=100:1, v/v) to obtain product (G) as a yellow solid (3.02 g, yield 73.3%).

¹ H NMR (400MHz,DMSO-d ₆ )δ10.83(s,1H),9.10(s,1H),7.87(d,J=2.0Hz,1H),7.41(d,J=2.0Hz,1H) ,2.86(s,3H).

Example 1: N-(2-methoxy-5-(4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-6-yl)pyridine- 3-yl)-2,4-difluorobenzenesulfonamide (1)

Step 1: Preparation of 6-bromo-4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline (H-1)

Compound (G) (0.717g, 3mmol), triphenylphosphine (0.944g, 3.6mmol) and tetrahydro-2H-pyran-4-ol (0.368g, 3.6 To a solution of mmol) in anhydrous THF (30 mL) was added DEAD (0.627 g, 3.6 mmol). The resulting reaction mixture was stirred overnight at room temperature. Silica gel (4 g) was added, and the resulting mixture was evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, DCM/EtOAc=4:1, v/v) to obtain product (H-1) as a yellow solid (0.95 g, yield 98%).

¹ H NMR (400MHz,DMSO-d ₆ )δ9.11(s,1H),8.00(d,J=2.0Hz,1H),7.71(d,J=2.0Hz,1H),5.03–4.88(m, 1H), 3.95–3.87(m,2H), 3.58–3.49(m,2H), 2.87(s,3H), 2.10–2.01(m,2H), 1.78–1.61(m,2H).

Step 2: N-(2-Methoxy-5-(4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-6-yl)pyridine-3 Preparation of -yl)-2,4-difluorobenzenesulfonamide (1)

Compound (H-1) (125 mg, 0.39 mmol), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol Alk-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (199mg, 0.47mmol) and 2M aqueous potassium carbonate (0.585mL, 1.17mmol) in dioxane (7mL) The mixture was degassed, then _PdCl2 (dppf) (29mg, 0.04mmol) was added. The resulting reaction mixture was degassed and backfilled with argon (three cycles), then stirred at 100 °C under argon atmosphere for 5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL) and water (30 mL), acidified to pH 5-6 with hydrochloric acid. The two phases were separated and the aqueous layer was extracted (30 mL x 2) with ethyl acetate. The combined organic layers were 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, DCM/MeOH=70:1 then 50:1, v/v) to give product (1) as a yellow foamy solid (178 mg, 85% yield).

¹ H NMR (400MHz,DMSO-d ₆ )δ10.35(s,1H),9.08(s,1H),8.56(d,J=2.3Hz,1H),8.11(d,J=2.3Hz,1H) ,7.94(d,J＝1.6Hz,1H),7.81–7.70(m,2H),7.66–7.54(m,1H),7.22(dt,J＝8.8,2.4Hz,1H),5.12–4.98(m ,1H),3.98–3.90(m,2H),3.66(s,3H),3.61–3.48(m,2H),2.96(s,3H),2.16–2.03(m,2H),1.80–1.65(m ,2H).

MS (ESI+) m/z 543.1 [M+H] ⁺ .

Example 2: N-(2-methoxy-5-(4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-6-yl)pyridine- 3-yl)-2-chloro-4-fluorobenzenesulfonamide (2)

According to the method of step 2 in Example 1, from compound (H-1) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (2) was prepared from borolan-2-yl)pyridin-3-yl)-2-chloro-4-fluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.23(s,1H),9.08(s,1H),8.54(d,J=2.3Hz,1H),8.05(d,J=2.2Hz,1H) ,7.94(dd,J=8.8,6.0Hz,1H),7.90(d,J=1.6Hz,1H),7.77(dd,J=8.8,2.4Hz,1H),7.74(d,J=1.6Hz, 1H), 7.37(dt, J＝8.4, 2.4Hz, 1H), 5.11–5.00(m, 1H), 3.97–3.90(m, 2H), 3.67(s, 3H), 3.58–3.50(m, 2H) ,2.95(s,3H),2.15–2.03(m,2H),1.81–1.66(m,2H).

MS (ESI+) m/z 559.1 [M+H] ⁺ .

Example 3: N-(2-methoxy-5-(4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-6-yl)pyridine- 3-yl)-5-chlorothiophene-2-sulfonamide (3)

According to the method of step 2 in Example 1, from compound (H-1) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (3) was prepared from borolan-2-yl)pyridin-3-yl)-5-chlorothiophene-2-sulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.40(s,1H),9.09(s,1H),8.59(d,J=2.2Hz,1H),8.10(d,J=2.2Hz,1H) ,7.94(d,J=1.4Hz,1H),7.77(d,J=1.4Hz,1H),7.40(d,J=4.0Hz,1H),7.25(d,J=4.0Hz,1H),5.14 –5.00(m,1H),3.98–3.90(m,2H),3.76(s,3H),3.62–3.48(m,2H),2.96(s,3H),2.16–2.03(m,2H),1.82 –1.66(m,2H).

MS (ESI+) m/z 547.1 [M+H] ⁺ .

Example 4: N-(2-methoxy-5-(4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-6-yl)pyridine- 3-yl)methanesulfonamide (4)

According to the method of step 2 in Example 1, from compound (H-1) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (4) was prepared from borolan-2-yl)pyridin-3-yl)methanesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.42(s,1H),9.08(s,1H),8.55(d,J=2.3Hz,1H),8.08(d,J=2.3Hz,1H) ,7.96(d,J=1.6Hz,1H),7.77(d,J=1.6Hz,1H),5.13–4.99(m,1H),4.00(s,3H),3.97–3.90(m,2H), 3.61–3.47(m,2H), 3.10(s,3H), 2.96(s,3H), 2.14–2.01(m,2H), 1.82–1.66(m,2H).

MS (ESI+) m/z 445.2 [M+H] ⁺ .

Example 5: N-(2-methoxy-5-(4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-6-yl)pyridine- 3-yl)cyclopropylsulfonamide (5)

According to the method of step 2 in Example 1, from compound (H-1) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (5) was prepared from borolan-2-yl)pyridin-3-yl)cyclopropylsulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.48(s,1H),9.08(s,1H),8.56(d,J=2.4Hz,1H),8.10(d,J=2.4Hz,1H) ,7.96(d,J=1.6Hz,1H),7.78(d,J=1.6Hz,1H),5.12–5.02(m,1H),4.01(s,3H),3.99–3.90(m,2H), 3.60–3.48(m,2H),2.96(s,3H),2.81–2.73(m,1H),2.16–2.03(m,2H),1.81–1.66(m,2H),1.01–0.86(m,4H ).

MS (ESI+) m/z 471.2 [M+H] ⁺ .

Example 6: (R)-N-(2-methoxy-5-(4-methyl-8-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)pyridine-3- base)-2,4-difluorobenzenesulfonamide (6)

Step 1: Preparation of (R)-6-bromo-4-methyl-8-((tetrahydrofuran-3-yl)oxy)quinazoline (H-6)

According to the method of step 1 in Example 1, compound (H-6) was prepared from compound (G) and (S)-tetrahydrofuran-3-ol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.10(s, 1H), 8.02(d, J=1.9Hz, 1H), 7.55(d, J=1.9Hz, 1H), 5.37–5.31(m, 1H), 4.05–3.85(m,3H), 3.83–3.76(m,1H), 2.87(s,3H), 2.39–2.25(m,1H), 2.14–2.01(m,1H).

Step 2: (R)-N-(2-methoxy-5-(4-methyl-8-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)pyridin-3-yl )-2,4-difluorobenzenesulfonamide (6) preparation

According to the method of step 2 in Example 1, from compound (H-6) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (6) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.35(s,1H),9.08(s,1H),8.57(d,J=2.4Hz,1H),8.12(d,J=2.4Hz,1H) ,7.95(d,J=1.6Hz,1H),7.76(dt,J=8.6,6.4Hz,1H),7.65–7.54(m,2H),7.22(dt,J=8.6,2.4Hz,1H), 5.51–5,45(m,1H),4.05–3.90(m,3H),3.86–3.78(m,1H),3.66(s,3H),2.96(s,3H),2.40–2.29(m,1H ), 2.21–2.08(m,1H).

MS (ESI+) m/z 529.1 [M+H] ⁺ .

Example 7: (R)-N-(2-methoxy-5-(4-methyl-8-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)pyridine-3- base) methanesulfonamide (7)

According to the method of step 2 in Example 1, from compound (H-6) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (7) was prepared from borolan-2-yl)pyridin-3-yl)methanesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.42(s,1H),9.08(s,1H),8.55(d,J=2.4Hz,1H),8.09(d,J=2.4Hz,1H) ,7.97(d,J=1.6Hz,1H),7.63(d,J=1.6Hz,1H),5.53–5.42(m,1H),4.06–3.90(m,6H),3.86–3.78(m,1H ), 3.11(s,3H), 2.96(s,3H), 2.41–2.28(m,1H), 2.20–2.09(m,1H).

MS (ESI+) m/z 431.1 [M+H] ⁺ .

Example 8: (S)-N-(2-methoxy-5-(4-methyl-8-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)pyridine-3- base)-2,4-difluorobenzenesulfonamide (8)

Step 1: Preparation of (S)-6-bromo-4-methyl-8-((tetrahydrofuran-3-yl)oxy)quinazoline (H-8)

According to the method of step 1 in Example 1, compound (H-8) was prepared from compound (G) and (R)-tetrahydrofuran-3-ol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.10(s, 1H), 8.02(d, J=1.9Hz, 1H), 7.55(d, J=1.9Hz, 1H), 5.37–5.31(m, 1H), 4.05–3.85(m,3H), 3.83–3.76(m,1H), 2.87(s,3H), 2.39–2.27(m,1H), 2.14–2.01(m,1H).

Step 2: (S)-N-(2-methoxy-5-(4-methyl-8-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)pyridin-3-yl )-2,4-difluorobenzenesulfonamide (8) preparation

According to the method of step 2 in Example 1, from compound (H-8) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (8) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.35(s,1H),9.08(s,1H),8.57(d,J=2.2Hz,1H),8.12(d,J=2.2Hz,1H) ,7.95(d,J=1.2Hz,1H),7.77(dt,J=8.8,6.6Hz,1H),7.66–7.55(m,2H),7.22(dt,J=8.8,2.4Hz,1H), 5.52–5.43(m,1H),4.06–3.89(m,3H),3.86–3.78(m,1H),3.66(s,3H),2.96(s,3H),2.40–2.29(m,1H), 2.20–2.08(m,1H).

MS (ESI+) m/z 529.1 [M+H] ⁺ .

Example 9: (S)-N-(2-methoxy-5-(4-methyl-8-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)pyridine-3- base) methanesulfonamide (9)

According to the method of step 2 in Example 1, from compound (H-8) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (9) was prepared from borolan-2-yl)pyridin-3-yl)methanesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.42(s,1H),9.08(s,1H),8.55(d,J=2.3Hz,1H),8.09(d,J=2.3Hz,1H) ,7.98(d,J=1.6Hz,1H),7.63(d,J=1.6Hz,1H),5.51–5.45(m,1H),4.04–3.9(m,6H),3.88–3.76(m,1H ), 3.11(s,3H), 2.96(s,3H), 2.42–2.26(m,1H), 2.22–2.06(m,1H).

MS (ESI+) m/z 431.1 [M+H] ⁺ .

Example 10: N-(2-methoxy-5-(4-methyl-8-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-6-yl)pyridine -3-yl)-2,4-difluorobenzenesulfonamide (10)

Step 1: Preparation of 6-bromo-4-methyl-8-((tetrahydro-2H-pyran-4-yl)methoxy)quinazoline (H-10)

According to the method of step 1 in Example 1, compound (H-10) was prepared from compound (G) and (tetrahydro-2H-pyran-4-yl)methanol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.11(s, 1H), 7.99(d, J=1.9Hz, 1H), 7.56(d, J=1.9Hz, 1H), 4.08(d, J= 6.5Hz, 2H), 3.94–3.87(m, 2H), 3.38(dt, J＝11.8, 2.0Hz, 2H), 2.87(s, 3H), 2.21–2.08(m, 1H), 1.80–1.72(m ,2H), 1.48–1.34(m,2H).

Step 2: N-(2-methoxy-5-(4-methyl-8-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-6-yl)pyridine- Preparation of 3-yl)-2,4-difluorobenzenesulfonamide (10)

According to the method of step 2 in Example 1, from compound (H-10) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (10) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.34(s,1H),9.08(s,1H),8.58(d,J=2.3Hz,1H),8.12(d,J=2.3Hz,1H) ,7.92(d,J=1.6Hz,1H),7.76(dt,J=8.6,6.4Hz,1H),7.63(d,J=1.6Hz,1H),7.62–7.55(m,1H),7.22( dt,J=8.4,2.2Hz,1H), 4.17(d,J=6.5Hz,2H),3.96–3.87(m,2H),3.66(s,3H),3.40(dt,J=11.4,1.8Hz ,2H), 2.96(s,3H), 2.26–2.11(m,1H), 1.84–1.76(m,2H), 1.51–1.38(m,2H).

MS (ESI+) m/z 557.2 [M+H] ⁺ .

Example 11: N-(2-methoxy-5-(4-methyl-8-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-6-yl)pyridine -3-yl)methanesulfonamide (11)

According to the method of step 2 in Example 1, from compound (H-10) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (11) was prepared from borolan-2-yl)pyridin-3-yl)methanesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ9.41(s,1H),9.08(s,1H),8.56(d,J=2.4Hz,1H),8.09(d,J=2.4Hz,1H) ,7.94(d,J=1.6Hz,1H),7.65(d,J=1.6Hz,1H),4.17(d,J=6.5Hz,2H),4.01(s,3H),3.96–3.88(m, 2H), 3.39(dt, J＝11.7, 1.9Hz, 2H), 3.10(s, 3H), 2.95(s, 3H), 2.25–2.11(m, 1H), 1.84–1.75(m, 2H), 1.51 –1.37(m,2H).

MS (ESI+) m/z 459.2 [M+H] ⁺ .

Example 12: N-(5-(8-(cyclohexyloxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluoro Benzenesulfonamide (12)

Step 1: Preparation of 6-bromo-8-(cyclohexyloxy)-4-methylquinazoline (H-12)

According to the method of step 1 in Example 1, compound (H-12) was prepared from compound (G) and cyclohexanol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.09(s, 1H), 7.97(d, J=1.9Hz, 1H), 7.61(d, J=1.9Hz, 1H), 4.78–4.65(m, 1H),2.86(s,3H),2.05–1.93(m,2H),1.82–1.72(m,2H),1.62–1.49(m,3H),1.49–1.37(m,2H),1.37–1.25( m, 1H).

Step 2: N-(5-(8-(cyclohexyloxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzene Preparation of sulfonamide (12)

According to the method of step 2 in Example 1, from compound (H-12) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (12) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.35(s,1H),9.07(s,1H),8.55(d,J=2.4Hz,1H),8.09(d,J=2.4Hz,1H) ,7.90(d,J=1.6Hz,1H),7.76(dt,J=8.6,6.4Hz,1H),7.67(d,J=1.6Hz,1H),7.64–7.56(m,1H),7.26– 7.19(m,1H),4.90–4.77(m,1H),3.67(s,3H),2.95(s,3H),2.08–1.95(m,2H),1.87–1.73(m,2H),1.65– 1.53(m,3H), 1.52–1.27(m,3H).

MS (ESI+) m/z 541.2 [M+H] ⁺ .

Example 13: N-(5-(8-(cyclopentyloxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-di Fluorbensulfonamide (13)

Step 1: Preparation of 6-bromo-8-(cyclopentyloxy)-4-methylquinazoline (H-13)

According to the method of step 1 in Example 1, compound (H-13) was prepared from compound (G) and cyclopentanol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.09(s, 1H), 7.96(d, J=2.0Hz, 1H), 7.50(d, J=2.0Hz, 1H), 5.17–5.06(m, 1H), 2.86(s,3H), 2.09–1.96(m,2H), 1.88–1.72(m,4H), 1.68–1.57(m,2H).

Step 2: N-(5-(8-(cyclopentyloxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluoro Preparation of Benzenesulfonamide (13)

According to the method of step 2 in Example 1, from compound (H-13) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (13) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.35(s,1H),9.06(s,1H),8.55(d,J=2.4Hz,1H),8.08(d,J=2.4Hz,1H) ,7.90(d,J=1.6Hz,1H),7.77(dt,J=8.6,6.4Hz,1H),7.64–7.57(m,1H),7.57(d,J=1.6Hz,1H),7.27– 7.19(m,1H),5.29–5.21(m,1H),3.67(s,3H),2.95(s,3H),2.12–1.96(m,2H),1.94–1.73(m,4H),1.73– 1.57(m,2H).

MS (ESI+) m/z 527.2 [M+H] ⁺ .

Example 14: N-(5-(8-((4,4-difluorocyclohexyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl )-2,4-difluorobenzenesulfonamide (14)

Step 1: Preparation of 6-bromo-8-((4,4-difluorocyclohexyl)oxy)-4-methylquinazoline (H-14)

According to the method of step 1 in Example 1, compound (H-14) was prepared from compound (G) and 4,4-difluorocyclohexanol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.12(s, 1H), 8.03(d, J=1.9Hz, 1H), 7.75(d, J=1.9Hz, 1H), 5.02–4.94(m, 1H), 2.87(s, 3H), 2.25–1.85(m, 8H).

Step 2: N-(5-(8-((4,4-difluorocyclohexyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl) Preparation of -2,4-difluorobenzenesulfonamide (14)

According to the method of step 2 in Example 1, from compound (H-14) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (14) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.35(s,1H),9.10(s,1H),8.57(d,J=2.4Hz,1H),8.12(d,J=2.4Hz,1H) ,7.97(d,J=1.6Hz,1H),7.82(d,J=1.6Hz,1H),7.76(dt,J=8.6,6.4Hz,1H),7.64–7.55(m,1H),7.22( dt,J＝8.4,2.2Hz,1H),5.15–5.05(m,1H),3.66(s,3H),2.96(s,3H),2.31–2.11(m,2H),2.10–1.93(m, 6H).

MS (ESI+) m/z 577.2 [M+H] ⁺ .

Example 15: N-(5-(8-((2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)-4-methylquinazolin-6-yl)- 2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (15)

Step 1: Preparation of 6-bromo-8-((2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy)-4-methylquinazoline (H-15)

According to the method of step 1 in Example 1, compound (H-15) was prepared from compound (G) and 2,2-dimethyltetrahydro-2H-pyran-4-ol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.09(s, 1H), 7.99(d, J=1.8Hz, 1H), 7.72(d, J=1.8Hz, 1H), 5.12–4.97(m, 1H),3.84–3.62(m,2H),2.86(s,3H),2.14–1.94(m,2H),1.64–1.45(m,2H),1.25(s,3H),1.24(s,3H) .

Step 2: N-(5-(8-((2,2-Dimethyltetrahydro-2H-pyran-4-yl)oxy)-4-methylquinazolin-6-yl)-2 Preparation of -methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (15)

According to the method of step 2 in Example 1, from compound (H-15) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (15) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.35(s,1H),9.07(s,1H),8.57(d,J=2.4Hz,1H),8.12(d,J=2.4Hz,1H) ,7.93(d,J＝1.6Hz,1H),7.81–7.71(m,2H),7.64–7.56(m,1H),7.26–7.19(m,1H),5.24–5.09(m,1H),3.86 –3.77(m,1H),3.75–3.67(m,1H),3.66(s,3H),2.96(s,3H),2.14–2.01(m,2H),1.65–1.52(m,2H),1.26 (s,3H),1.25(s,3H).

MS (ESI+) m/z 571.2 [M+H] ⁺ .

Example 16: N-(2-methoxy-5-(4-methyl-8-((3-methyloxetan-3-yl)methoxy)-quinazoline-6- Base) pyridin-3-yl)-2,4-difluorobenzenesulfonamide (16)

Step 1: Preparation of 6-bromo-4-methyl-8-((3-methyloxetan-3-yl)methoxy)quinazoline (H-16)

According to the method of step 1 in Example 1, compound (H-16) was prepared from compound (G) and (3-methyloxetan-3-yl)methanol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.13(s, 1H), 8.02(d, J=1.9Hz, 1H), 7.64(d, J=1.9Hz, 1H), 4.57(d, J= 5.8Hz, 2H), 4.37(d, J=5.8Hz, 2H), 4.32(s, 2H), 2.88(s, 3H), 1.45(s, 3H).

Step 2: N-(2-methoxy-5-(4-methyl-8-((3-methyloxetan-3-yl)methoxy)-quinazolin-6-yl ) pyridin-3-yl)-2, the preparation of 4-difluorobenzenesulfonamide (16)

According to the method of step 2 in Example 1, from compound (H-16) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (16) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.34(s,1H),9.10(s,1H),8.59(d,J=2.4Hz,1H),8.14(d,J=2.4Hz,1H) ,7.96(d,J=1.6Hz,1H),7.80–7.74(m,1H),7.73(d,J=1.6Hz,1H),7.64–7.56(m,1H),7.22(dt,J=8.4 ,2.4Hz,1H),4.61(d,J=5.8Hz,2H),4.41(s,2H),4.40(d,J=5.8Hz,2H),3.65(s,3H),2.97(s,3H ), 1.49(s,3H). MS (ESI+) m/z 543.1 [M+H] ⁺ .

Example 17: N-(2-methoxy-5-(4-methyl-8-((tetrahydrofuran-2-yl)methoxy)quinazolin-6-yl)pyridin-3-yl)- 2,4-Difluorobenzenesulfonamide (17)

Step 1: Preparation of 6-bromo-4-methyl-8-((tetrahydrofuran-2-yl)methoxy)quinazoline (H-17)

According to the method of step 1 in Example 1, compound (H-17) was prepared from compound (G) and tetrahydrofurfuryl alcohol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.11(s, 1H), 7.99(d, J=1.8Hz, 1H), 7.57(d, J=1.8Hz, 1H), 4.34–4.25(m, 1H), 4.24–4.12(m, 2H), 3.83(dd, J＝14.2, 7.2Hz, 1H), 3.71(dd, J＝14.2, 7.2Hz, 1H), 2.87(s, 3H), 2.11–1.92 (m,2H),1.90–1.70(m,2H).

Step 2: N-(2-Methoxy-5-(4-methyl-8-((tetrahydrofuran-2-yl)methoxy)quinazolin-6-yl)pyridin-3-yl)-2 , Preparation of 4-difluorobenzenesulfonamide (17)

According to the method of step 2 in Example 1, from compound (H-17) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (17) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.34(s,1H),9.08(s,1H),8.58(d,J=2.2Hz,1H),8.13(d,J=2.2Hz,1H) ,7.93(d,J=1.2Hz,1H),7.76(dt,J=8.4,6.4Hz,1H),7.65(d,J=1.2Hz,1H),7.64–7.55(m,1H),7.21( dt, J＝8.6, 2.2Hz, 1H), 4.39–4.21 (m, 3H), 3.86 (dd, J＝14.2, 7.0Hz, 1H), 3.73 (dd, J＝14.2, 7.0Hz, 1H), 3.65 (s,3H), 2.96(s,3H), 2.14–1.93(m,2H), 1.93–1.73(m,2H).

MS (ESI+) m/z 543.1 [M+H] ⁺ .

Example 18: N-(2-methoxy-5-(4-methyl-8-((tetrahydrofuran-3-yl)methoxy)quinazolin-6-yl)pyridin-3-yl)- 2,4-Difluorobenzenesulfonamide (18)

Step 1: Preparation of 6-bromo-4-methyl-8-((tetrahydrofuran-3-yl)methoxy)quinazoline (H-18)

According to the method of step 1 in Example 1, compound (H-18) was prepared from compound (G) and (tetrahydrofuran-3-yl)methanol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.12(s, 1H), 8.00(d, J=1.8Hz, 1H), 7.59(d, J=1.8Hz, 1H), 4.21–4.08(m, 2H),3.91–3.75(m,2H),3.74–3.59(m,2H),2.87(s,3H),2.84–2.75(m,1H),2.11–2.02(m,1H),1.80–1.69( m, 1H).

Step 2: N-(2-Methoxy-5-(4-methyl-8-((tetrahydrofuran-3-yl)methoxy)quinazolin-6-yl)pyridin-3-yl)-2 , Preparation of 4-difluorobenzenesulfonamide (18)

According to the method of step 2 in Example 1, from compound (H-18) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (18) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.34(s,1H),9.09(s,1H),8.58(d,J=2.2Hz,1H),8.13(d,J=2.2Hz,1H) ,7.94(d,J=1.0Hz,1H),7.76(dd,J=8.6,6.6Hz,1H),7.67(d,J=1.0Hz,1H),7.65–7.53(m,1H),7.22( dt,J＝8.6,2.4Hz,1H),4.35–4.16(m,2H),3.93–3.78(m,2H),3.75–3.60(m,5H),2.96(s,3H),2.92–2.76( m,1H), 2.16–2.05(m,1H), 1.83–1.73(m,1H).

MS (ESI+) m/z 543.1 [M+H] ⁺ .

Example 19: N-(2-methoxy-5-(4-methyl-8-((1-methylpiperidin-4-yl)oxy)quinazolin-6-yl)pyridine-3 -yl)-2,4-difluorobenzenesulfonamide (19)

Step 1: Preparation of 6-bromo-4-methyl-8-((1-methylpiperidin-4-yl)oxy)quinazoline (H-19)

According to the method of step 1 in Example 1, compound (H-19) was prepared from compound (G) and 1-methylpiperidin-4-ol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.10(s,1H),7.99(d,J=1.9Hz,1H),7.64(d,J=1.9Hz,1H),4.80–4.66(m, 1H), 2.88–2.85(m,3H), 2.74–2.63(m,2H), 2.30–2.14(m,6H), 2.07–1.95(m,2H), 1.82–1.69(m,2H).

Step 2: N-(2-methoxy-5-(4-methyl-8-((1-methylpiperidin-4-yl)oxy)quinazolin-6-yl)pyridine-3- base)-2,4-difluorobenzenesulfonamide (19)

According to the method of step 2 in Example 1, from compound (H-19) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (19) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.07(s, 1H), 8.35(d, J=2.2Hz, 1H), 7.93(d, J=2.2Hz, 1H), 7.86(d, J= 1.6Hz, 1H), 7.79(dt, J=8.6, 6.6Hz, 1H), 7.66(d, J=1.6Hz, 1H), 7.54–7.44(m, 1H), 7.18(dt, J=8.4, 2.4 Hz,1H),4.95–4.82(m,1H),3.70(s,3H),2.94(s,3H),2.93–2.86(m,2H),2.51(s,1H),2.39(s,3H) ,2.15–2.04(m,2H),1.92–1.80(m,2H).

MS (ESI+) m/z 556.2 [M+H] ⁺ .

Example 20: N-(2-methoxy-5-(4-methyl-8-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-6-yl)pyridine-3- base)-2,4-difluorobenzenesulfonamide (20)

Step 1: Preparation of 6-bromo-4-methyl-8-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (H-20)

According to the method of step 1 in Example 1, compound (H-20) was prepared from compound (G) and 2-(pyrrolidin-1-yl)ethan-1-ol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.10(s, 1H), 7.99(d, J=1.9Hz, 1H), 7.58(d, J=1.9Hz, 1H), 4.30(t, J= 5.8Hz, 2H), 2.93(t, J=5.8Hz, 2H), 2.87(s, 3H), 2.64–2.55(m, 4H), 1.76–1.62(m, 4H).

Step 2: N-(2-methoxy-5-(4-methyl-8-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-6-yl)pyridin-3-yl )-2,4-difluorobenzenesulfonamide (20) preparation

According to the method of step 2 in Example 1, from compound (H-20) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (20) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.08(s, 1H), 8.37(d, J=2.2Hz, 1H), 7.96(d, J=2.2Hz, 1H), 7.86(d, J= 1.4Hz, 1H), 7.80(dt, J=8.6, 6.6Hz, 1H), 7.61(d, J=1.4Hz, 1H), 7.53–7.45(m, 1H), 7.19(dt, J=8.4, 2.4 Hz, 1H), 4.45(t, J=5.5Hz, 2H), 3.69(s, 3H), 3.18(t, J=5.5Hz, 2H), 2.95(s, 3H), 2.91–2.81(m, 4H ), 1.83–1.75 (m, 4H).

MS (ESI+) m/z 556.2 [M+H] ⁺ .

Example 21: N-(5-(8-(2-(1H-pyrazol-1-yl)ethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridine- 3-yl)-2,4-difluorobenzenesulfonamide (21)

Step 1: Preparation of 8-(2-(1H-pyrazol-1-yl)ethoxy)-6-bromo-4-methylquinazoline (H-21)

According to the method of step 1 in Example 1, compound (H-21) was prepared from compound (G) and 2-(1H-pyrazol-1-yl)ethan-1-ol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.11(s, 1H), 8.01(d, J=1.9Hz, 1H), 7.87(dd, J=2.2, 0.6Hz, 1H), 7.54(d, J = 1.9Hz, 1H), 7.46 (dd, J = 1.8, 0.6Hz, 1H), 6.24 (t, J = 2.0Hz, 1H), 4.65–4.57 (m, 4H), 2.86 (s, 3H).

Step 2: N-(5-(8-(2-(1H-pyrazol-1-yl)ethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridine-3 Preparation of -yl)-2,4-difluorobenzenesulfonamide (21)

According to the method of step 2 in Example 1, from compound (H-21) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (21) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.33(s,1H),9.09(s,1H),8.56(d,J=2.3Hz,1H),8.12(d,J=2.3Hz,1H) ,7.95(d,J=1.6Hz,1H),7.92(dd,J=2.2,0.6Hz,1H),7.76(dt,J=8.4,6.4Hz,1H),7.62(d,J=1.6Hz, 1H),7.61–7.56(m,1H),7.46(dd,J＝1.8,0.6Hz,1H),7.22(dt,J＝8.4,2.0Hz,1H),6.27–6.23(m,1H),4.76 –4.60(m,4H),3.65(s,3H),2.95(s,3H).

MS (ESI+) m/z 553.1 [M+H] ⁺ .

Example 22: N-(2-methoxy-5-(4-methyl-8-(2-morpholinoethoxy)quinazolin-6-yl)pyridin-3-yl)-2, 4-Difluorobenzenesulfonamide (22)

Step 1: Preparation of 4-(2-((6-bromo-4-methylquinazolin-8-yl)oxy)ethyl)morpholine (H-22)

According to the method of Step 1 in Example 1, compound (H-22) was prepared from compound (A-8) and 2-morpholinoethan-1-ol.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.10(s, 1H), 7.99(d, J=1.9Hz, 1H), 7.61(d, J=1.9Hz, 1H), 4.33(t, J= 5.7Hz, 2H), 3.63–3.53(m, 4H), 2.87(s, 3H), 2.82(t, J=5.7Hz, 2H), 2.59–2.51(m, 4H).

Step 2: N-(2-methoxy-5-(4-methyl-8-(2-morpholinoethoxy)quinazolin-6-yl)pyridin-3-yl)-2,4 -Preparation of difluorobenzenesulfonamide (22)

According to the method of step 2 in Example 1, from compound (H-22) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (22) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.33(s,1H),9.08(s,1H),8.57(d,J=2.4Hz,1H),8.12(d,J=2.4Hz,1H) ,7.93(d,J=1.6Hz,1H),7.76(dt,J=8.6,6.4Hz,1H),7.67(d,J=1.6Hz,1H),7.59(ddd,J=10.6,9.2,2.4 Hz,1H),7.27–7.18(m,1H),4.43(t,J=5.6Hz,2H),3.66(s,3H),3.64–3.57(m,4H),2.96(s,3H),2.89 (t, J = 5.6Hz, 2H), 2.65–2.56 (m, 4H).

MS (ESI+) m/z 571.2 [M+H] ⁺ .

Example 23: N-(2-methoxy-5-(4-methyl-8-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-yl)pyridine- 3-yl)-2,4-difluorobenzenesulfonamide (23)

Step 1: Preparation of 6-bromo-4-methyl-8-((1-methylpiperidin-4-yl)methoxy)quinazoline (H-23)

According to the method of step 1 in Example 1, compound (H-23) was prepared from compound (G) and (1-methylpiperidin-4-yl)methanol.

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.11(s, 1H), 7.98(d, J=1.8Hz, 1H), 7.54(d, J=1.8Hz, 1H), 4.06(d, J= 6.0Hz, 2H), 2.86(s, 3H), 2.84–2.76(m, 1H), 2.17(s, 3H), 1.95–1.75(m, 5H), 1.44–1.31(m, 2H).

Step 2: N-(2-Methoxy-5-(4-methyl-8-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-yl)pyridine-3 Preparation of -yl)-2,4-difluorobenzenesulfonamide (23)

According to the method of step 2 in Example 1, from compound (H-23) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (23) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.06(s, 1H), 8.25(d, J=1.6Hz, 1H), 7.86–7.80(m, 2H), 7.78(d, J=1.4Hz, 1H), 7.51(d, J=1.4Hz, 1H), 7.43(dt, J=9.8, 2.4Hz, 1H), 7.16(dt, J=8.4, 2.4Hz, 1H), 4.15(d, J=6.0 Hz,2H),3.72(s,3H),3.16–3.07(m,2H),2.93(s,3H),2.48–2.34(m,5H),2.08–1.87(m,3H),1.61–1.41( m,2H).

MS (ESI+) m/z 570.2 [M+H] ⁺ .

Example 24: N-(5-(8-(2-(Dimethylamino)ethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)- 2,4-Difluorobenzenesulfonamide (24)

Step 1: Preparation of 2-((6-bromo-4-methylquinazolin-8-yl)methoxy)-N,N-dimethylethanol-1-amine (H-24)

According to the method of step 1 in Example 1, compound (H-24) was prepared from compound (G) and 2-(dimethylamino)ethan-1-ol.

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.11(s, 1H), 8.03(d, J=1.9Hz, 1H), 7.63(d, J=1.9Hz, 1H), 4.40(t, J= 5.2Hz, 2H), 3.03(t, J=5.2Hz, 2H), 2.88(s, 3H), 2.48(s, 6H).

Step 2: N-(5-(8-(2-(Dimethylamino)ethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2 , Preparation of 4-difluorobenzenesulfonamide (24)

According to the method of step 2 in Example 1, from compound (H-24) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (24) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.08(s, 1H), 8.44(d, J=2.3Hz, 1H), 8.01(d, J=2.3Hz, 1H), 7.89(d, J= 1.6Hz, 1H), 7.79(dt, J＝8.6, 6.4Hz, 1H), 7.64(d, J＝1.6Hz, 1H), 7.56–7.48(m, 1H), 7.24–7.16(m, 1H), 4.43 (t, J = 5.6Hz, 2H), 3.68 (s, 3H), 2.98 (t, J = 5.6Hz, 2H), 2.95 (s, 3H), 2.44 (s, 6H).

MS (ESI+) m/z 530.2 [M+H] ⁺ .

Example 25: N-(5-(8-(cyclopropylmethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4- Difluorobenzenesulfonamide (25)

Step 1: Preparation of 6-bromo-8-(cyclopropylmethoxy)-4-methylquinazoline (H-25)

To a stirred mixture of compound (G) (0.120g, 0.5mmol), cyclopropylmethyl bromide (0.675g, 5mmol) and potassium carbonate (0.691g, 5mmol) in acetonitrile (8mL) in a sealed tube at 85 Stir overnight at °C. The resulting mixture was cooled to room temperature, then filtered. Silica gel (1 g) was added to the filtrate, and the resulting mixture was evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, DCM/MeOH=150:1, v/v) to obtain the product (H-25) as a yellow oil (0.142 g, yield 97%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.11(s, 1H), 7.97(d, J=2.0Hz, 1H), 7.49(d, J=2.0Hz, 1H), 4.05(d, J= 7.1Hz, 2H), 2.87(s, 3H), 1.41–1.29(m, 1H), 0.68–0.57(m, 2H), 0.43–0.36(m, 2H).

Step 2: N-(5-(8-(cyclopropylmethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-di Preparation of fluorobenzenesulfonamide (25)

According to the method of step 2 in Example 1, from compound (H-25) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (25) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.33(s,1H),9.08(s,1H),8.55(d,J=2.2Hz,1H),8.09(d,J=2.2Hz,1H) ,7.91(d,J=1.4Hz,1H),7.76(dt,J=8.6,6.4Hz,1H),7.63–7.57(m,1H),7.57(d,J=1.4Hz,1H),7.21( dt,J=8.4,2.4Hz,1H),4.15(d,J=7.0Hz,2H),3.65(s,3H),2.96(s,3H),1.47–1.32(m,1H),0.71–0.60 (m,2H),0.46–0.37(m,2H).

MS (ESI+) m/z 513.1 [M+H] ⁺ .

Example 26: N-(5-(8-isopropoxy-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzene Sulfonamide (26)

Step 1: Preparation of 6-bromo-8-isopropoxy-4-methylquinazoline (H-26)

According to the method of step 1 in Example 25, compound (H-26) was prepared from compound (G) and isopropyl bromide.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.08(s, 1H), 7.97(d, J=2.0Hz, 1H), 7.57(d, J=2.0Hz, 1H), 5.00–4.89(m, 1H), 2.86(s, 3H), 1.37(d, J=6.0Hz, 6H).

Step 2: N-(5-(8-isopropoxy-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide Preparation of (26)

According to the method of step 2 in Example 1, from compound (H-26) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide The title compound (26) was prepared.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.34(s,1H),9.06(s,1H),8.55(d,J=2.3Hz,1H),8.08(d,J=2.3Hz,1H) ,7.91(d,J=1.6Hz,1H),7.77(dt,J=8.6,6.4Hz,1H),7.63(d,J=1.6Hz,1H),7.62–7.55(m,1H),7.22( dt, J = 8.4, 2.2 Hz, 1H), 5.13–5.02 (m, 1H), 3.67 (s, 3H), 2.95 (s, 3H), 1.40 (d, J = 6.0 Hz, 6H).

MS (ESI+) m/z 501.1 [M+H] ⁺ .

Example 27: N-(5-(8-cyclobutoxy-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonate Amides (27)

Step 1: Preparation of 6-bromo-8-cyclobutoxy-4-methylquinazoline (H-27)

According to the method of Step 1 in Example 25, compound (H-27) was prepared from compound (G) and cyclobutyl bromide.

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.10(s, 1H), 7.99(d, J=1.9Hz, 1H), 7.33(d, J=1.9Hz, 1H), 4.97(p, J= 7.2Hz, 1H), 2.86(s, 3H), 2.59–2.52(m, 2H), 2.23–2.08(m, 2H), 1.91–1.80(m, 1H), 1.79–1.61(m, 1H).

Step 2: N-(5-(8-cyclobutoxy-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide Preparation of (27)

According to the method of step 2 in Example 1, from compound (H-27) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (27) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.36(s,1H),9.07(s,1H),8.54(d,J=2.2Hz,1H),8.07(d,J=2.2Hz,1H) ,7.92(s,1H),7.76(dt,J=8.4,6.4Hz,1H),7.64–7.56(m,1H),7.40(s,1H),7.23(dt,J=8.4,2.4Hz,1H ),5.16–5.02(m,1H),3.68(s,3H),2.95(s,3H),2.62–2.52(m,2H),2.29–2.10(m,2H),1.94–1.81(m,1H ), 1.80–1.65(m,1H).

MS (ESI+) m/z 513.1 [M+H] ⁺ .

Example 28: N-(5-(8-(difluoromethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-di Fluorbensulfonamide (28)

Step 1: Preparation of 6-bromo-8-(difluoromethoxy)-4-methylquinazoline (H-28)

Compound (G) (0.120 g, 0.5 mmol), methyl chlorodifluoroacetate (0.217 g, 1.5 mmol) and sodium carbonate (0.159 g, 1.5 mmol) were dissolved in dimethylformamide ( 3 mL) was stirred at 70 °C for 8 h. The resulting mixture was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative thin-layer chromatography (silica gel, DCM/MeOH=40:1, v/v) to obtain the product (H-28) as a yellow oil (0.080 g, yield 55%).

¹ H NMR (400MHz, DMSO-d ₆ )δ9.21(s, 1H), 8.43(d, J=2.0Hz, 1H), 7.98(d, J=2.0Hz, 1H), 7.53(t, J= 73.8Hz, 1H), 2.94(s, 3H).

Step 2: N-(5-(8-(difluoromethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluoro Preparation of Benzenesulfonamide (28)

According to the method of step 2 in Example 1, from compound (H-28) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Compound (28) was prepared from borolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.37(s,1H),9.18(s,1H),8.59(d,J=2.4Hz,1H),8.35(d,J=1.8Hz,1H) ,8.16(d,J=2.4Hz,1H),8.06(d,J=1.8Hz,1H),7.76(dt,J=8.6,6.4Hz,1H),7.64–7.55(m,1H),7.56( t,J=74.0Hz, 1H), 7.21(dt,J=8.4,2.0Hz,1H), 3.66(s,3H), 3.03(s,3H).

Example 29: N-(2-methoxy-5-(8-methoxy-4-methylquinazolin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (29)

According to the method of step 2 in Example 1, compound (F) and N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane Compound (29) was prepared from pentaboran-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.

¹ H NMR (400MHz,DMSO-d ₆ )δ10.35(s,1H),9.06(s,1H),8.58(d,J=2.2Hz,1H),8.13(d,J=2.2Hz,1H) ,7.93(d,J=1.6Hz,1H),7.77(dt,J=8.4,6.4Hz,1H),7.65–7.54(m,2H),7.23(dt,J=8.6,2.4Hz,1H), 4.08(s,3H), 3.67(s,3H), 2.96(s,3H).

MS (ESI+) m/z 473.1 [M+H] ⁺ .

Example 30: N-(2-Chloro-5-(4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-6-yl)pyridine-3- Base) -4-fluorobenzenesulfonamide (30)

A mixture of compound (H-1) (71 mg, 0.22 mmol), anhydrous potassium acetate (65 mg, 0.66 mmol) and pinacol diborate (64 mg, 0.25 mmol) in dioxane (8 mL) was degassed , then _PdCl2 (dppf) (16mg, 0.022mmol) was added. The resulting reaction mixture was degassed and backfilled with argon (three cycles) and stirred at 100 °C for 4 h under argon atmosphere. After cooling to room temperature, N-(5-bromo-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (91 mg, 0.25 mmol) and 2M aqueous potassium carbonate (0.44 mL, 0.88 mmol). The resulting mixture was degassed, then _PdCl2 (dppf) (16mg, 0.022mmol) was added. The resulting reaction mixture was degassed and backfilled with argon (three cycles), then stirred at 100 °C under argon atmosphere for 5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL) and water (30 mL), acidified to pH 5-6 with hydrochloric acid. The two phases were separated and the aqueous layer was extracted (30 mL x 2) with ethyl acetate. The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative thin-layer chromatography (DCM/MeOH=15:1, v/v) to give product (30) as a yellow foamy solid (42 mg, 35% yield).

¹ H NMR (400MHz,DMSO-d ₆ )δ10.57(s,1H),9.12(s,1H),8.79(d,J=2.2Hz,1H),8.16(d,J=2.2Hz,1H) ,8.00(d,J=1.6Hz,1H),7.87–7.80(m,2H),7.78(d,J=1.6Hz,1H),7.50–7.39(m,2H),5.12–5.00(m,1H ), 3.98–3.90(m,2H), 3.60–3.50(m,2H), 2.97(s,3H), 2.15–2.02(m,2H), 1.82–1.65(m,2H).

MS (ESI+) m/z 529.1 [M+H] ⁺ .

Example 31: N-(2-methyl-5-(4-methyl-8-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-6-yl)pyridine-3 -yl)-2,4-difluorobenzenesulfonamide (31)

A mixture of compound (H-1) (71 mg, 0.22 mmol), anhydrous potassium acetate (65 mg, 0.66 mmol) and pinacol diborate (64 mg, 0.25 mmol) in dioxane (8 mL) was degassed , then _PdCl2 (dppf) (16mg, 0.022mmol) was added. The resulting reaction mixture was degassed and backfilled with argon (three cycles) and stirred at 100 °C for 4 h under argon atmosphere. After cooling to room temperature, N-(5-bromo-2-methylpyridin-3-yl)-2,4-difluorobenzenesulfonamide (91 mg, 0.25 mmol) and 2M aqueous potassium carbonate ( 0.44 mL, 0.88 mmol). The resulting mixture was degassed, then _PdCl2 (dppf) (16mg, 0.022mmol) was added. The resulting reaction mixture was degassed and backfilled with argon (three cycles), then stirred at 100 °C under argon atmosphere for 5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL) and water (30 mL), acidified to pH 5-6 with hydrochloric acid. The two phases were separated and the aqueous layer was extracted (30 mL x 2) with ethyl acetate. The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative thin-layer chromatography (DCM/MeOH=15:1, v/v) to give product (31) as a yellow foamy solid (46 mg, 40% yield).

¹ H NMR (400MHz,DMSO-d ₆ )δ10.53(s,1H),9.10(s,1H),8.84(s,1H),7.88(d,J=1.6Hz,1H),7.85(d, J＝2.0Hz, 1H), 7.80(dt, J＝8.6, 6.4Hz, 1H), 7.71(d, J＝1.6Hz, 1H), 7.67–7.59(m, 1H), 7.30–7.24(m, 1H ),5.08–4.99(m,1H),3.97–3.90(m,2H),3.58–3.50(m,2H),2.94(s,3H),2.34(s,3H),2.16–2.01(m,2H ), 1.82–1.64(m,2H).

MS (ESI+) m/z 527.2 [M+H] ⁺ .

Pharmacological activity evaluation

Example 32: Biochemical detection of PI3Kα activity

The potency of the compounds of the invention against PI3Kα was assessed using an in vitro kinase assay. The kinase activity of PI3K-α was determined by detecting the level of ADP produced in the kinase reaction using a luciferase-based luminescence assay. Kinase-Glo ^TM Kinase Detection Kit was purchased from Promega. All assays were performed at room temperature using OptiPlate ^™ -384 white 384-well plates. PI3Kα kinase was from Invitrogen. The substrate was PIP2 (Invitrogen). Kinase buffer included 50 mM Hepes (pH 7.5), 3 mM MgCl ₂ , 100 mM NaCl, 1 mM EGTA, 0.03% CHAPS and 2 mM DTT. PI3Kα kinase solutions were prepared by diluting PI3Kα kinase to 6.6 nM in kinase buffer. The substrate solution included 100 μM PIP2 and 50 μM ATP. The compounds to be tested were diluted to 10 mM in 100% DMSO and then serially diluted 3-fold into 10 different concentrations in 100% DMSO. Compounds diluted in 100% DMSO were then diluted 25-fold in IX kinase buffer. Add 2.5 μL of diluted compound solution and 2.5 μL of PI3Kα kinase solution to each well of a 384-well plate. The reaction was started by adding 5 μL per well of the substrate solution to a final reaction volume of 10 μL with an ATP concentration of 25 μM, a PIP2 concentration of 50 μM, and a PI3Kα kinase concentration of 1.65 nM. The plate was covered and the reaction proceeded for 1 hour at room temperature before being terminated by the addition of 10 μL per well of Kinase-Glo ^™ reagent. Plates were incubated for 15 minutes before luminescence was read on an EnVision 2104 Multilabel Microplate Reader plate reader.

Percent inhibition was calculated based on the following formula:

Inhibition %=100-(max-sample RLU)/(max-min)*100.

Where sample RLU is the luminescence reading at a given compound concentration, min refers to the reading of the DMSO control, and max refers to the reading of the no-enzyme control. The IC ₅₀ of the compound was calculated by using the XLfit program in Excel, and the results are shown in Table 1.

Table 1: PI3Kα Kinase Inhibitory Activity

Example 33: MTT method to measure the survival rate of tumor cells

Human lung cancer cells NCI-H460 in the logarithmic growth phase were digested with 0.25% trypsin-EDTA, prepared into a single cell suspension at a certain concentration, seeded in a 96-well plate at 1200 cells/well, and added 100 μL to each well, and after 24 hours , add different concentrations of the test compound and the fresh medium of the corresponding solvent control, add 100 μL to each well (DMSO final concentration <0.2%), set 6-9 concentration groups for each test compound, and set three parallel wells for each group . Continue culturing at 5% CO ₂ and 37°C for 96 h, add 20 μL of freshly prepared PBS solution containing 5 mg/mL MTT to each well, and continue culturing for 4 h, discard the supernatant, add 150 μL DMSO to each well to dissolve the MTT formazan precipitate, and After oscillating and mixing with a micro-oscillator, measure the optical density (optical density, OD) at a wavelength of 570nm, and use the tumor cells treated with DMSO solvent as the control group, and calculate the inhibitory rate of the test compound on the growth of tumor cells by the following formula , and calculate IC ₅₀ by SPSS16.0:

Inhibition rate (%) = (OD _control - OD _compound ) / OD _control × 100%

Wherein, OD _control is the average OD value of the control group, and OD _control is the average OD value at a given compound concentration.

The results are shown in Table 2.

Table 2: Antiproliferative activity against human lung cancer cell line NCI-H460

Example 35: Xenograft Efficacy Study in Nude Mice

Human lung cancer NCI-H460 tumor cells were collected under sterile conditions, and the cell density was adjusted to 1× ¹⁰⁶ cells/ml with sterilized saline, and 0.2 ml was inoculated subcutaneously in the back of the axilla of nude mice until the tumor grew to a diameter of 1 cm. The tumors were taken out under bacterial conditions, cut into 1mm×1mm tumor pieces, and evenly inoculated subcutaneously in the axils and backs of nude mice. Six days later, when the tumor grew to 100-300 mm ³ , the animals were randomly divided into groups, and the administration was started (referred to as the first day). Test compounds were administered orally daily. The body weight was weighed twice a week and the length and width of the tumor were measured with a vernier caliper. After 16 days of administration, the nude mice were killed by dislocation, the tumor tissue was stripped, weighed and photographed. Finally, the tumor inhibition rate was calculated, and the intensity of the anti-tumor effect was evaluated by the tumor inhibition rate. The results are shown in Table 3 and Figure 1.

Tumor volume was calculated according to the following formula:

Tumor volume=(a×b ² )/2, a and b represent tumor length and width, respectively.

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

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

Table 3. Example 1 inhibits the growth of human lung cancer NCI-H460 in subcutaneous xenograft tumors in nude mice

effect

Pharmacological Activity Summary:

All examples showed strong inhibitory activity on PI3Kα kinase, and their IC ₅₀ values were all less than 11 nM. All examples showed strong anti-proliferation activity against human lung cancer cell NCI-H460, and their IC ₅₀ values were all less than 4 μM. Among them, Example 1 has a significant inhibitory effect on the growth of human lung cancer NCI-H460 in subcutaneous xenograft tumors in nude mice.

Claims (10)

1. A compound shown in formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts: in R ₁ is C _1-3 alkyl; L is selected from a single bond or C _1-3 alkylene, wherein said C _1-3 alkylene is optionally substituted by one or more R; Ra is selected from halogen or C _1-3 alkyl; R ₂ is selected from hydrogen, C _1-3 alkyl, C _1-3 alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, wherein C _1-3 alkyl, C _1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl are optionally substituted by one or more Rb; Rb is selected from halogen, cyano, hydroxyl, trifluoromethyl, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _1-3 alkylamino or two (C _{1 -3} alkyl) amino; R ₃ is selected from C _1-3 alkoxy, halogen or C _1-3 alkyl; _R is selected from C _1-3 alkyl, 3-7 membered cycloalkyl, aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more groups selected from : Halogen, C _1-3 alkyl, amino, C _1-3 alkylamino, di(C _1-3 alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C _1-3 alkoxy base. 2. The compound according to claim 1, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, wherein the compound is a compound shown in formula (II): in R ₁ is selected from C _1-3 alkyl; L is selected from a single bond or C _1-3 alkylene, wherein said C _1-3 alkylene is optionally substituted by one or more R; Ra is selected from halogen or C _1-3 alkyl; _R is selected from methoxy, chlorine or methyl; _R is selected from C _1-3 alkyl, 3-7 membered cycloalkyl, phenyl or thienyl, wherein the phenyl and thienyl are optionally substituted by one or more groups selected from the group consisting of: halogen , C _1-3 alkyl, amino, C _1-3 alkylamino, di(C _1-3 alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C _1-3 alkoxy; Ring A is selected from 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; R ₅ is selected from C _1-3 alkyl, halogen, cyano, trifluoromethyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _1-3 alkylamino or two (C _{1-3 3} alkyl) amino; m is 0, 1, 2, 3 or 4; when m is 2, 3 or 4, R ₅ may be the same or different groups. 3. The compound according to claim 2, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt: in R ₁ is methyl; L is selected from a single bond or C _1-3 alkylene, wherein said C _1-3 alkylene is optionally substituted by one or more R; Ra is selected from halogen or C _1-3 alkyl; R ₃ is methoxy; _R is selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally substituted by one or more groups selected from the group consisting of halogen, C _1-3 alkyl, amino, C _1-3 alkane Amino, two (C _1-3 alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C _1-3 alkoxy; Ring A is a 3-7 membered cycloalkyl group; R ₅ is selected from C _1-3 alkyl, halogen, cyano, trifluoromethyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _1-3 alkylamino or two (C _{1-3 3} alkyl) amino; m is 0, 1, 2, 3 or 4; when m is 2, 3 or 4, R ₅ may be the same or different groups. 4. The compound according to claim 2, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt: in R ₁ is methyl; L is selected from a single bond or C _1-3 alkylene, wherein said C _1-3 alkylene is optionally substituted by one or more R; Ra is selected from halogen or C _1-3 alkyl; R ₃ is methoxy; _R is selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally substituted by one or more groups selected from the group consisting of halogen, C _1-3 alkyl, amino, C _1-3 alkane Amino, two (C _1-3 alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C _1-3 alkoxy; Ring A is a 3-7 membered heterocycloalkyl group; R ₅ is selected from C _1-3 alkyl, halogen, cyano, trifluoromethyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _1-3 alkylamino or two (C _{1-3 3} alkyl) amino; m is 0, 1, 2, 3 or 4; when m is 2, 3 or 4, R ₅ may be the same or different groups. 5. The compound according to claim 4, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt: in R ₁ is methyl; L is selected from a single bond or C _1-3 alkylene, wherein said C _1-3 alkylene is optionally substituted by one or more R; Ra is selected from halogen or C _1-3 alkyl; R ₃ is methoxy; _R is selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally substituted by one or more groups selected from the group consisting of halogen, C _1-3 alkyl, amino, C _1-3 alkane Amino, two (C _1-3 alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C _1-3 alkoxy; Ring A is selected from: R ₅ is selected from C _1-3 alkyl, halogen, cyano, trifluoromethyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _1-3 alkylamino or two (C _{1-3 3} alkyl) amino; m is 0, 1, 2, 3 or 4; when m is 2, 3 or 4, R ₅ may be the same or different groups. 6. The compound according to any one of claims 1-5, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, wherein the compound is selected from: 7. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 6, a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt and optionally a pharmaceutically acceptable carrier or excipient. 8. The pharmaceutical composition according to claim 7, further comprising a pharmaceutically active ingredient other than the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt . 9. The compound according to any one of claims 1-6, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, or the compound according to claim 7 or 8 Use of the pharmaceutical composition in preparing medicines for preventing and/or treating diseases mediated by PI3K. 10. The compound according to any one of claims 1-6, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, or the compound according to claim 7 or 8 Use of the pharmaceutical composition in preparing medicines for preventing and/or treating cancer, immune disease, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction or neurological disease.