PI3K inhibitor as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a PI3K inhibitor as well as a preparation method and application thereof. The invention discloses a compound shown in a formula I, or an optical isomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a hydrate thereof, or a solvate thereof, or a crystal form thereof, and the compound can be used for preparing a PI3K inhibitor, and can be used as a medicine for treating PI3K-mediated diseases. A new choice is provided for clinical screening and / or preparation of drugs for diseases related to PI3K activity.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a PI3K inhibitor and a preparation method and use thereof. Background Art

[0002] PI3K is an intracellular phosphatidylinositol kinase that is associated with the products of oncogenes such as vsrc and vras. PI3K itself has the activity of serine / threonine (Ser / Thr) kinase and phosphatidylinositol kinase. Some studies have shown that PI3K is closely related to some diseases.

[0003] Abnormal expression and activation of PI3K are associated with a variety of cancers. For example, in a variety of cancers such as breast cancer, ovarian cancer, prostate cancer, and lung cancer, abnormal activation and mutation of PI3K have been found to be associated with the occurrence and development of tumors. In some cases, excessive activation of PI3K may lead to uncontrolled cell growth and division, thus forming tumors. In addition, PI3K is also associated with the occurrence of diabetes. In diabetic patients, abnormal regulation of the PI3K signaling pathway may lead to insulin resistance, resulting in failure of blood sugar control. Therefore, diabetes treatment strategies targeting PI3K are also under study. Another disease associated with PI3K is neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. In these diseases, abnormalities in the PI3K signaling pathway may affect the growth and survival of nerve cells, leading to the occurrence of the disease.

[0004] Therefore, the study of PI3K and related diseases has always been one of the hot topics in the medical and scientific fields. Targeted therapy for PI3K may provide new ideas for the prevention and treatment of diseases such as cancer, diabetes and neurodegenerative diseases.

[0005] PI3K inhibitors are compounds that inhibit the PI3K signaling pathway and are being extensively studied to develop drugs to treat a variety of human diseases. These diseases include cancer, diabetes, neurodegenerative diseases, etc. Some of the most intensively studied PI3K inhibitors are tezepelumab and lapatinib, which are currently undergoing clinical trials for various cancers. Tezepelumab has shown significant therapeutic effects in clinical trials for non-small cell lung cancer, while lapatinib is approved for the treatment of breast cancer and thyroid cancer.

[0006] However, individual patients have different differences and responses to drugs, and people hope to obtain drugs with higher specificity and stronger activity. Therefore, the development of new PI3K inhibitors remains an important topic in this field. Summary of the invention

[0007] In view of the problems of the prior art, the present invention provides a PI3K inhibitor and a preparation method and use thereof.

[0008] The compound represented by formula I, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form:

[0009]

[0010] in,

[0011] R1 is selected from hydrogen, substituted or unsubstituted C1-C 10 Alkyl, halogen, wherein the substituent is selected from halogen, hydroxyl, cyano, carboxyl, amino;

[0012] R2 is selected from hydrogen, substituted or unsubstituted C1-C 10 Alkyl, wherein the substituent is selected from halogen, hydroxyl, cyano, carboxyl, amino;

[0013] R3 is selected from substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C6-C 10 cycloalkyl, substituted or unsubstituted 9-20 membered spiroheterocycloalkyl, substituted or unsubstituted 7-20 membered bridged heterocycloalkyl,

[0014] Wherein the substituent is selected from oxygen atoms, C1-C 10 Alkoxy, deuterium substituted C1-C 10 Alkoxy, C1-C 10 Alkyl, deuterium substituted C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C1-C 10 Ester, SEM, BOC, C1-C 10 Haloalkyl, halogen, cyano, hydroxyl, carboxyl, amino;

[0015] R4 is selected from hydrogen, substituted or unsubstituted C1-C 10 Alkyl, wherein the substituent is selected from halogen, hydroxyl, cyano, carboxyl, amino;

[0016] Ring A is selected from substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the substituent is selected from halogen, carboxyl, amino, C1-C 10 Ester group, Among them, C1-C 10 The ester group can be further substituted by amino, halogen, cyano, hydroxyl, carboxyl, or two substituents on ring A can be linked to form a 5-10 membered lactam;

[0017] L is selected from None or

[0018] M A Selected from O or NH;

[0019] R A1 , R A2 are independently selected from H, hydroxyl, amino, methoxy, cyano, C1-C 10 amide, substituted or unsubstituted 6-10 membered heterocycloalkoxy, substituted or unsubstituted 6-10 membered heterocycloalkylmethyl, substituted or unsubstituted C6-C 10 arylmethyl, substituted or unsubstituted 6-10 membered heteroaryl, substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkynyl, wherein the substituent is selected from deuterium, hydroxyl, C1-C 10 Alcohol, C1-C 10 Alkoxy, C2-C 10 Ether group, C1-C 10 Alkyl, halogen, C1-C 10 Amine, carboxyl, C1-C 10 haloalkyl, 4-10 membered heterocycloalkyl, amino, cyano, wherein the 4-10 membered heterocycloalkyl may be further C1-C 10 Alkyl substitution;

[0020] or, R A1 With R A2 connected to form a substituted or unsubstituted 5-10 membered heterocycloalkyl, wherein the substituent is selected from hydroxyl, C1-C 10 Alcohol, C1-C 10 Alkoxy, C1-C 10 Alkyl, halogen, C1-C 10 Amine, carboxyl, C1-C 10 Haloalkyl, amino, cyano;

[0021] R5 is selected from H,

[0022] Or, R5 and R A1 connected to form a substituted or unsubstituted 6-10 membered heterocycloalkyl group, wherein the substituent is selected from an oxygen atom;

[0023] Selected from

[0024] M3 is selected from N, CH or CR1.

[0025] Preferably, the compound represented by formula I is represented by formula II or formula III:

[0026]

[0027] Preferably, ring A is selected from phenyl which is substituted or unsubstituted by 1-2 substituents, 6-membered heteroaryl which is substituted or unsubstituted by 1-2 substituents, wherein the substituents are selected from F, Cl, amino, Or two substituents on ring A are connected to form a 5-membered lactam;

[0028] M A Selected from O or NH;

[0029] R A1 , R A2 Each of the following is independently selected from H, hydroxy, amino, methoxy, cyano, C2 amide, 6-membered heterocycloalkyloxy substituted or unsubstituted by 1-2 substituents, 6-membered heterocycloalkylmethyl substituted or unsubstituted by 1-2 substituents, benzyl substituted or unsubstituted by 1-2 substituents, 6-membered heteroaryl substituted or unsubstituted by 1-2 substituents, 4-5-membered heterocycloalkyl substituted or unsubstituted by 1-2 substituents, phenyl substituted or unsubstituted by 1-2 substituents, C3-C6 cycloalkyl substituted or unsubstituted by 1-2 substituents, C1-C4 alkyl substituted or unsubstituted by 1-2 substituents, and C2-C3 alkynyl substituted or unsubstituted by 1-2 substituents, wherein the substituent is selected from hydroxy, hydroxymethyl, methoxy, methyl, F, Cl, N,N-dimethylamino, carboxyl, C1 haloalkyl, amino, and cyano.

[0030] or, R A1 With R A2 They are connected to form a 5-6 membered heterocycloalkyl group which is substituted or unsubstituted with 1-2 substituents, wherein the substituents are selected from hydroxyl, hydroxymethyl, methoxy, methyl, F, N,N-dimethylamino, and carboxyl.

[0031] Preferably, the compound represented by formula I is represented by formula IV or formula V:

[0032]

[0033] Among them, R A3 is selected from H, F, Cl; M4 is selected from N, CH.

[0034] Preferably, R2 is selected from methyl.

[0035] Preferably, R4 is selected from methyl.

[0036] Preferably, R5 is selected from H.

[0037] Preferably, the compound represented by formula I is represented by formula VI or formula VII:

[0038]

[0039] Preferably, R1 is selected from methyl, F or Cl.

[0040] Preferably, R3 is selected from 5-6 membered heterocycloalkyl substituted or unsubstituted by 1-2 substituents, 5-6 membered heteroaryl substituted or unsubstituted by 1-3 substituents, phenyl substituted or unsubstituted by 1-2 substituents, C6 cycloalkyl substituted or unsubstituted by 1-2 substituents, 9-10 membered spiroheterocycloalkyl substituted or unsubstituted by 1-2 substituents, 7 membered bridged heterocycloalkyl substituted or unsubstituted by 1-2 substituents,

[0041] Wherein, the substituent is selected from oxygen atom, methoxy group, deuterium substituted methoxy group, C1-C4 alkyl group, cyclopropane group, deuterium substituted methyl group, C2 ester group, SEM, BOC, C1 haloalkyl group, F, cyano group, hydroxyl group.

[0042] Preferably, the compound represented by formula I is represented by formula VIII or formula IX:

[0043]

[0044] Among them, R A1 Selected from C3 cycloalkyl substituted or unsubstituted by 1-2 substituents, C1-C4 alkyl substituted or unsubstituted by 1-2 substituents;

[0045] Wherein, the substituent is selected from hydroxyl, hydroxymethyl, methoxy, cyano, and F.

[0046] Preferably, R3 is selected from a 5-6 membered heteroaryl group which is substituted or unsubstituted by one substituent, or a phenyl group which is substituted or unsubstituted by one substituent, wherein the substituent is selected from a methoxy group, a C1-C2 alkyl group, or F.

[0047] Preferably, R A1 , R A2Each of the following is independently selected from H, hydroxyl, amino, methoxy, cyano, C1-C2 amide substituted or unsubstituted by 1 substituent, 6-membered heterocycloalkyloxy substituted or unsubstituted by 1-2 substituents, 6-membered heterocycloalkylmethyl substituted or unsubstituted by 1-2 substituents, benzyl substituted or unsubstituted by 1-2 substituents, 6-membered heteroaryl substituted or unsubstituted by 1-2 substituents, 4-5-membered heterocycloalkyl substituted or unsubstituted by 1-2 substituents, -2 substituents substituted or unsubstituted phenyl, substituted or unsubstituted C3-C6 cycloalkyl substituted or unsubstituted C1-C4 alkyl substituted or unsubstituted C1-2 substituents, deuterated methyl, substituted or unsubstituted C3 alkynyl substituted or unsubstituted C3 alkynyl substituted or unsubstituted C3 alkynyl, wherein the substituent is selected from hydroxyl, hydroxymethyl, methoxy, methyl, ether, F, Cl, N,N-dimethylamino, carboxyl, C1 haloalkyl, methyl-substituted 6-membered heteroaryl, amino, cyano,

[0048] or, R A1 With R A2 They are connected to form a 5-6 membered heterocycloalkyl group which is substituted or unsubstituted with 1-2 substituents, wherein the substituents are selected from hydroxyl, hydroxymethyl, methoxy, methyl, F, N,N-dimethylamino, and carboxyl.

[0049] Preferably, R A1 , R A2 are independently selected from H, C3 cycloalkyl which may be substituted by 1-2 substituents, C1-C4 alkyl which may be substituted by 1-2 substituents,

[0050] Wherein, the substituent is selected from hydroxyl, hydroxymethyl, methoxy, cyano, and F.

[0051] Preferably, R5 and R A1 connected to form a 7-membered heterocycloalkyl group which is substituted or unsubstituted by 1-2 substituents, wherein the substituents are selected from oxygen atoms;

[0052] R A1 With R A2 They are connected to form a substituted or unsubstituted 5-membered heterocycloalkyl group, wherein the substituent is selected from hydroxyl group.

[0053] Preferably, the compound represented by formula I is selected from one of the compounds represented by the following structural formulas:

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067] The present invention also provides a method for preparing the above compound, comprising the following steps:

[0068] Step 1, raw material A reacts with raw material B to obtain intermediate C;

[0069]

[0070] Step 2, intermediate C is reacted to obtain intermediate D;

[0071]

[0072] Step 3, the intermediate D reacts with the raw material E to obtain a compound represented by formula IV;

[0073]

[0074] Preferably, in step 1, the reaction is carried out under the action of a catalyst, and the base is selected from DIPEA;

[0075] And / or, in step 1, the reaction solvent is selected from at least one of DMAc and DMF;

[0076] And / or, in step 1, the reaction conditions are 80-150° C. for 2-24 hours;

[0077] And / or, in step 2, the reaction is carried out under the action of a base, wherein the base is selected from at least one of TMSOK, sodium hydroxide or lithium hydroxide;

[0078] And / or, in step 2, the reaction solvent is selected from at least one of THF, methanol or water or a mixed solvent thereof;

[0079] And / or, in step 2, the reaction conditions are 20-40° C. for 1-24 hours;

[0080] And / or, in step 3, the reaction is carried out under the action of a catalyst, wherein the catalyst is selected from at least one of HATU, T4P, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate;

[0081] And / or, in step 3, the reaction is carried out under the action of a base, and the base is selected from DIPEA and N-methylimidazole;

[0082] And / or, in step 3, the reaction solvent is selected from at least one of DMAc, DCM, acetonitrile and DMF;

[0083] And / or, in step 3, the reaction conditions are 20-40° C. for 0.5-24 hours.

[0084] The present invention also provides the use of the above-mentioned compound, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form in the preparation of a PI3K inhibitor.

[0085] The present invention also provides the use of the above-mentioned compound, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form in the preparation of a drug for treating PI3K-mediated diseases.

[0086] Preferably, the PI3K-mediated disease is one or more of breast cancer, ovarian cancer, prostate cancer, lung cancer, endometrial cancer, colon cancer, head and neck squamous cell carcinoma, diabetes, Parkinson's disease or Alzheimer's disease.

[0087] Preferably, the PI3K-mediated disease is one or more of the following diseases with brain metastasis: breast cancer, ovarian cancer, prostate cancer, lung cancer, endometrial cancer, and colon cancer.

[0088] The present invention also provides a pharmaceutical composition, which is a preparation prepared by using the above-mentioned compound, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form as an active ingredient, and adding pharmaceutically acceptable excipients.

[0089] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0090] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0091] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0092] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～4 The term "alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.

[0093] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group with 1 to 6 member atoms, such as 1 to 4 member atoms. The alkyl group can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group can also be part of other groups, such as C1-C6 alkoxy.

[0094] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms and no ring heteroatoms and having a single ring. For polycyclic systems with aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8,-tetrahydronaphthalene-5-yl) is applicable when the point of attachment is located at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. "Alkenyl" refers to a straight or branched hydrocarbon group having 2 to 10 carbon atoms and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least 1 vinyl unsaturation site (>C=C<). For example, (Ca-Cb)alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, etc.

[0095] "Alkynyl" refers to a straight chain monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon groups having one triple bond and one double bond. For example, (C2-C6)alkynyl is intended to include ethynyl, propynyl, and the like.

[0096] "Halogen" is fluorine, chlorine, bromine or iodine.

[0097] "Haloalkyl" means that the hydrogen atoms in the alkyl group may be replaced by one or more halogen atoms. 1～4 The halogenalkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms.

[0098] "Heterocycle" and "heterocycloalkyl" refer to a saturated or non-aromatic unsaturated ring containing at least one heteroatom and having a single ring; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0099] "Aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom and having a single ring; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0100] "Spiroheterocycloalkyl" refers to a spirocyclic ring consisting of a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0101] "Bridged heterocycloalkyl" refers to a bridged ring consisting of a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0102] "Heterocycloalkoxy" refers to a group of heterocycloalkyl attached to the attachment site through an oxygen atom, for example It is a "6-membered heterocycloalkoxy";

[0103] "Heterocycloalkylmethyl" refers to a group of heterocycloalkyl attached to the attachment site through a methylene group, e.g. It is a "6-membered heterocycloalkylmethyl";

[0104] "Arylmethyl" refers to a group in which an aryl group is attached to the attachment site through a methylene group, for example, benzyl is a C6 arylmethyl group.

[0105] "Alkoxy" refers to an alkyl group attached to the site of attachment through an oxygen atom, for example, methoxy refers to -OCH3.

[0106] “R a , R b "connected to form a ring" refers to R a and R b There is at least one atom in each of them connected by a chemical bond, so that R a , R b Together with the molecular skeleton structure in which they are located, they form a ring structure.

[0107] In the present invention, the group "SEM" refers to (trimethylsilyl)ethoxymethyl, and "BOC" refers to tert-butyloxycarbonyl.

[0108] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form and physiologically compatible with the receptor.

[0109] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compound. It can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent). These salts may form a precipitate in the solution and be collected by filtering, or be recovered after solvent evaporation, or be obtained by freeze drying after reaction in an aqueous medium. The salt described in the present invention can be a hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

[0110] In certain embodiments, one or more compounds of the present invention may be used in combination with each other. It is also possible to select the compounds of the present invention and any other active agent for use in combination to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately or sequentially.

[0111] The present invention provides a new class of compounds shown in formula I, which exhibit good PI3K inhibitory activity and provide a new drug option for clinical treatment of diseases related to abnormal PI3K activity.

[0112] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0113] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0114] In the following examples and experimental examples, reagents and raw materials not particularly described are all commercially available.

[0115] Example 1 Synthesis of Common Intermediate (R)-8-(1-aminoethyl)-6-fluoro-2-(5-fluoropyridin-2-yl)-3-methylquinazolin-4(3H)-one (Int.6)

[0116]

[0117] 1. Synthesis of intermediate 2-amino-3-bromo-5-methyl-N-methylbenzamide (Int.1)

[0118]

[0119] 2-Amino-3-bromo-5-methylbenzoic acid (SM1, 195.5 g, 0.85 mol) was dissolved in anhydrous THF (2 L), and CDI (151 g, 0.94 mol) was added in batches. The system gradually bubbled. After reacting for 2 h, the system was cooled to 0-10 ° C, and methylamine aqueous solution (1.2 L) was added dropwise, and the reaction was 1 h. TLC detected that the reaction was complete. Water (2 L) was added, the liquid was separated, and EA (500 mL × 2) was used for extraction, and the product was dried over anhydrous sodium sulfate. The crude product was slurried with EA / PE and filtered to obtain Int.1 (165 g, 0.68 mol), with a yield of 80%. M / S: 243 / 245 (M+H + ).

[0120] 2. Synthesis of intermediate 8-bromo-2-(4-methoxyphenyl)-3,6-dimethylquinolin-4(3H)-one (Int.2)

[0121]

[0122] Int.1 (4 g, 16.46 mmol), 4-methoxybenzaldehyde (2.69 g, 19.75 mmol) and iodine (6.72 g, 24.69 mmol) were dissolved in DMSO (400 mL) in turn, stirred at 100 ° C, monitored by TLC, and after the reaction was completed. Ice water was added to the system and the solid was filtered. The solid was slurried with ethanol and filtered to obtain Int.2 (5.5 g, 15.32 mol), with a yield of 93%. M / S: 359 / 361 (M+H + ).

[0123] 3. Synthesis of intermediate 8-acetyl-2-(4-methoxyphenyl)-3,6-dimethylquinolin-4(3H)-one (Int.3)

[0124]

[0125] Int.2 (5.5 g, 15.32 mmol), tin reagent (8.31 g, 0.68 mmol), DPIEA (3.95 g, 30.64 mmol) and Pd(PPh3)2Cl2 (1.6 g, 2.30 mmol) were added to Dioxane (55 mL) in sequence, and the mixture was reacted at 105°C for 12 h under nitrogen protection and monitored by TLC. After cooling, DCM (28 mL) was added, and the pH was adjusted to 2-3 with 6 M HCl. After stirring for 1-2 h, the mixture was tested by TLC. KF was added for saturated dissolution and stirred for 1 h, filtered, extracted with DCM (28 mL×2), dried over anhydrous sodium sulfate, and slurried with MTBE to obtain Int.3 (4.5 g, 13.98 mmol) with a yield of 91%. M / S: 323 (M+H + ).

[0126] 4. Synthesis of intermediate (R,Z)-N-(1-(2-(4-methoxyphenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinolin-8-yl)ethylidene)-2-methylpropane-2-sulfenamide (Int.4)

[0127]

[0128] Int.3 (1.5 g, 4.66 mmol), (R)-(+)-tert-butylsulfenamide (1.13 g, 9.32 mmol) and tetraethyl titanate (5.3 g, 23.3 mmol) were added to anhydrous THF (15 mL) in sequence, stirred at 85 ° C for 12 h, and monitored by TLC. The reaction solution was poured into ice water (100 mL), filtered, separated, and extracted with DCM (50 ml × 2). Dry over anhydrous sodium sulfate and spin dry. 1.7 g of crude Int.4 was obtained and used directly in the next step. M / S: 426 (M+H + ).

[0129] 5. Synthesis of intermediate N-((R)-1-(2-(4-methoxyphenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinolin-8-yl)ethyl)-2-methylpropane-2-sulfenamide (Int.5)

[0130]

[0131] Int.4 crude product (1.7 g, 4 mmol) and CeCl3·7H2O (0.73 g, 0.2 mmol) were added to MeOH (17 mL) in sequence, and nitrogen was used for protection. After dissolving, the temperature was lowered to -60~-70℃, and NaBH4 (0.37 g, 0.98 mmol) was added in batches. After addition, the temperature was naturally raised to room temperature. DCM and water were added for extraction. After pre-TLC, Int.5 (1.1 g, 2.58 mol) was obtained by recrystallization with anhydrous ethanol and water. The two-step yield was 55%. M / S: 428 (M+H + ). HNMR: de value: 98%.

[0132] 6. Synthesis of intermediate (R)-8-(1-aminoethyl)-2-(4-methoxyphenyl)-3,6-dimethylquinolin-4(3H)-one (Int.6)

[0133]

[0134] Int.5 (600 mg, 1.4 mmol) was dissolved in DCM (6 mL), cooled in an ice-water bath, and a dioxane solution of HCl (4N, 2 mL) was added. The mixture was stirred at room temperature and monitored by TLC. After the reaction was completed, water (60 mL) was added, and the mixture was separated. The pH of the aqueous phase was adjusted to 7-8 with sodium bicarbonate, filtered, and dried to obtain Int.6 (400 mg, 1.24 mmol). The yield was 88%. M / S: 324 (M+H + ). 1HNMR(400MHz,Chloroform-d)δ8.02(dd,J=2.0,1.0Hz,1H),7.58-7.50(m,3H),7.04(d,J=2.1Hz,1H),7. 02(d,J=2.1Hz,1H),4.81(q,J=6.8Hz,1H),3.89(s,3H),3.55(s,3H),2.48(s,3H),1.60(d,J=6.8Hz,3H).

[0135] Example 2 Synthesis of Compound (R)-6-chloro-N-(2-hydroxyethyl)-3-((1-(2-(4-methoxyphenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinolin-8-yl)ethyl)amino)picolinamide (Compound 60)

[0136]

[0137] 1. Synthesis of intermediate (R)-6-chloro-3-((1-(2-(4-methoxyphenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinolin-8-yl)ethyl)amino)picolinic acid methyl ester (Int.7)

[0138]

[0139] Int.6 (323 mg, 1 mmol), 2-chloro-5-fluoro-pyridine-6-carboxylic acid methyl ester (189 g, 1 mmol), and DIPEA (193.5 g, 1.5 mmol) were added to DMAc (3.5 mL), stirred at 100°C for 4 hours, and monitored by TLC. After the reaction was completed, water (15 mL) was added, and EA (15 ml×3) was extracted. Column chromatography was performed to obtain Int.7 (482 mg, 0.98 mmol), with a yield of 98%. M / S: 493 (M+H + ). 1HNMR(400MHz,Chloroform-d)δ8.02(dd,J=2.1,1.0Hz,1H),7.59(d,J=2.0Hz,1H),7.58(d,J=2.1Hz,1H),7.50(d,J=2.0Hz,1H),7.08 -7.00(m,3H),6.91(d,J=9.0Hz,1H),5.65(q,J=6.7Hz,1H),3.98(s,3H),3.91(s,3H),3.58(s,3H),2.42(s,3H),1.64(d,J=6.6Hz,3H).

[0140] 2. Synthesis of intermediate (R)-6-chloro-3-((1-(2-(4-methoxyphenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinolin-8-yl)ethyl)amino)picolinic acid (Int.8)

[0141]

[0142] Int.7 (482 mg, 0.98 mmol) was dissolved in THF (5 ml), TMSOK (501 mg, 3.92 mmol) was added, and the mixture was stirred at room temperature and monitored by TLC. After the reaction was completed, the pH was adjusted to about 3 with HCl (1 N), and EA was extracted and column chromatography was performed to obtain Int.8 (361 mg, 0.75 mmol) with a yield of 77%. M / S: 472 (M+H + ). 1HNMR(400MHz,Chloroform-d)δ8.23(s,1H),8.02(dd,J=2.1,1.0Hz,1H),7.59(d,J=2.0Hz,1H),7.57(d,J=2.1Hz,1H),7.51(d,J=2.0H z,1H),7.09-7.03(m,3H),6.96(d,J=9.0Hz,1H),5.65(q,J=6.7Hz,1H),3.91(s,3H),3.58(s,3H),2.43(s,3H),1.64(d,J=6.7Hz,3H).

[0143] 3. Synthesis of compound (R)-6-chloro-N-(2-hydroxyethyl)-3-((1-(2-(4-methoxyphenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinolin-8-yl)ethyl)amino)picolinamide (Compound 60)

[0144]

[0145] Int.8 (50 mg, 0.1 mmol) was dissolved in DMAc (0.5 ml), and ethanolamine (7 mg, 0.12 mmol), HATU (57 mg, 0.15 mmol), and DIPEA (26 mg, 0.2 mmol) were added; the mixture was stirred at room temperature and monitored by TLC. After the reaction was completed, column chromatography was performed to obtain compound 60 (32 mg, 0.06 mmol) with a yield of 60%. M / S: 522 (M+H + ). 1 H NMR (400MHz, DMSO-d6) δ9.08(d,J=6.9Hz,1H),8.42(t,J=5.9Hz,1H),7.87(dd,J=2.1,1.0H z,1H),7.78-7.70(m,2H),7.57(d,J=2.1Hz,1H),7.25(d,J=8.9Hz,1H),7.14-7.08(m,2H), 6.94(d,J=9.0Hz,1H),5.43(t,J=6.8Hz,1H),4.82(t,J=5.4Hz,1H),3.85(s,3H),3.54(q,J =5.8Hz,2H),3.44(s,3H),3.37(td,J=5.9,2.4Hz,2H),2.39(s,3H),1.55(d,J=6.7Hz,3H).

[0146] Example 3 Synthesis of Compound (R)-6-chloro-N-cyclopropyl-3-((1-(2-(4-methoxyphenyl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinamide

[0147]

[0148] 1. Synthesis of intermediate 2-bromo-4-methylpropionic acid phenyl ester (1)

[0149]

[0150] Operation: 2-bromo-4-methylphenol (88.5 g, 473.2 mmol) and pyridine (48.2 g, 520.5 mmol) were added to dichloromethane (500 mL) in sequence, cooled to 0°C in an ice-water bath, and propionyl chloride (56.1 g, 709.8 mmol) was added dropwise. After the addition was completed, the temperature was naturally raised to react overnight, and dichloromethane (500 mL) was added. 1M hydrochloric acid (2000 mL) was washed once, and the aqueous layer was extracted with dichloromethane (500 mL × 2). The organic layers were combined, washed once with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 113 g of the product (intermediate 1), with a yield of 98.2%.

[0151] 2. Synthesis of intermediate 1-(3-bromo-2-hydroxy-5-methylphenyl)propan-1-one (2)

[0152]

[0153] Operation: Add intermediate 1 (50.0 g, 205.6 mmol) and aluminum chloride (82.3 g, 617.0 mol) to the reaction bottle in sequence, heat the oil bath to 140 °C for 2 hours, cool to room temperature, add dichloromethane (500 mL), slowly pour into water (2000 mL) to quench, extract the aqueous layer with dichloromethane (500 mL × 2), combine the organic layers, wash once with saturated brine (500 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a solid crude product, slurry with methyl tert-butyl ether (500 mL), filter, and dry the filter cake to obtain 35.9 g of product (intermediate 2), yield: 72.0%. 1 H NMR (400MHz, DMSO-d6) δ12.67(s,1H),7.82-7.80(m,1H),7.71(d,J=2.0Hz,1H),3.15(q,J=7.1Hz,2H),2.29(s,3H),1.10(t,J=7.1Hz,3H).

[0154] 3. Synthesis of intermediate 8-bromo-4-hydroxy-3,6-dimethyl-2H-chromene-2-thione (3)

[0155]

[0156] Operation: Dissolve intermediate 2 (4.5 g, 18.5 mmol) in tetrahydrofuran (45 mL), cool to -60 °C in a dry ice bath, add lithium bis(trimethylsilyl)amide (64.8 ml, 64.8 mmol), return to 0 °C and keep warm for 1 hour, cool to -20 °C, add carbon disulfide (2.8 g, 37.0 mol), and after the addition, naturally heat to react overnight, cool to -20 °C, add 15% sulfuric acid aqueous solution (45 mL), extract with ethyl acetate (500 mL × 2), combine the organic layers, wash once with saturated brine (500 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is slurried with petroleum ether / dichloromethane (7:3, 45 mL) to obtain 4.1 g of product (intermediate 3), with a yield of 77.7%. Ms: 284.9 / 286.9 (M+H + ).

[0157] 4. Synthesis of intermediate 8-bromo-2-(ethylthio)-3,6-dimethyl-4H-chromen-4-one (4)

[0158]

[0159] Procedure: Add intermediate 3 (4.1 g, 14.4 mmol) and potassium carbonate (4.0 g, 28.8 mmol) to tetrahydrofuran (80 mL) in sequence, add iodoethane (4.5 g, 28.8 mmol), react at room temperature overnight, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography to obtain 2.5 g of product (intermediate 4), yield: 55.5%. Ms: 313.0 / 315.0 (M+H + ).

[0160] 5. Synthesis of intermediate 8-acetyl-2-(ethylthio)-3,6-dimethyl-4H-chromen-4-one (5)

[0161]

[0162] Operation: Add intermediate 4 (2.5 g, 8.0 mmol), 4-hydroxybutyl vinyl ether (1.9 g, 16.0 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (1.2 g, 1.6 mmol), potassium carbonate (3.3 g, 23.9 mmol) to acetonitrile / water (4:1 50 mL) in sequence, replace with nitrogen three times, heat to 80 °C in an oil bath for overnight reaction, cool to room temperature, add 2N hydrochloric acid dropwise to adjust pH=2, stir at room temperature for 1 hour, extract with ethyl acetate (100 mL×2), combine the organic layers, wash once with saturated sodium bicarbonate aqueous solution (50 mL), wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 1.8 g of product (intermediate 5), yield: 81.6%. Ms: 277.1 (M+H+ ).

[0163] 6. Synthesis of intermediate (R,Z)-N-(1-(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethylidene)-2-methylpropane-2-sulfenamide (6)

[0164]

[0165] Operation: Add intermediate 5 (1.8 g, 6.5 mmol), (R)-(+)-tert-butylsulfenamide (1.6 g, 13.0 mmol), and tetraethyl titanate (7.4 g, 32.6 mmol) to tetrahydrofuran (10 mL) in sequence, heat to 90 °C in an oil bath and react overnight, cool to room temperature, add ethyl acetate (50 mL) to dilute, add water (50 mL), stir for 1 hour, filter, slurry the filter cake with ethyl acetate (20 mL × 2), combine the filtrate and separate the layers, wash the organic layer with water (50 mL × 2), wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 2.5 g of crude product (intermediate 6), which is directly used in the next step. Ms: 380.1 (M+H + ).

[0166] 7. Synthesis of intermediate (R)-N-((R)-1-(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfenamide (7)

[0167]

[0168] Operation: Add intermediate 6 (2.5 g, 6.6 mmol) and cerium (III) chloride heptahydrate (1.2 g, 3.3 mmol) to methanol (100 mL) in sequence, cool to -60 °C in a dry ice bath, add dropwise a solution of sodium borohydride (0.5 g, 13.2 mmol) in N, N-dimethylacetamide (10 mL), remove the dry ice bath after the addition, and allow the reaction to rise naturally. After rising to room temperature, slowly add saturated aqueous ammonium chloride solution (200 mL) to quench, extract with ethyl acetate (100 mL × 2), combine the organic layers, wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 1.4 g of the product (intermediate 7), de value: 98%, two-step reaction yield: 56.3%. Ms: 382.2 (M+H + ). 1H NMR (400MHz, DMSO-d6) δ7.74-7.69(m,2H),5.85(d,J=7.2Hz,1H),4.97(p,J=6.8Hz,1H),3.29(qd,J= 7.4, 3.9Hz, 2H), 2.42 (s, 3H), 1.94 (s, 3H), 1.49 (d, J = 6.8Hz, 3H), 1.40 (t, J = 7.3Hz, 3H), 1.08 (s, 9H).

[0169] 8. Synthesis of intermediate (R)-N-((R)-1-(2-(4-methoxyphenyl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfenamide (8)

[0170]

[0171] Operation: Add intermediate 7 (572 mg, 1.5 mmol), 4-methoxyphenylboronic acid (1.14 g, 7.5 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (439 mg, 0.6 mmol), cuprous thiophene-2-carboxylate (1.14 g, 6.0 mmol), cesium carbonate (977 mg, 3.0 mmol), 4A molecular sieve (600 mg) to 1,4-dioxane (25 mL) in sequence, replace with nitrogen three times, heat the oil bath to 75 ° C and react overnight, cool to room temperature, filter, wash the filter cake with ethyl acetate (50 mL × 2), combine the filtrate, wash once with water (50 mL), wash once with saturated brine (50 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 420 mg of product (intermediate 8), yield: 65.5%. Ms: 428.2 (M+H + ).

[0172] 9. Synthesis of intermediate (R)-8-(1-aminoethyl)-2-(4-methoxyphenyl)-3,6-dimethyl-4H-chromen-4-one (9)

[0173]

[0174] Procedure: Dissolve intermediate 8 (420 mg, 0.98 mmol) in dichloromethane (20 mL), add hydrogen chloride 1,4-dioxane solution (4.0 M, 5 mL), react at room temperature for 4 hours, slowly add saturated sodium bicarbonate aqueous solution to adjust pH>7, extract with dichloromethane (20 mL×2), combine the organic layers, wash once with saturated brine (20 mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 300 mg of product (intermediate 9), yield: 94.4%. Ms: 324.2 (M+H + ).

[0175] 10. Synthesis of intermediate (R)-6-chloro-3-((1-(2-(4-methoxyphenyl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinic acid methyl ester (10)

[0176]

[0177] Procedure: Add intermediate 9 (300 mg, 0.93 mmol), methyl 6-chloro-3-fluoropicolinate (352 mg, 1.8 mmol), and N,N-diisopropylethylamine (360 mg, 2.8 mmol) to N,N-dimethylacetamide (6 mL) in sequence, heat to 110 °C in an oil bath and react overnight, cool to room temperature, add ethyl acetate (30 mL) to dilute, wash with water (50 mL × 2), wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 230 mg of product (intermediate 10), yield: 50.3%. Ms: 493.2 (M+H + ).

[0178] 11. Synthesis of intermediate (R)-6-chloro-3-((1-(2-(4-methoxyphenyl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinic acid (11)

[0179]

[0180] Procedure: Dissolve intermediate 10 (230 mg, 0.47 mmol) in tetrahydrofuran / methanol / water (2:2:1 10 mL), add lithium hydroxide monohydrate (98 mg, 2.3 mmol), react at room temperature for 4 hours, add 2N hydrochloric acid dropwise to adjust pH=3, extract with dichloromethane (20 mL×2), combine the organic layers, wash once with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 190 mg of product (intermediate 11), yield: 85.0%. Ms: 479.1 (M+H + ). 1 H NMR (400MHz, DMSO-d6) δ13.07(s,1H),8.30(d,J=6.6Hz,1H),7.78-7.71(m,3H),7.51(d,J=2.2Hz,1H),7.30(d,J=8.9Hz,1H), 7.14-7.09(m,2H),7.06(d,J=9.1Hz,1H),5.16(p,J=6.6Hz,1H),3.86(s,3H),2.36(s,3H),2.08(s,3H),1.60(d,J=6.6Hz,3H).

[0181] 12. Synthesis of compound (R)-6-chloro-N-cyclopropyl-3-((1-(2-(4-methoxyphenyl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinamide

[0182]

[0183] Procedure: Add intermediate 11 (48 mg, 0.10 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (34 mg, 0.12 mmol), N-methylimidazole (20 mg, 0.25 mmol), cyclopropylamine (11 mg, 0.20 mmol) to N,N-dimethylacetamide (1 mL) in sequence, react at room temperature for 4 hours, add ethyl acetate (10 mL) to dilute, wash once with water (20 mL), wash once with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 30 mg of the product, yield: 57.9%. Ms: 518.2 (M+H + ).

[0184] Example 4 Synthesis of Common Intermediate (R)-2-((1-(6-chloro-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid (1-8)

[0185]

[0186] 1. Synthesis of intermediate 2-amino-3-bromo-5-chloro-N-methylbenzamide (1-1)

[0187]

[0188] Operation: Add 2-amino-3-bromo-5-chlorobenzoic acid (20 g; 80 mmol) to THF (100 mL), replace with nitrogen three times, add N, N'-carbonyldiimidazole (13 g; 88 mmol) in batches under stirring in an ice-water bath, and heat to room temperature and stir for 60 minutes after addition. Slowly drop methylamine aqueous solution (40 mL) under cooling and stirring in an ice-water bath, and return to room temperature naturally after the addition is complete, and stir overnight. After the reaction is complete, pour the reaction solution into 1 L of water and stir to precipitate solids, filter, rinse the filter cake with water 3 times, collect the filter cake after draining, and dry to obtain compound 1-1 (20 g; 76 mmol); yield 86%. Ms: 262 (M+H+)

[0189] 2. Synthesis of intermediate 8-bromo-6-chloro-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one (1-2)

[0190]

[0191] Operation: Add 5-1 (20 g; 76 mmol) to dimethyl sulfoxide (200 mL), add 1-methyl-1H-pyrazole-4-carboxaldehyde (84 g; 84 mmol) and iodine (23.3 g; 92 mmol), stir at 100°C overnight. After the reaction is completed, monitor by LCMS, cool to room temperature, pour into 1L water, stir to precipitate solid, filter, rinse the filter cake once with ethanol, collect the filter cake after drying, and dry to obtain compound 1-2 (20 g; 56.8 mmol), with a yield of 75%. Ms: 352 (M+H + )

[0192] 3. Synthesis of intermediate 8-acetyl-6-chloro-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one (1-3)

[0193]

[0194] Operation: 5-2 (20 g; 56.8 mmol), 4-(vinyloxy)butan-1-ol (66 g; 568 mmol), potassium carbonate (15.7 g; 114 mmol), 1,3-bis(diphenylphosphino)propane (4.7 g; 11.4 mmol), palladium acetate (1.27 g; 5.68 mmol) were added to a mixed solvent (200 mL) of acetonitrile / water (1 / 1), protected by nitrogen, and stirred at 85°C overnight; after the reaction solution was cooled to room temperature, concentrated hydrochloric acid (20 mL) was added, stirred for thirty minutes, filtered, extracted with ethyl acetate, and subjected to column chromatography to obtain intermediate 1-3 (15 g; 47.5 mmol), with a yield of 84%.

[0195] Ms:316(M+H + )

[0196] 4. Synthesis of intermediate (R, E)-N-(1-(6-chloro-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfamide (1-4)

[0197]

[0198] Procedure: Add 5-3 (15 g; 47.5 mmol) and (R)-(+)-tert-butylsulfenamide (11.5 g; 94.9 mmol) to tetrahydrofuran (1.1 ml), then add tetraethyl titanate (43 g; 190 mmol), and stir overnight at 80°C. Add water and ethyl acetate, filter, extract with ethyl acetate, and column chromatography to obtain intermediate 1-4 (15 g; 35.8 mmol), with a yield of 75%. Ms: 419 (M+H + )

[0199] 5. Synthesis of intermediate (R)-N-((R)-1-(6-chloro-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfamide (1-5)

[0200]

[0201] Operation: Add 5-4 (15 g; 35.8 mmol) and cerium chloride heptahydrate (6.7 g; 18 mmol) to methanol (300 ml), protect with nitrogen, and after dissolving, cool to -78°C; add sodium borohydride (2.7 g; 71.6 mmol) under low temperature stirring and stir overnight. After the reaction is completed, add ethyl acetate, filter, and column chromatography to obtain intermediate 1-5 (10 g; 23.7 mmol), with a yield of 66%. Ms: 421 (M+H + )

[0202] 6. Synthesis of intermediate (R)-8-(1-aminoethyl)-6-chloro-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one (1-6)

[0203]

[0204] Procedure: Dissolve 5-5 (10 g; 23.7 mmol) in ethyl acetate (50 ml), add a solution of hydrogen chloride in dioxane (30 mL) and stir at room temperature. Monitor by TLC. After the reaction is complete, spin dry, add water, extract with ethyl acetate, adjust the pH of the aqueous phase to alkaline, extract with EA, dry with sodium sulfate, and concentrate to obtain intermediate 1-6 (7.0 g; 22 mmol), with a yield of 93%. Ms: 317 (M+H + )

[0205] 7. Synthesis of intermediate (R)-2-((1-(6-chloro-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid methyl ester (5-7)

[0206]

[0207] Procedure: 1-6 (300 mg; 0.95 mmol) was dissolved in 1,4-dioxane (50 ml), methyl 2-bromo-5-fluorobenzoate (441 mg; 1.89 mmol), cesium carbonate (926 mg; 2.84 mmol), XantPhos (164 mg; 0.28 mmol) and Pd2(dba)3 (173 mg; 0.19 mmol) were added, and then nitrogen was replaced three times, and stirred at 100°C overnight. LCMS monitored the completion of the reaction, cooled to room temperature, added silica gel for concentration, and column chromatography was performed to obtain intermediate 1-7 (300 mg; 0.64 mmol), with a yield of 68%. Ms: 469 (M+H + )

[0208] 8. Synthesis of intermediate (R)-2-((1-(6-chloro-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzoic acid (1-8)

[0209]

[0210] Procedure: 1-7 (300 mg; 0.64 mmol) was dissolved in tetrahydrofuran (5 ml), potassium trimethylsilanol (247 mg; 1.92 mmol) was added and stirred at room temperature for 1 hour. After TLC monitoring, the reaction was completed, cooled to room temperature, quenched with water, adjusted to pH = 4 with dilute hydrochloric acid, extracted with ethyl acetate, dried with sodium sulfate, and concentrated to obtain intermediate 1-8 (260 mg; 0.57 mmol), with a yield of 90%. Ms: 455 (M+H + )

[0211] Example 5 Synthesis of (R)-2-((1-(6-chloro-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorobenzamide (312)

[0212]

[0213] Procedure: Compound 1-8 (60 mg; 0.11 mmol) was dissolved in N, N-dimethylacetamide (1 ml), and HATU (63 mg; 0.16 mmol), N, N-diisopropylethylamine (57 mg; 0.66 mmol) were added in sequence under stirring at room temperature, and finally ammonium chloride (24 mg; 0.44 mmol) was added, and stirred overnight. TLC monitoring, column chromatography was performed after the reaction was completed. Pure compound 1 (30 mg; 0.06 mmol) was obtained, with a yield of 60%. Ms: 454 (M+H + ); 1H NMR (400MHz, DMSO-d6) δ8.56 (s, 1H), 8.45 (d, J = 4.4Hz, 1H), 8.32 (d, J = 7.2Hz ,1H),8.16(s,1H),7.93(d,J=2.4Hz,1H),7.56(dd,J=7.2,3.6Hz,2H),7.40( dd,J=10.2,3.2Hz,1H),6.98(td,J=8.6,3.2Hz,1H),6.33(dd,J=9.2,4.6Hz, 1H),5.43(t,J=6.8Hz,1H),3.96(s,3H),3.73(s,3H),1.54(d,J=6.4Hz,3H).

[0214] Example 6 Synthesis of (R)-6-chloro-N-cyclopropyl-3-((1-(6-fluoro-2-(5-fluoropyridin-2-yl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinamide (333)

[0215]

[0216] 1. The synthesis of intermediates 3-8 can refer to the synthesis of general intermediates 1-8

[0217] 2. Synthesis of the target compound (R)-6-chloro-N-cyclopropyl-3-((1-(6-fluoro-2-(5-fluoropyridin-2-yl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinamide (333)

[0218]

[0219] Procedure: Add intermediate 3-8 (60 mg, 0.13 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (43 mg, 0.15 mmol), and N-methylimidazole (21 mg, 0.25 mmol) to acetonitrile (1.5 mL) in sequence, stir at room temperature for 0.5 hours, add cyclopropylamine (14 mg, 0.25 mmol), react at room temperature for 1 hour, add ethyl acetate (10 mL) to dilute, wash once with water (20 mL), wash once with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and column chromatography. Pure compound 3 (57 mg, 0.11 mmol) was obtained with a yield of 84.6%. Ms: 511.1 (M+H + ); 1H NMR (400MHz, DMSO-d6) δ9.11(d,J=7.2Hz,1H),8.76(d,J=2.6Hz,1H),8.42(d,J=4.6Hz,1 H),8.18(dd,J=8.7,4.5Hz,1H),8.03(td,J=8.7,2.8Hz,1H),7.82-7.73(m,1H),7.66(dd ,J=9.3,2.9Hz,1H),7.26-7.19(m,1H),6.96(d,J=9.5Hz,1H),5.42(p,J=6.7Hz,1H),3.5 1(s,3H),2.87-2.79(m,1H),1.60(d,J=6.7Hz,3H),0.87-0.78(m,2H),0.72-0.65(m,2H).

[0220] Example 7 Synthesis of Compound 6-chloro-3-(((R)-1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4H-chromen-8-yl)ethyl)amino)-N-((1R,2S)-2-fluorocyclopropyl)picolinamide (346)

[0221]

[0222] 1. Synthesis of intermediate 2-bromo-4-methylpropionic acid phenyl ester (4-1)

[0223]

[0224] Operation: 2-bromo-4-methylphenol (88.5 g, 473.2 mmol) and pyridine (48.2 g, 520.5 mmol) were added to dichloromethane (500 mL) in sequence, cooled to 0°C in an ice-water bath, and propionyl chloride (56.1 g, 709.8 mmol) was added dropwise. After the addition was completed, the temperature was naturally raised to react overnight, and dichloromethane (500 mL) was added. 1M hydrochloric acid (2000 mL) was washed once, and the aqueous layer was extracted with dichloromethane (500 mL×2). The organic layers were combined, washed once with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 4-1 (113 g; 465 mmol), with a yield of 98.2%.

[0225] 2. Synthesis of intermediate 1-(3-bromo-2-hydroxy-5-methylphenyl)propan-1-one (4-2)

[0226]

[0227] Operation: Add intermediate 4-1 (50.0 g, 205.6 mmol) and aluminum chloride (82.3 g, 617.0 mol) to the reaction bottle in sequence, heat the oil bath to 140 ° C for 2 hours, cool to room temperature, add dichloromethane (500 mL), slowly pour into water (2000 mL) to quench, extract the aqueous layer with dichloromethane (500 mL × 2), combine the organic layers, wash once with saturated brine (500 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a solid crude product, slurry with methyl tert-butyl ether (500 mL), filter, and dry the filter cake to obtain intermediate 4-2 (35.9 g; 148 mmol), yield: 72.0%. 1 H NMR (400MHz, DMSO-d6) δ12.67(s,1H),7.82-7.80(m,1H),7.71(d,J=2.0Hz,1H),3.15(q,J=7.1Hz,2H),2.29(s,3H),1.10(t,J=7.1Hz,3H).

[0228] 3. Synthesis of intermediate 8-bromo-4-hydroxy-3,6-dimethyl-2H-chromene-2-thione (4-3)

[0229]

[0230] Operation: Dissolve the intermediate 4-2 (4.5 g, 18.5 mmol) in tetrahydrofuran (45 mL), cool to -60 °C in a dry ice bath, add lithium bis(trimethylsilyl)amide (64.8 ml, 64.8 mmol), return to 0 °C and keep warm for 1 hour, cool to -20 °C, add carbon disulfide (2.8 g, 37.0 mol), after the addition is completed, naturally heat up to react overnight, cool to -20 °C, add 15% sulfuric acid aqueous solution (45 mL), extract with ethyl acetate (500 mL × 2), combine the organic layers, wash once with saturated brine (500 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and slurry the crude product with petroleum ether / dichloromethane (7:3, 45 mL) to obtain the intermediate 4-3 (4.1 g; 15.3 mmol), yield: 77.7%. Ms: 284.9 / 286.9 (M+H + ).

[0231] 4. Synthesis of intermediate 8-bromo-2-(ethylthio)-3,6-dimethyl-4H-chromen-4-one (4-4)

[0232]

[0233] Procedure: Add intermediate 4-3 (4.1 g, 14.4 mmol) and potassium carbonate (4.0 g, 28.8 mmol) to tetrahydrofuran (80 mL) in sequence, add iodoethane (4.5 g, 28.8 mmol), react at room temperature overnight, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography to obtain intermediate 4-4 (2.5 g; 7.9 mmol), yield: 55.5%. Ms: 313.0 / 315.0 (M+H + ).

[0234] 5. Synthesis of intermediate 8-acetyl-2-(ethylthio)-3,6-dimethyl-4H-chromen-4-one (4-5)

[0235]

[0236] Operation: Add intermediate 4-4 (2.5 g, 8.0 mmol), 4-hydroxybutyl vinyl ether (1.9 g, 16.0 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (1.2 g, 1.6 mmol), potassium carbonate (3.3 g, 23.9 mmol) to acetonitrile / water (4:1 50 mL) in sequence, replace with nitrogen three times, heat to 80 °C in an oil bath for overnight reaction, cool to room temperature, add 2N hydrochloric acid dropwise to adjust pH=2, stir at room temperature for 1 hour, extract with ethyl acetate (100 mL×2), combine the organic layers, wash once with saturated sodium bicarbonate aqueous solution (50 mL), wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain intermediate 4-5 (1.8 g; 6.4 mmol), yield: 81.6%. Ms: 277.1 (M+H + ).

[0237] 6. Synthesis of intermediate (R,Z)-N-(1-(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethylidene)-2-methylpropane-2-sulfenamide (4-6)

[0238]

[0239] Operation: Add intermediate 5 (1.8 g, 6.5 mmol), (R)-(+)-tert-butylsulfenamide (1.6 g, 13.0 mmol), and tetraethyl titanate (7.4 g, 32.6 mmol) to tetrahydrofuran (10 mL) in sequence, heat to 90 °C in an oil bath and react overnight, cool to room temperature, add ethyl acetate (50 mL) to dilute, add water (50 mL), stir for 1 hour, filter, slurry the filter cake with ethyl acetate (20 mL × 2), combine the filtrate and separate the layers, wash the organic layer with water (50 mL × 2), wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude intermediate 4-6 (2.5 g), which is directly used in the next step. Ms: 380.1 (M+H + ).

[0240] 7. Synthesis of intermediate (R)-N-((R)-1-(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfenamide (4-7)

[0241]

[0242] Operation: Add intermediate 4-6 (2.5 g, 6.6 mmol) and cerium chloride heptahydrate ((Ⅲ1.) 2 g, 3.3 mmol) to methanol (100 mL) in sequence, cool to -60 °C in a dry ice bath, and dropwise add sodium borohydride (0.5 g, 13.2 mmol) in N, N-dimethylacetamide (10 mL). After the addition is complete, remove the dry ice bath, and allow the temperature to rise naturally. After rising to room temperature, slowly add saturated aqueous ammonium chloride solution (200 mL) to quench, extract with ethyl acetate (100 mL × 2), combine the organic layers, wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain intermediate 4-7 (1.4 g; 3.7 mmol), de value: 98%, two-step reaction yield: 56.3%. Ms: 382.2 (M+H + ). 1 H NMR (400MHz, DMSO-d6) δ7.74-7.69(m,2H),5.85(d,J=7.2Hz,1H),4.97(p,J=6.8Hz,1H),3.29(qd,J= 7.4, 3.9Hz, 2H), 2.42 (s, 3H), 1.94 (s, 3H), 1.49 (d, J = 6.8Hz, 3H), 1.40 (t, J = 7.3Hz, 3H), 1.08 (s, 9H).

[0243] 8. Synthesis of intermediate (R)-N-((R)-1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4H-chromen-8-yl)ethyl)-2-isobutane-2-sulfenamide (4-8)

[0244]

[0245] Operation: Add intermediate 4-7 (382 mg, 1.0 mmol), (1-methyl-1H-pyrazol-4-yl)boric acid (630 mg, 5.0 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (366 mg, 0.5 mmol), cuprous thiophene-2-carboxylate (950 mg, 5.0 mmol), cesium carbonate (652 mg, 2.0 mmol), 4A molecular sieves (382 mg) to 1,4-dioxane (8 mL) in sequence, replace with nitrogen three times, heat the oil bath to 75 ° C and react overnight, cool to room temperature, filter, wash the filter cake with ethyl acetate (50 mL × 2), combine the filtrate, wash once with water (50 mL), wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain intermediate 4-8 (265 mg; 0.66 mmol), yield: 65.5%. Ms: 402.2 (M+H + ).

[0246] 9. Synthesis of intermediate (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4H-chromen-4-one (4-9)

[0247]

[0248] Procedure: Dissolve intermediate 4-8 (265 mg, 0.66 mmol) in dichloromethane (3 mL), add hydrogen chloride 1,4-dioxane solution (4.0 M, 1 mL), react at room temperature for 4 hours, slowly add saturated sodium bicarbonate aqueous solution to adjust pH>7, extract with dichloromethane (5 mL×2), combine the organic layers, wash once with saturated brine (20 mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain intermediate 4-9 (193 mg; 0.65 mmol), yield: 98%. Ms: 298.2 (M+H + ).

[0249] 10. Synthesis of intermediate (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinic acid methyl ester (4-10)

[0250]

[0251] Procedure: Add intermediate 4-9 (193 mg, 0.65 mmol), methyl 6-chloro-3-fluoropicolinate (135 mg, 0.71 mmol), and N,N-diisopropylethylamine (168 mg, 1.3 mmol) to N,N-dimethylacetamide (2 mL) in sequence, heat to 110 °C in an oil bath and react overnight, cool to room temperature, add ethyl acetate (10 mL) to dilute, wash with water (10 mL × 2), wash once with saturated brine (10 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain intermediate 4-10 (212 mg; 0.45 mmol), yield: 69.8%. Ms: 467.2 (M+H + ).

[0252] 11. Synthesis of intermediate (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinic acid (4-11)

[0253]

[0254] Procedure: Dissolve intermediate 4-10 (212 mg, 0.45 mmol) in tetrahydrofuran / methanol / water (4:1:13 mL), add lithium hydroxide monohydrate (76 mg, 1.8 mmol), react at room temperature for 4 hours, add 2N hydrochloric acid dropwise to adjust pH = 1, extract with dichloromethane (10 mL × 2), combine the organic layers, wash once with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain intermediate 4-11 (183 mg; 0.40 mmol), yield: 90.0%. Ms: 453.1 (M+H + ).

[0255] 12. Synthesis of compound 6-chloro-3-(((R)-1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4H-chromen-8-yl)ethyl)amino)-N-((1R,2S)-2-fluorocyclopropyl)picolinamide (346)

[0256]

[0257] Operation: Add intermediate 4-11 (45 mg, 0.10 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (34 mg, 0.12 mmol), N-methylimidazole (20 mg, 0.25 mmol), and (1R,2S)-2-fluorocyclopropylamine TsOH salt (49 mg, 0.20 mmol) to acetonitrile (1 mL) in sequence, react at room temperature for 30 minutes, and purify by column chromatography to obtain product 4 (40 mg; 0.078 mmol), yield: 78.4%. 1 H NMR (400MHz, DMSO-d6) δ8.98(d,J=6.5Hz,1H),8.53(s,1H),8.51(d,J=4.4Hz,1H),8.11(d,J=0.8Hz ,1H),7.73(dd,J=2.2,1.0Hz,1H),7.46(d,J=2.2Hz,1H),7.31(d,J=8.9Hz,1H),7.04(d,J=9.0Hz,1H ),5.31(p,J=6.6Hz,1H),4.89(m,0.5H),4.73(m,0.5H),3.98(s,3H),2.85(dq,J=9.4,4.8Hz,1H),2 .33(s,3H),2.19(s,3H),1.63(d,J=6.6Hz,3H),1.41-1.28(m,1H),1.19-1.07(m,1H).Ms:510.2(M+H + ).

[0258] Example 8 Synthesis of Compound (R)-6-chloro-N-isopropyl-3-((1-(2-(2-methoxypyridin-4-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinamide (353)

[0259]

[0260] 1. Synthesis of intermediate (R)-N-((R)-1-(2-(2-methoxypyridin-4-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfamide (1-2)

[0261]

[0262] Procedure: 1-1 (2.0 g; 5.25 mmol) and (2-methoxypyridin-4-yl)boronic acid (4.02 g; 26.25 mmol) were dissolved in 1,4-dioxane (50 mL), and CuTc (4.98 g; 26.25 mmol) was added.

[0263] [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.9 g; 2.62 mmol), cesium carbonate (3.42 g; 10.5 mmol), molecular sieve (2 g), after nitrogen replacement three times, the temperature was raised to 80 ° C and stirred for 12 hours. Filter, wash the filter cake with ethyl acetate, extract the filtrate with ethyl acetate, column chromatography, and obtain intermediate 1-2 (2.0 g; 4.67 mmol), with a yield of 90%. Ms: 429 (M+H + )

[0264] 2. Synthesis of intermediate (R)-8-(1-aminoethyl)-2-(2-methoxypyridin-4-yl)-3,6-dimethyl-4H-methen-4-one (1-3)

[0265]

[0266] Procedure: Dissolve 1-2 (2.0 g; 4.67 mmol) in a mixed solution of ethyl acetate (17 mL) and methanol (17 mL), add HCl / dioxane solution (17 mL), and stir at room temperature for 1 h. Add potassium carbonate aqueous solution to adjust pH = 9, then extract with ethyl acetate, wash with saturated brine, and concentrate to obtain intermediate 1-3 (1.48 g; 4.57 mmol), with a yield of 98%. Ms: 325 (M+H + )

[0267] 3. Synthesis of intermediate methyl (R)-6-chloro-3-((1-(2-(2-methoxypyridin-4-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinic acid methyl ester (1-4)

[0268]

[0269] Operation: 1-3 (1.48 g; 4.57 mmol) was dissolved in N, N-dimethylacetamide (30 mL), 6-chloro-3-fluoropicolinic acid methyl ester (1.74 g; 9.14 mmol) and N, N-diisopropylethylamine (3.54 g; 27.42 mmol) were added, and the atmosphere was replaced with nitrogen three times, and the temperature was raised to 110 ° C and stirred for 12 h, and LCMS was monitored. After the reaction was completed, water and ethyl acetate were added for extraction, saturated salt was added for washing, and the mixture was concentrated under reduced pressure and purified by column chromatography to obtain intermediate 1-4 (2.1 g; 4.26 mmol), with a yield of 93%. Ms: 494 (M+H + )

[0270] 4. Synthesis of intermediate (R)-6-chloro-3-((1-(2-(2-methoxypyridin-4-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinic acid (1-5)

[0271]

[0272] Procedure: 1-4 (2.1 g; 4.26 mmol) was dissolved in tetrahydrofuran (25 mL), and potassium trimethylsilanol (1.63 g; 12.78 mmol) was added, and stirred at room temperature for 1 h. After the reaction was completed, water and ethyl acetate were added, and HCl (2N) was added to adjust the pH to 1. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain intermediate 1-5 (2 g; 4.17 mmol), with a yield of 98%. Ms: 480 (M+H + )

[0273] 5. Synthesis of (R)-6-chloro-N-isopropyl-3-((1-(2-(2-methoxypyridin-4-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinamide (1-6, compound 353)

[0274]

[0275] Procedure: 1-5 (40 mg; 0.083 mmol) was dissolved in acetonitrile (1.5 mL), and tetramethyl chlorourea hexafluorophosphate (35 mg; 0.125 mmol) and N-methylimidazole (21 mg; 0.25 mmol) were added. After stirring at room temperature for 5 min, isopropylamine (20 mg; 0.334 mmol) was added. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 1-6 (30 mg; 0.058 mmol), with a yield of 70%. Ms: 521 (M+H + )

[0276] 1 H NMR (400MHz, DMSO-d6) δ9.04(d,J=6.9Hz,1H),8.38(d,J=5.2Hz,1H),8.16(d,J=8.4Hz, 1H),7.79(d,J=2.2Hz,1H),7.55(d,J=2.2Hz,1H),7.37(dd,J=5.2,1.4Hz,1H),7.31-7. 16(m,2H),7.06(d,J=8.9Hz,1H),5.10(p,J=6.6Hz,1H),4.06(dp,J=8.3,6.5Hz,1H),3. 94(s,3H),2.38(s,3H),2.06(s,3H),1.59(d,J=6.6Hz,3H),1.19(dd,J=6.6,2.9Hz,6H).

[0277] Example 9 Synthesis of (R)-6-chloro-3-((1-(2-(6-fluoropyridin-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (344)

[0278]

[0279] 1. Synthesis of intermediate 8-bromo-2-mercapto-3,6-dimethylquinazoline-4(3H)-one (2-1)

[0280]

[0281] Procedure: Add 1-(3-bromo-2-amino-5-methylphenyl)ethanone (50 g; 220 mmol) to EtOH (500 mL), drop TFA (48.3 g; 440 mmol), drop methyl isothiocyanate (17.5 g; 220 mmol) and heat to 80°C after the addition is complete. Stir overnight. Cool down, filter, rinse the solid with a small amount of EtOH, spin dry the solid to obtain compound 2-1 (51 g; 179 mmol); yield 81%. Ms: 258 (M+H + )

[0282] 2. Synthesis of intermediate 8-bromo-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (2-2)

[0283]

[0284] Operation: Add 2-1 (50 g; 179 mmol) to acetone (800 mL), add potassium carbonate (48.5 g; 358 mmol) and iodomethane (37.4 g; 268.5 mmol), stir at room temperature, and monitor by TLC. After the reaction is completed, add water (2 L), extract with EA (300 mL × 3), dry, concentrate, and slurry with tert-methyl ether (500 mL) to obtain intermediate 2-2 (45 g; 151 mmol), with a yield of 96%. Ms: 300 (M+H + )

[0285] 3. Synthesis of intermediate 8-acetyl-3,6-dimethyl-2-(methylthio)quinazolin-4(3H)-one (2-3)

[0286]

[0287] Operation: Add 2-2 (45 g; 151 mmol), 4-hydroxybutyl vinyl ether (35 g; 302 mmol), K2CO3 (42 g; 302 mmol), tetrakistriphenylphosphine palladium (22 g; 30.2 mmol) to acetonitrile / water (450 mL), protect with nitrogen, and stir at 80°C for 4 hours; after the reaction solution is cooled to room temperature, add dilute hydrochloric acid (10 mL), stir for 30 minutes, then add saturated potassium fluoride solution (300 mL), and stir for one hour. Filter, extract with ethyl acetate, and column chromatography to obtain intermediate 2-3 (35 g; 114 mmol), with a yield of 88%. Ms: 263 (M+H + )

[0288] 4. Synthesis of intermediate (R, Z)-N-(1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfamide (2-4)

[0289]

[0290] Procedure: Dissolve 2-3 (35 g; 114 mmol), tetraethyl titanate (40 g; 228 mmol), and tert-butylsulfenamide (40 g; 171 mmol) in tetrahydrofuran (200 mL) and stir at 80°C for eight hours. Add water and ethyl acetate, filter, extract with ethyl acetate, and perform column chromatography to obtain intermediate 2-4 (40 g; 109 mmol) with a yield of 83%. Ms: 366 (M+H + )

[0291] 5. Synthesis of intermediate (R)-N-(1-(3,6-dimethyl-2-(methylthio)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfamide (2-5)

[0292]

[0293] Procedure: Add 2-4 (40 g; 109 mmol) and cerium chloride heptahydrate (23 g; 54.5 mmol) to methanol (250 ml), protect with nitrogen, dissolve and cool to -78°C; add sodium borohydride (6.6 g; 152 mmol) under low temperature stirring and stir overnight. After the reaction is complete, add ethyl acetate, filter, and column chromatography to obtain intermediate 2-5 (23 g; 62 mmol), with a yield of 57%. Ms: 368 (M+H + )

[0294] 6. Synthesis of intermediate (R)-N-(1-(2-(6-fluoropyridin-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfonamide (2-6)

[0295]

[0296] Procedure: Dissolve 2-5 (300 mg; 0.81 mmol) in dioxane (10 mL), add 2-fluoro-5-pyridineboronic acid (300 mg; 4.05 mmol), CuTc (230 mg; 4.05 mmol), tetrakistriphenylphosphine palladium (200 mg; 0.324 mmol), cesium carbonate (400 mg; 1.62 mmol), molecular sieve (300 mg), and then bubble nitrogen for three minutes. Seal the tube and stir at 85°C for 12 hours. Add water and ethyl acetate, filter, extract with ethyl acetate, and column chromatography to obtain intermediate 2-6 (198 mg; 0.47 mmol), with a yield of 58%. Ms: 417 (M+H + )

[0297] 7. Synthesis of intermediate (R)-8-(1-aminoethyl)-2-(6-fluoropyridin-3-yl)-3,6-dimethylquinazolin-4(3H)-one (2-7)

[0298]

[0299] Procedure: Dissolve 2-6 (198 mg; 0.47 mmol) in dichloromethane (3 ml), add a solution of hydrogen chloride in dioxane (1 mL) and stir at room temperature. Monitor by TLC. After the reaction is complete, spin dry, add water, extract with ethyl acetate, adjust the pH of the aqueous phase to alkaline, extract with EA, dry and spin dry to obtain intermediate 2-7 (114 mg; 0.36 mmol), with a yield of 67%. Ms: 316 (M+H + )

[0300] 8. Intermediate methyl (R)-6-chloro-3-((1-(2-(6-fluoropyridin-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (2-7)

[0301]

[0302] Procedure: Dissolve 2-7 (114 mg; 0.36 mmol) and methyl 6-chloro-3-fluoropyridine-2-carboxylate (83 mg; 0.432 mmol) in DMAc (3 ml), add DIEA (94 mg; 0.72 mmol) and stir at 100°C for 12 hours. After TLC monitoring, the reaction is complete, add water, extract with ethyl acetate, dry and spin dry, and column purification to obtain intermediate 2-8 (80 mg; 0.18 mmol), with a yield of 45%. Ms: 482 (M+H + )

[0303] 9. Synthesis of intermediate (R)-6-chloro-3-((1-(2-(6-fluoropyridin-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (2)

[0304]

[0305] Procedure: Dissolve compound 2-8 (80 mg; 0.18 mmol) in THF (1 ml), add sodium hydroxide aqueous solution (1 mL), and stir at room temperature overnight. Monitor by TLC. After the reaction is completed, extract with EA (10 mL × 3), dry with anhydrous sodium sulfate, and spin dry. Pure compound 2 (30 mg; 0.06 mmol) is obtained with a yield of 38%. Ms: 468 (M+H+) 1 H NMR (400MHz, DMSO-d6) δ9.50(d,J=63.8Hz,1H),8.72(s,1H),8.46(d,J=8.4Hz,1H),7.88(s,1H ),7.66-6.63(m,3H),5.41(d,J=28.6Hz,1H),3.43(s,1H),2.40(s,3H),1.50(d,J=47.3Hz,3H).

[0306] Example 10 Synthesis of Compound (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4H-chromen-8-yl)ethyl)amino)-N-isopropylpicolinamide (349)

[0307]

[0308] 1. Synthesis of compound (R)-6-chloro-3-((1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4H-chromen-8-yl)ethyl)amino)-N-isopropylpicolinamide (349)

[0309] Procedure: Compound 4-11 (synthesis see Example 7, 60 mg; 0.13 mmol) was dissolved in DMAc (1 mL), and isopropylamine (12 mg; 0.20 mmol) and DIPEA (34 mg; 0.26 mmol) were added successively under stirring at room temperature, and stirred at room temperature for 1 h. TLC monitoring, after the reaction was completed, water was added, EA was extracted, and column chromatography was performed. Pure compound 5 (32 mg; 0.06 mmol) was obtained, with a yield of 49%. Ms: 494.2 (M+H + ); 1 H NMR (400MHz, DMSO-d6) δ9.07(d,J=6.5Hz,1H),8.52(s,1H),8.21(d,J=8.5Hz,1H ),8.11(s,1H),7.73(d,J=2.2,1.0Hz,1H),7.47(d,J=2.2Hz,1H),7.28(d,J=8.9H z,1H),7.01(d,J=9.0Hz,1H),5.27(p,J=6.5Hz,1H),4.18-4.04(m,1H),3.97(s,3 H),2.34(s,3H),2.18(s,3H),1.62(d,J=6.6Hz,3H),1.20(dd,J=6.6,2.4Hz,6H).

[0310] Example 11 Synthesis of Compound (R)-1-(1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4H-chromen-8-yl)ethyl)-3-(pyridin-3-yl)urea (367)

[0311]

[0312] 1. Synthesis of the target compound (R)-1-(1-(3,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-oxo-4H-chromen-8-yl)ethyl)-3-(pyridin-3-yl)urea (367)

[0313] Operation: Compound 4-9 (synthesis see Example 7, 60 mg; 0.20 mmol) was dissolved in DMF (1 mL), and DIPEA (52 mg; 0.40 mmol) and CDI (39 mg; 0.24 mmol) were added successively under stirring at room temperature. After stirring at room temperature for 1 hour, 3-aminopyridine (28 mg; 0.30 mmol) was added, and stirred at 60°C overnight, monitored by TLC. After the reaction was completed, water was added, filtered, and the filter cake was slurried with anhydrous ethanol, filtered, and dried. Pure compound 8 (20 mg; 0.05 mmol) was obtained, with a yield of 25%. Ms: 418.2 (M+H + ); 1HNMR(400MHz, DMSO-d6)δ8.64(s,1H),8.52(d,J=2.6Hz,1H),8.47(s,1H),8.12-8.08(m,2H),7.88-7.84(m,1H),7.74(d,J=2.2,1.0Hz,1H),7.60 (d,J=2.2Hz,1H),7.27-7.21(m,1H),6.97(d,J=7.7Hz,1H),5.51(p,J=7 .0Hz,1H),3.95(s,3H),2.42(s,3H),2.18(s,3H),1.52(d,J=6.9Hz,3H).

[0314] Example 12 Synthesis of Compound (R)-6-chloro-N-cyclopropyl-3-((1-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dimethyl-4-oxo-4H-benzopyran-8-yl)ethyl)amino)picolinamide (376)

[0315]

[0316] 1. Synthesis of intermediate (R)-8-(1-aminoethyl)-2-(ethylthio)-3,6-dimethyl-4H-benzopyran-4-one (1-2)

[0317]

[0318] Procedure: Dissolve 1-1 (2.0 g; 5.25 mmol) in a mixed solution of ethyl acetate (17 mL) and methanol (17 mL), add HCl / dioxane solution (17 mL), and stir at room temperature for 1 h. Add potassium carbonate aqueous solution to adjust pH = 9, then extract with ethyl acetate, wash with saturated brine, and concentrate to obtain intermediate 1-2 (1.42 g; 5.14 mmol), with a yield of 98%. Ms: 278 (M+H + )

[0319] 2. Synthesis of intermediate (R)-6-chloro-3-((1-(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-benzopyran-8-yl)ethyl)amino)picolinic acid methyl ester (1-3)

[0320]

[0321] Procedure: Dissolve 1-2 (6 g; 21.66 mmol) and methyl 6-chloro-3-fluoropicolinate (8.88 g; 43.32 mmol) in N,N-dimethylacetamide (60 mL), add DIPEA (8.4 g; 64.98 mmol), heat to 100°C and stir for 12 hours. Add water and ethyl acetate, filter, extract with ethyl acetate, concentrate, and column chromatography to obtain intermediate 1-3 (7.6 g; 17 mmol), with a yield of 78%. Ms: 447 (M+H + )

[0322] 3. Synthesis of intermediate (R)-6-chloro-3-((1-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dimethyl-4-oxo-4H-benzopyran-8-yl)ethyl)amino)picolinic acid methyl ester (1-4)

[0323]

[0324] Procedure: 1-3 (450 mg; 1 mmol) was dissolved in dioxane (5 mL), nitrogen was bubbled for three minutes, (1-cyclopropyl-1H-pyrazol-4-yl)boric acid (1.2 g; 5 mmol), CuTc (950 mg; 5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (218 mg; 0.3 mmol), cesium carbonate (978 mg; 3 mmol), molecular sieves (400 mg) were added, and the tube was sealed and stirred at 90°C for 3 hours. Water and dichloromethane were added, filtered, extracted with dichloromethane, concentrated, and column chromatographed to obtain intermediate 1-4 (320 mg; 0.65 mmol) with a yield of 65%.

[0325] Ms:493(M+H + )

[0326] 4. Synthesis of intermediate (R)-6-chloro-3-((1-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dimethyl-4-oxo-4H-benzopyran-8-yl)ethyl)amino)picolinic acid (1-5)

[0327]

[0328] Procedure: 1-4 (320 g; 0.64 mmol) was dissolved in tetrahydrofuran (3 mL), potassium trimethylsilanol (166 mg; 1.3 mmol) was added, and the mixture was stirred at room temperature for 2 hours and monitored by TLC. After the reaction was completed, 2M HCl was added dropwise to adjust the pH to 1, and ethyl acetate was added, filtered, extracted with ethyl acetate, and concentrated under reduced pressure to obtain intermediate 1-5 (240 mg; 0.5 mmol), with a yield of 78%. Ms: 479 (M+H + )

[0329] 5. Synthesis of intermediate (R)-6-chloro-N-cyclopropyl-3-((1-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dimethyl-4-oxo-4H-benzopyran-8-yl)ethyl)amino)picolinamide (1-6)

[0330]

[0331] Procedure: 1-5 (120 mg; 0.25 mmol) was dissolved in N,N-dimethylacetamide (1.5 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (143 mg; 0.37 mmol) and N,N-diisopropylethylamine (95 mg; 0.74 mmol) were added, and the mixture was stirred at room temperature for 15 minutes. Cyclopropylamine (30 mg; 0.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water and ethyl acetate were added, filtered, extracted with ethyl acetate, and purified by TLC to obtain intermediate 1-6 (60 mg; 0.12 mmol), with a yield of 46%. Ms: 518 (M+H + )

[0332] 1 H NMR(400MHz,Chloroform-d)δ9.07(d,J=5.7Hz,1H),8.03-7.95(m,3H),7.91(d,J=2.2Hz,1H),7.44(d, J=2.2Hz,1H),7.02(d,J=8.8Hz,1H),6.67(d,J=8.8Hz,1H),5.08(t,J=6.4Hz,1H),3.74(tt,J=7.4,3.8H z,1H),2.87(tq,J=7.3,3.7Hz,1H),2.37(s,3H),2.31(s,3H),1.73(d,J=6.6Hz,3H),1.29(d,J=11.1Hz, 1H), 1.25 (d, J = 4.0Hz, 1H), 1.14 (dt, J = 5.8, 2.6Hz, 2H), 0.91 (td, J = 6.9, 5.0Hz, 2H), 0.76-0.67 (m, 2H).

[0333] Example 13 Synthesis of Compound (R)-6-chloro-3-((1-(2-(2-methoxypyridin-4-yl)-3,6-dimethyl-4-oxo-4H-benzopyran-8-yl)ethyl)amino)picolinamide (207)

[0334]

[0335] Synthesis of target compound (207)

[0336]

[0337] Procedure: Methyl (R)-6-chloro-3-((1-(2-(2-methoxypyridin-4-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinic acid (see Example 8 for the synthesis of intermediate 1-4, 40 mg; 0.081 mmol) was dissolved in NH3·MeOH (2 mL) and stirred at 50°C for 12 h. LCMS showed that the reaction was complete. Post-treatment: Directly spin-dried and purified by Prep-HPLC to obtain 1-5 (30 mg; 0.063 mmol) with a yield of 77%. Ms: 479 (M+H + );

[0338] Example 14 Synthesis of Compound (392)

[0339]

[0340] 1. Synthesis of intermediate 4-bromo-2-(methoxy-d3)pyridine

[0341]

[0342] Procedure: Dissolve 4-bromo-2-fluoropyridine (5 g; 28.5 mmol) in THF (50 mL), slowly add NaH (1 g; 42.8 mmol) in batches at 0°C, stir for 30 min, add deuterated methanol-D4, and then react at room temperature overnight. LCMS shows that the reaction is complete. Post-treatment: Slowly pour the reaction solution into ice water, and after quenching, add ethyl acetate to extract, dry over anhydrous sodium sulfate, concentrate, and purify by MPLC to obtain 4-bromo-2-(methoxy-d3)pyridine (4.5 g; 23.5 mmol); yield 82%. Ms: 191 (M+H + )

[0343] 2. Synthesis of intermediate (2-(methoxy-d3)pyridin-4-yl)boronic acid

[0344]

[0345] Operation: Add 4-bromo-2-(methoxy-d3)pyridine (4.5 g; 23.5 mmol), B2Pin2 (9.9 g; 39.2 mmol), KOAc (14.9 g; 70.5 mmol), Pd(dppf)Cl2 (1.7 g; 2.35 mmol), Dio (45 ml) into the reaction bottle, replace N2 three times, and stir at 90°C for 16 h under N2 protection. LCMS shows that the reaction is complete. Post-treatment: Add diatomaceous earth for filtration, rinse with EA (50 mL×3), and concentrate to obtain the crude compound intermediate (2-(methoxy-d3)pyridin-4-yl)boronic acid (3.5 g; 22.2 mmol); yield 94%.

[0346] Ms:157(M+H + )

[0347] 3. The synthesis of compound 392 is similar to that of compound 207, and can be obtained by using the intermediate (2-(methoxy-d3)pyridin-4-yl)boronic acid instead of (2-methoxypyridin-4-yl)boronic acid. 1 H NMR (400MHz, DMSO-d6) δ9.01(d,J=6.8Hz,1H),8.38(d,J=5.3Hz,1H),7.91(d,J=2.5Hz,1H),7.78(t,J=1.5Hz,1H),7.63(d,J=2.5Hz,1H),7.51(d, J=2.3Hz,1H),7.36(dd,J=5.3,1.4Hz,1H),7.27-7.18(m,2H),7.02(d,J= 9.0Hz,1H),5.10(p,J=6.6Hz,1H),3.94(s,3H),2.36(s,3H),2.06(s,3H).

[0348] Example 15 Synthesis of Compounds 1-255 and Compounds 300-392

[0349] According to the methods of Examples 1-3, a variety of compounds with similar structures can be further synthesized. The method for preparing the compound provided in this example is the same as the method of Examples 1, 2 or 3, except that different raw materials are selected for synthesis according to the different substituents of the specific compound.

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[0433]

[0434] The beneficial effects of the present invention are demonstrated below through specific examples.

[0435] Experimental Example 1: Cell Anti-Proliferation Experiment

[0436] In this experiment, four types of cells, MCF-10A, SK-BR-3, MCF-7 and MDA-MB-361, were used. MCF-10A and SK-BR-3 are PI3Kα wild-type cells, while MCF-7 and MDA-MB-361 are PI3KαE545K mutant cells.

[0437] According to the different cell sizes and proliferation time, MCF-10A, SK-BR-3, MCF-7 and MDA-MB-361 cells in the logarithmic growth phase were taken and cultured at 5.0×10 2 pcs / hole, 2.0×10 3 pcs / hole, 1.0×10 3 / hole and 2.0×10 3 The cells were inoculated at a density of 100 / well in a 96-well culture plate. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours of incubation, the test compound was added to the 96-well plate. The negative control wells were added with the same volume of DMSO as the drug.

[0438] The working concentrations of the tested compounds were: 0 μM, 0.02 μM, 0.05 μM, 0.14 μM, 0.41 μM, 1.23 μM, 3.70 μM, 11.11 μM, 33.33 μM and 100 μM.

[0439] After adding drugs and incubating for 4 days, 50 μL CellTiter-Glo was added to each well and lysed at room temperature for 10 minutes. The chemiluminescence value of each well was measured in an ELISA instrument. The cell survival rate in each well was calculated according to the formula. Survival rate (%) = (signal value of drug-added well / signal value of control well) × 100%. IC was calculated using Graphpad Prism 50 value.

[0440] The results are shown in Table 1:

[0441] Table 1. Inhibitory effects of compounds on cell proliferation (IC 50 uM)

[0442]

[0443]

[0444] It can be seen from the above experimental data that the compounds provided by the present invention have good inhibitory activity on MCF-7 and MDA-MB-361 cells and have good selectivity.

[0445] Experimental Example 2: Inhibitory effect of compounds on AKT phosphorylation

[0446] In this experiment, two types of cells, MCF-10A and MCF-7, were used. MCF-10A is a PI3Kα wild-type cell, and MCF-7 is a PI3KαE545K mutant cell.

[0447] MCF-10A and MCF-7 cells in the logarithmic growth phase were cultured at 1.0×10 5 The cells were inoculated at a density of 100 / well in a 96-well culture plate. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours of incubation, the test compound was added to the 96-well plate. The negative control wells were added with the same volume of DMSO as the drug.

[0448] The working concentrations of the tested compounds were 0 μM, 0.02 μM, 0.05 μM, 0.14 μM, 0.41 μM, 1.23 μM, 3.70 μM, 11.11 μM, 33.33 μM and 100 μM.

[0449] After adding drugs and incubating for 24 hours, the content of phosphorylated AKT protein in cells was determined using the phospho-Akt (Ser473) ELISA detection kit (CST, #80895). The absorbance value (OD) of each well was measured at a wavelength of 450nm in an ELISA reader. The ratio of the remaining phosphorylated AKT protein in each well was calculated according to the formula. Ratio (%) = (OD value of drug-added well / OD value of control well) × 100%. IC was calculated using Graphpad Prism 50 value.

[0450] The results are shown in Table 2:

[0451] Table 2. IC of compounds inhibiting AKT phosphorylation 50 (uM) value

[0452]

[0453]

[0454] From the above experimental data, it can be seen that the compounds provided by the present invention have good inhibitory activity on the phosphorylation of AKT in MCF-7 cells. At the same time, the compounds of the present invention have good selectivity.

[0455] Example 3: Cell anti-proliferation experiment

[0456] In this experiment, four types of cells, MCF-10A, T47D, MCF-7 and MDA-MB-361, were used. MCF-10A is a PI3Kα wild-type cell, MCF-7 is a PI3KαE545K mutant cell, and T47D and MDA-MB-361 are PI3KαH1047R mutant cells.

[0457] According to the different cell sizes and proliferation time, MCF-10A, SK-BR-3, MCF-7 and MDA-MB-361 cells in the logarithmic growth phase were taken and cultured at 5.0×10 2 pcs / hole, 2.0×10 3 pcs / hole, 1.0×10 3 / hole and 2.0×10 3 The cells were inoculated at a density of 100 / well in a 96-well culture plate. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours of incubation, the test compound was added to the 96-well plate. The negative control wells were added with the same volume of DMSO as the drug.

[0458] The working concentrations of the tested compounds were: 0 μM, 0.02 μM, 0.05 μM, 0.14 μM, 0.41 μM, 1.23 μM, 3.70 μM, 11.11 μM, 33.33 μM and 100 μM.

[0459] After adding drugs and incubating for 4 days, 50 μL CellTiter-Glo was added to each well and lysed at room temperature for 10 minutes. The chemiluminescence value of each well was measured in an ELISA instrument. The cell survival rate in each well was calculated according to the formula. Survival rate (%) = (signal value of drug-added well / signal value of control well) × 100%. IC was calculated using Graphpad Prism 50 The results are shown in Table 3:

[0460] Table 3. Inhibitory effects of compounds on cell proliferation (IC 50 uM)

[0461]

[0462]

[0463]

[0464]

[0465] It can be seen from the above experimental data that the compounds provided by the present invention have good inhibitory activity on MCF-7 and MDA-MB-361 cells and have good selectivity.

[0466] Example 4: Pharmacokinetics of the compounds of the present invention in mice

[0467] 1. Experimental methods

[0468] Six healthy adult SD male mice (three animals for each compound administration method) were fasted overnight (>12h) by gavage, but not water deprivation; they were fed 4h after administration, and the drugs were injected by tail vein and gavage, respectively. At different time points, venous blood was collected for anticoagulation, and the anticoagulant was EDTA-K2 (the blood samples were placed in an ice bath after collection), and the plasma was separated by centrifugation at 6000g for 5min at 4℃. The plasma was stored at -70℃ for testing, and the concentration of the compound in the plasma was determined by LC-MS / MS.

[0469] The plasma concentration data of the compound at all time points were used to calculate the main pharmacokinetic parameters using Winnolin 8.3 non-compartmental model.

[0470] Area under the drug-time curve (AUC) all Value: Calculated using the trapezoidal method; AUC inf =AUC all +C t / ke,C t is the plasma drug concentration at the last measurable time point, ke is the elimination rate constant;

[0471] Elimination half-life 1 / 2 =0.693 / ke;

[0472] Clearance CL = D / AUC inf (D is the dosage);

[0473] Steady-state distribution volume Vss = CL x MRT, mean residence time MRT = AUMC / AUC;

[0474] Absolute bioavailability F = (AUCi.g x Di.v.) / (AUCi.v x Di.g.) × 100%

[0475] 2. Experimental results

[0476] Table 3. Pharmacokinetic results of the compounds of the present invention in mice

[0477]

[0478]

[0479] Note: "iv (1 mpk)" in the table means administration by tail vein injection, the dosage is 1 mg / kg; ig (3 mpk) means administration by gavage, the dosage is 3 mg / kg;

[0480] The above experimental results show that the compounds of the present invention have good pharmacokinetics.

[0481] It can be seen from the above embodiments and experimental examples that the present invention provides a new class of compounds with good PI3K inhibitory activity, which provides a new drug option for the clinical treatment of diseases related to abnormal PI3K activity.

Claims

1. A compound of formula I, or an optical isomer thereof, or a tautomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a hydrate thereof, or a solvate thereof, or a crystalline form thereof: in, R1 is selected from hydrogen, substituted or unsubstituted C1-C 10 Alkyl, halogen, wherein the substituent is selected from halogen, hydroxyl, cyano, carboxyl, amino; R2 is selected from hydrogen, substituted or unsubstituted C1-C 10 Alkyl, wherein the substituent is selected from halogen, hydroxyl, cyano, carboxyl, amino; R3 is selected from substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C6-C 10 cycloalkyl, substituted or unsubstituted 9-20 membered spiroheterocycloalkyl, substituted or unsubstituted 7-20 membered bridged heterocycloalkyl, Wherein the substituent is selected from oxygen atoms, C1-C 10 Alkoxy, deuterium substituted C1-C 10 Alkoxy, C1-C 10 Alkyl, deuterium substituted C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C1-C 10 Ester, SEM, BOC, C1-C 10 Haloalkyl, halogen, cyano, hydroxyl, carboxyl, amino; R4 is selected from hydrogen, substituted or unsubstituted C1-C 10 Alkyl, wherein the substituent is selected from halogen, hydroxyl, cyano, carboxyl, amino; Ring A is selected from substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the substituent is selected from halogen, carboxyl, amino, C1-C 10 Ester group, Among them, C1-C 10 The ester group can be further substituted by amino, halogen, cyano, hydroxyl, carboxyl, or two substituents on ring A can be linked to form a 5-10 membered lactam; L is selected from None or M A Selected from O or NH; R A1 , R A2 are independently selected from H, hydroxyl, amino, methoxy, cyano, C1-C 10 amide, substituted or unsubstituted 6-10 membered heterocycloalkoxy, substituted or unsubstituted 6-10 membered heterocycloalkylmethyl, substituted or unsubstituted C6-C 10 arylmethyl, substituted or unsubstituted 6-10 membered heteroaryl, substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkynyl, wherein the substituent is selected from deuterium, hydroxyl, C1-C 10 Alcohol, C1-C 10 Alkoxy, C2-C 10 Ether group, C1-C 10 Alkyl, halogen, C1-C 10 Amine, carboxyl, C1-C 10 haloalkyl, 4-10 membered heterocycloalkyl, amino, cyano, wherein the 4-10 membered heterocycloalkyl may be further C1-C 10 Alkyl substitution; or, R A1 With R A2 connected to form a substituted or unsubstituted 5-10 membered heterocycloalkyl, wherein the substituent is selected from hydroxyl, C1-C 10 Alcohol, C1-C 10 Alkoxy, C1-C 10 Alkyl, halogen, C1-C 10 Amine, carboxyl, C1-C 10 Haloalkyl, amino, cyano; R5 is selected from H, Or, R5 and R A1 connected to form a substituted or unsubstituted 6-10 membered heterocycloalkyl group, wherein the substituent is selected from an oxygen atom; Selected from M3 is selected from N, CH or CR1.

2. The compound according to claim 1, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form, characterized in that: The compound shown in formula I is shown in formula II or formula III:

3. The compound according to claim 1 or 2, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystalline form, characterized in that: Ring A is selected from phenyl which is substituted or unsubstituted by 1-2 substituents, 6-membered heteroaryl which is substituted or unsubstituted by 1-2 substituents, wherein the substituents are selected from F, Cl, amino, Or two substituents on ring A are connected to form a 5-membered lactam; M A Selected from O or NH; R A1 , R A2 Each of the following is independently selected from H, hydroxy, amino, methoxy, cyano, C2 amide, 6-membered heterocycloalkyloxy substituted or unsubstituted by 1-2 substituents, 6-membered heterocycloalkylmethyl substituted or unsubstituted by 1-2 substituents, benzyl substituted or unsubstituted by 1-2 substituents, 6-membered heteroaryl substituted or unsubstituted by 1-2 substituents, 4-5-membered heterocycloalkyl substituted or unsubstituted by 1-2 substituents, phenyl substituted or unsubstituted by 1-2 substituents, C3-C6 cycloalkyl substituted or unsubstituted by 1-2 substituents, C1-C4 alkyl substituted or unsubstituted by 1-2 substituents, and C2-C3 alkynyl substituted or unsubstituted by 1-2 substituents, wherein the substituent is selected from hydroxy, hydroxymethyl, methoxy, methyl, F, Cl, N,N-dimethylamino, carboxyl, C1 haloalkyl, amino, and cyano. or, R A1 With R A2 They are connected to form a 5-6 membered heterocycloalkyl group which is substituted or unsubstituted with 1-2 substituents, wherein the substituents are selected from hydroxyl, hydroxymethyl, methoxy, methyl, F, N,N-dimethylamino, and carboxyl.

4. The compound according to claim 1, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form, characterized in that: The compound represented by formula I is represented by formula IV or formula V: Among them, R A3 is selected from H, F, Cl; M4 is selected from N, CH.

5. The compound according to claim 1 or 4, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form, characterized in that: R2 is selected from methyl.

6. The compound according to claim 1 or 4, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form, characterized in that: R4 is selected from methyl.

7. The compound according to claim 1 or 4, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form, characterized in that: R5 is selected from H.

8. The compound according to claim 1, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form, characterized in that: The compound represented by formula I is represented by formula VI or formula VII:

9. The compound according to claim 8, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form, characterized in that: The compound represented by formula I is represented by formula VIII or formula IX: Among them, R A1 Selected from C3 cycloalkyl substituted or unsubstituted by 1-2 substituents, C1-C4 alkyl substituted or unsubstituted by 1-2 substituents; Wherein, the substituent is selected from hydroxyl, hydroxymethyl, methoxy, cyano, and F.

10. A compound according to any one of claims 1, 2, 4, 8 or 9, or an optical isomer thereof, or a tautomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a hydrate thereof, or a solvate thereof, or a crystalline form thereof, characterized in that: R1 is selected from methyl, F or Cl.

11. A compound according to any one of claims 1, 2, 4, 8 or 9, or an optical isomer thereof, or a tautomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a hydrate thereof, or a solvate thereof, or a crystalline form thereof, characterized in that: R3 is selected from 5-6 membered heterocycloalkyl substituted or unsubstituted by 1-2 substituents, 5-6 membered heteroaryl substituted or unsubstituted by 1-3 substituents, phenyl substituted or unsubstituted by 1-2 substituents, C6 cycloalkyl substituted or unsubstituted by 1-2 substituents, 9-10 membered spiroheterocycloalkyl substituted or unsubstituted by 1-2 substituents, 7 membered bridged heterocycloalkyl substituted or unsubstituted by 1-2 substituents, Wherein, the substituent is selected from oxygen atom, methoxy group, deuterium substituted methoxy group, C1-C4 alkyl group, cyclopropane group, deuterium substituted methyl group, C2 ester group, SEM, BOC, C1 haloalkyl group, F, cyano group, hydroxyl group.

12. The compound according to claim 11, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form, characterized in that: R3 is selected from a 5-6 membered heteroaryl group which is substituted or unsubstituted by one substituent, and a phenyl group which is substituted or unsubstituted by one substituent, wherein the substituent is selected from a methoxy group, a C1-C2 alkyl group, and F.

13. A compound according to any one of claims 1, 2, 4 or 8, or an optical isomer thereof, or a tautomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a hydrate thereof, or a solvate thereof, or a crystalline form thereof, characterized in that: R A1 , R A2 Each of the following is independently selected from H, hydroxyl, amino, methoxy, cyano, C1-C2 amide substituted or unsubstituted by 1 substituent, 6-membered heterocycloalkyloxy substituted or unsubstituted by 1-2 substituents, 6-membered heterocycloalkylmethyl substituted or unsubstituted by 1-2 substituents, benzyl substituted or unsubstituted by 1-2 substituents, 6-membered heteroaryl substituted or unsubstituted by 1-2 substituents, 4-5-membered heterocycloalkyl substituted or unsubstituted by 1-2 substituents, -2 substituents substituted or unsubstituted phenyl, substituted or unsubstituted C3-C6 cycloalkyl substituted or unsubstituted C1-C4 alkyl substituted or unsubstituted C1-2 substituents, deuterated methyl, substituted or unsubstituted C3 alkynyl substituted or unsubstituted C3 alkynyl substituted or unsubstituted C3 alkynyl, wherein the substituent is selected from hydroxyl, hydroxymethyl, methoxy, methyl, ether, F, Cl, N,N-dimethylamino, carboxyl, C1 haloalkyl, methyl-substituted 6-membered heteroaryl, amino, cyano, or, R A1 With R A2 They are connected to form a 5-6 membered heterocycloalkyl group which is substituted or unsubstituted with 1-2 substituents, wherein the substituents are selected from hydroxyl, hydroxymethyl, methoxy, methyl, F, N,N-dimethylamino, and carboxyl.

14. The compound according to claim 13, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form, characterized in that: R A1 , R A2 Each of the following is independently selected from H, C3 cycloalkyl which is substituted or unsubstituted by 1-2 substituents, and C1-C4 alkyl which is substituted or unsubstituted by 1-2 substituents; Wherein, the substituent is selected from hydroxyl, hydroxymethyl, methoxy, cyano, and F.

15. The compound according to claim 1, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form, characterized in that: R5 and R A1 connected to form a 7-membered heterocycloalkyl group which is substituted or unsubstituted by 1-2 substituents, wherein the substituents are selected from oxygen atoms; R A1 With R A2 They are connected to form a substituted or unsubstituted 5-membered heterocycloalkyl group, wherein the substituent is selected from hydroxyl group.

16. The compound according to claim 1, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form, characterized in that: The compound represented by formula I is selected from one of the compounds represented by the following structural formulas:

17. The method for preparing the compound according to claim 8, characterized in that: The steps include: Step 1, raw material A reacts with raw material B to obtain intermediate C; Step 2, intermediate C is reacted to obtain intermediate D; Step 3, the intermediate D reacts with the raw material E to obtain a compound represented by formula IV; 18. The preparation method according to claim 17, characterized in that: In step 1, the reaction is carried out under the action of a catalyst, and the base is selected from DIPEA; And / or, in step 1, the reaction solvent is selected from at least one of DMAc and DMF; And / or, in step 1, the reaction conditions are 80-150° C. for 2-24 hours; And / or, in step 2, the reaction is carried out under the action of a base, wherein the base is selected from at least one of TMSOK, sodium hydroxide or lithium hydroxide; And / or, in step 2, the reaction solvent is selected from at least one of THF, methanol or water or a mixed solvent thereof; And / or, in step 2, the reaction conditions are 20-40° C. for 1-24 hours; And / or, in step 3, the reaction is carried out under the action of a catalyst, wherein the catalyst is selected from at least one of HATU, T4P, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate; And / or, in step 3, the reaction is carried out under the action of a base, and the base is selected from DIPEA and N-methylimidazole; And / or, in step 3, the reaction solvent is selected from at least one of DMAc, DCM, acetonitrile and DMF; And / or, in step 3, the reaction conditions are 20-40° C. for 0.5-24 hours.

19. Use of the compound according to any one of claims 1 to 16, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form in the preparation of a PI3K inhibitor.

20. Use of the compound according to any one of claims 1 to 16, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form in the preparation of a medicament for treating a PI3K-mediated disease.

21. The use according to claim 20, characterized in that: The PI3K-mediated disease is one or more of breast cancer, ovarian cancer, prostate cancer, lung cancer, endometrial cancer, colon cancer, head and neck squamous cell carcinoma, diabetes, Parkinson's disease or Alzheimer's disease.

22. The use according to claim 21, characterized in that: The PI3K-mediated disease is one or more of the following diseases with brain metastasis: breast cancer, ovarian cancer, prostate cancer, lung cancer, endometrial cancer, and colon cancer.

23. A pharmaceutical composition, characterized in that: It is a preparation prepared with the compound described in any one of claim 116, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystal form as the active ingredient, and pharmaceutically acceptable excipients.

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