A benzheterocyclic compound as a PI3Kα kinase inhibitor, its preparation method and application

Abstract

The present invention relates to the technical field of pharmaceutical chemistry, and specifically relates to a benzheterocyclic compound as a PI3Kα kinase inhibitor, its preparation method and application. The present invention obtains a novel benzoxazole-based PI3Kα selective inhibitor compound. The compounds of the present invention can all effectively inhibit the PI3Kα kinase, and multiple compounds have PI3Kα inhibitory activity superior to that of the positive control TAK-117. The compounds of this class in the present invention have novel structures, relatively small molecular weights, conform to the rule of drug-likeness, and have significant anti-tumor activity, and can potentially be used for the treatment of related tumors. The compounds of the present invention have positive and predictable clinical application value for anti-proliferative diseases, especially anti-tumor, and have good development prospects. The compounds of the present invention have the characteristics of low cost, good efficacy and low toxicity. The intermediate products in the synthesis process of the compounds of the present invention have high yields, reducing resource waste, and thus being beneficial to reducing costs.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a benzheterocyclic compound as a PI3Kα kinase inhibitor, and a preparation method and application thereof. Background Art

[0002] According to the statistics of the World Health Organization, the number of cancer patients diagnosed in 2020 reached 19.3 million, and the number of people who died from cancer increased to 10 million. Research shows that malignant tumors are closely related to the kinase system. The overactivation of various kinases can lead to abnormal downstream signal transduction, thus having an important impact on the occurrence, development, metastasis and prognosis of tumors. The PI3K pathway is one of the most frequently activated pathways in human cancers, affecting nearly 50% of malignant tumors. Moreover, the PI3K signaling pathway also affects processes such as the proliferation, survival, transcription, translation and metabolism of malignant tumor cells. Therefore, organic small molecule kinase inhibitors targeting kinases such as PI3K in this pathway have become a hot spot in the research and development of molecular targeted anti-tumor drugs.

[0003] Phosphatidylinositol 3-kinases (PI3Ks) are a family of serine / threonine lipid kinases and key signal components of the PI3K / AKT / mTOR signal transduction pathway, playing important roles in regulating cell growth, proliferation, motility, and survival. The main mechanism of the PI3K pathway is as follows: After signal stimulation of cell membrane surface receptors, PI3K is mainly activated in two different ways. One is through the combination of p110 and Ras; the other is through interaction with RTKs or GPCRs, changing the dimer spatial conformation to form an active form. Activated PI3K can specifically phosphorylate PIP2 to generate PIP3. PIP3, as a second messenger, binds to the PH domain of downstream AKT, causing the translocation of cytoplasmic AKT to the cell membrane, where PDK1 on the cell membrane catalyzes the phosphorylation of Thr308 and Ser473 sites of AKT, resulting in the activation of AKT. Activated AKT dissociates from the cell membrane and enters the cytoplasm or nucleus, activating or inhibiting multiple downstream proteins, such as mTOR, Bad, GSK-3, FOXO, Caspase, and PARP, etc., regulating various physiological processes such as cell growth, differentiation, apoptosis, and angiogenesis. PI3K can be divided into classes I, II, and III according to the differences in its activation mechanism, structural characteristics, and substrate selection. Class I PI3K kinases include PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ subtypes. All four subtypes are related to the occurrence and development of tumors, especially PI3Kα is closely related to tumors. PI3Kα is a dimer containing the catalytic subunit p110α and the regulatory subunits p85 / 55 / 50, encoded by the PIK3CA gene. According to the action targets, PI3K inhibitors can be roughly divided into three types: PI3K-mTOR dual-target inhibitors, pan-PI3K inhibitors, and PI3K selective inhibitors. The high importance and mutation rate of the PIK3CA gene in solid tumors make PI3Kα inhibitors a research hotspot.

[0004] The research on PI3K inhibitors has a history of 20 years. There are nearly 30 candidate drugs entering clinical trials, and half of them have entered phase II clinical trials. Given the very close relationship between PI3K inhibitors and malignant tumors and the kinase system, its inhibitors have become potential anti-cancer drugs, and the following 6 PI3K inhibitors have been approved by the US Food and Drug Administration (FDA) for marketing:

[0005]

[0006] Currently, among the four class I PI3K subtypes (α, β, δ, and γ), PI3Kα, through gene amplification or mutation of PIK3CA, causes the occurrence and development of various malignancies. According to statistics, 29% of breast cancers and approximately 40% of HR+ / HER2- breast cancers carry abnormal PI3Kα signals. Due to the lack of subtype selectivity of pan-PI3K inhibitors, off-target related side effects such as myelosuppression occur; while PI3K / mTOR dual-target inhibitors also have significant side effects and no drugs have been marketed so far. Therefore, the research and development of subtype-selective PI3Kα inhibitors is an important direction in current research. Finding a subtype-selective PI3Kα inhibitor with higher kinase inhibition and cell anti-proliferative activities is the focus of current research. Summary of the Invention

[0007] To solve the above technical problems existing in the prior art, the present invention provides a benzheterocyclic compound as a PI3Kα kinase inhibitor, its preparation method and application, which are specifically realized through the following technical solutions:

[0008] A benzheterocyclic compound as a PI3Kα kinase inhibitor, which contains a structure represented by the following general formula (I):

[0009]

[0010] Further, in the general formula (I), A is one of the following structures:

[0011] Further, R1 is one of the following structures:

[0012] (1) R1 is R2NH-, where R2 is a straight-chain or branched-chain alkyl with 1 to 6 carbon atoms;

[0013] (2) R1 is R2NH-, where R2 is a nitrogen-containing heterocyclic compound with 3 to 8 members, a nitrogen-containing spirocyclic compound, or a bridged-ring compound;

[0014] (3) R1 is R2NHCO-, where R2 is a straight-chain or branched-chain alkyl with 1 to 6 carbon atoms;

[0015] (4) R1 is R2NHCO-, where R2 is a nitrogen-containing heterocyclic compound with 3 to 8 members, a nitrogen-containing spirocyclic compound, or a bridged-ring compound.

[0016] Further, R1 is one of the following structures:

[0017]

[0018] Further, the hydrogen atom connected to carbon in the general formula (I) can be replaced by deuterium, an isotope of hydrogen. For example, an alkyl group can be replaced by a deuterated alkyl group, an alkoxy group can be replaced by a deuterated epoxy group, a benzene ring can be replaced by a deuterated benzene ring, and an aromatic ring can be replaced by a deuterated aromatic ring.

[0019] Further, the benzheterocyclic compound described above includes one of the following structures:

[0020] (1) (R)-N-(1-Amino-1-oxopropan-2-yl)-6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide;

[0021] (2) Methyl 2-(6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamido)butanoate;

[0022] (3) N-(1-Amino-1-oxobutan-2-yl)-6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide;

[0023] (4) Methyl 2-(6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamido)-2-methylpropanoate;

[0024] (5) N-(1-Amino-2-methyl-1-oxopropan-2-yl)-6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide;

[0025] (6) Methyl (6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carbonyl)-L-alaninate;

[0026] (7) (6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carbonyl)-L-alanine;

[0027] (8) (S)-N-(1-Amino-1-oxopropan-2-yl)-6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide;

[0028] (9) (6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)methanone;

[0029] (10) ((4aR)-Hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl) (6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)methanone;

[0030] (11) N-(2-Amino-2-oxo-1-phenylethyl)-6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide;

[0031] (12) (S)-N-(2-Amino-2-oxo-1-phenylethyl)-6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide;

[0032] (13) (R)-N-(2-Amino-2-oxo-1-phenylethyl)-6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide;

[0033] (14) (S)-N-(1-Amino-3-(4-fluorophenyl)-1-oxopropan-2-yl)-6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide;

[0034] (15) (S,E)-N-(2-Amino-1-(4-hydroxyphenyl)-2-oxoethyl)-1-(2-(2-aminobenz[d]oxazol-5-yl)prop-1-en-1-yl)-1H-imidazole-5-carboxamide;

[0035] (16) N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide;

[0036] (17) (S)-N-(1-Amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)-6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide;

[0037] (18) (6-(2-Aminobenz[d]oxazol-6-yl)imidazo[1,2-a]pyridin-3-yl)(2-(hydroxymethyl)morpholino)methanone;

[0038] (19) (6-(2-Aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-(dimethylamino)piperidin-1-yl)methanone;

[0039] (20) (6-(2-Aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(piperazin-1-yl)methanone;

[0040] (21) 1-(6-(2-Aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carbonyl)pyrrolidine-2-carboxamide;

[0041] (22) (6-(2-Aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(3-methoxypyrrolidin-1-yl)methanone;

[0042] (23) (6-(2-Aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(3-(dimethylamino)pyrrolidin-1-yl)methanone;

[0043] (24) 5-(2-((4aR)-Hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinoxalin-6-yl)benz[d]oxazol-2-amine;

[0044] (25) 5-(2-((4aR,7aS)-Hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinoxalin-6-yl)benz[d]oxazol-2-amine;

[0045] (26) 5-(3-((4aR,7aS)-Hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinoxalin-6-yl)benz[d]oxazol-2-amine;

[0046] (27) 5-(4-((4aR,7aS)-Hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinazolin-6-yl)benz[d]oxazol-2-amine;

[0047] (28) (S)-2-((6-(2-Aminobenz[d]oxazol-5-yl)quinazolin-4-yl)amino)propanamide;

[0048] (29) (S)-2-((7-(2-Aminobenz[d]oxazol-5-yl)quinoxalin-2-yl)amino)propanamide;

[0049] (30) 2-((6-(2-Aminobenz[d]oxazol-5-yl)quinazolin-4-yl)amino)acetamide;

[0050] (31) 2-((7-(2-Aminobenz[d]oxazol-5-yl)quinoxalin-2-yl)amino)acetamide;

[0051] (32) 2-((6-(2-Aminobenz[d]oxazol-5-yl)quinoxalin-2-yl)amino)acetamide.

[0052] The preparation method of the benzheterocyclic compound uses 2-amino-4-bromophenol (A) as a raw material. The raw material (A) undergoes a cyclization reaction with cyanogen bromide to obtain an intermediate (B). The intermediate (B) undergoes a Suzuki coupling reaction with bis(pinacolato)diboron to obtain an intermediate (C). The boronate ester of the intermediate (C) is connected with different bromine-containing substituent fragments through a Suzuki coupling reaction to obtain a target compound (D) with the structure of general formula (I).

[0053] Furthermore, the specific reaction formula is as follows:

[0054]

[0055] Furthermore, in the specific reaction formula, the definitions of the substituents R1 and A in D are the same as those of the substituents R1 and A in the general formula (I).

[0056] A selective PI3Kα kinase inhibitor includes the benzheterocyclic compound in claim 1 or its stereoisomer, hydrate or pharmaceutically acceptable salt.

[0057] The pharmaceutically acceptable salt refers to converting the basic group in the parent compound into a salt form. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (ammonia) groups. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, that is, the basic group in the parent compound reacts with 1 - 4 equivalents of an acid in a solvent system. The basic groups of the compounds in the present invention can form salts with acids, and examples of these acid salts include but are not limited to: salts formed with inorganic acids, especially hydrohalic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid), nitric acid, sulfuric acid, phosphoric acid, carbonic acid, etc.; salts formed with lower alkyl sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid; salts formed with aryl sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; salts formed with organic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid or succinic acid; salts formed with amino acids, such as aspartic acid or glutamic acid.

[0058] The PI3Kα kinase inhibitor of the present invention also includes the form of a solvate or hydrate. Generally speaking, the form of a solvate or hydrate is equivalent to the non-solvated or non-hydrated form and is covered within the scope of the present invention. Some compounds in the present invention may exist in the form of polymorphs or amorphous forms. Generally speaking, all physical forms have the same use and should be covered within the scope of the present invention.

[0059] In addition, unless otherwise indicated, the structural formulas of the substituted benzoxazole compounds in the selective PI3Kα kinase inhibitors described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, the R and S configurations containing asymmetric centers, the (Z) and (E) isomers of double bonds, and the conformational isomers of (Z) and (E). Therefore, the individual stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention. All tautomeric forms of the pyrimidine compounds in the selective PI3Kα kinase inhibitors of the present invention are included within the scope of the present invention.

[0060] In addition, the structural formulas of the compounds described in the present invention include one or more enriched isotopes of different atoms.

[0061] A pharmaceutical composition comprising a benzheterocyclic compound or its stereoisomer, hydrate or pharmaceutically acceptable salt as described above.

[0062] Use of the benzheterocyclic compound, selective PI3Kα kinase inhibitor, and pharmaceutical composition as described above in the preparation of a drug for preventing and / or treating and / or adjuvant treating diseases related to proliferative diseases, metabolic diseases, neurological diseases, and malignancies caused by overactivation of PI3Kα kinase.

[0063] Furthermore, the metabolic disease is diabetes.

[0064] Furthermore, the proliferative diseases include colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumor, cervical cancer, cancers of the CNS, malignant glioma, myeloproliferative diseases, leukemia, or lymphoma.

[0065] Furthermore, the use in the preparation of a drug for preventing and / or treating and / or adjuvant treating diseases related to proliferative diseases, metabolic diseases, neurological diseases, and malignancies caused by overactivation of PI3Kα kinase is specifically the use in the preparation of a drug for inhibiting the growth of cancer cells in vitro.

[0066] The team where the present inventor belongs has been long-term committed to the research of PI3K-Akt-mTOR signaling pathway inhibitors and achieved a series of innovative results (Journal of Medicinal Chemistry, 2016, 59, 7268-7274; European Journal of Medicinal Chemistry, 2020, 204, 112637; European Journal of Medicinal Chemistry, 2022, 229, 114055.). On the basis of previous work, the present invention discloses a class of benzoxazole-based PI3Kα selective inhibitors. Compared with the benzoxazole-based clinical candidate drug TAK-117, the preferred compounds of the present invention have higher kinase inhibitory and cell anti-proliferative activities and better subtype selectivity.

[0067] The terms used in this article have the following meanings:

[0068] The term "alkyl" refers to a monovalent hydrocarbon group with a saturated straight or branched chain containing 1-20 carbon atoms, where the alkyl group can be independently and optionally substituted by one or more substituents described in the present invention. It can be: the alkyl group contains 1-10 carbon atoms; the alkyl group contains 1-8 carbon atoms; the alkyl group contains 1-6 carbon atoms; the alkyl group contains 1-4 carbon atoms. The alkyl group further includes but is not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), etc. The term "alkyl" and its prefix "alkane" are used here to include both straight and branched saturated carbon chains.

[0069] The term "alkoxy" involves a part of the alkyl group with the same definition as the aforementioned "alkyl", and it is formed by connecting to the main carbon chain of the "alkyl" through an oxygen atom.

[0070] The term "haloalkyl" or "haloalkoxy" means the case where the "alkyl" or "alkoxy" can be substituted by one or more identical or different halogen atoms. The alkyl and alkoxy groups have the meanings as described above in the present invention, and such examples include but are not limited to trifluoromethyl, trifluoromethoxy, etc.

[0071] The terms "hydroxyalkyl" or "hydroxyalkoxy" denote the situation where "alkyl" or "alkoxy" can be substituted by one or more hydroxyl groups. Wherein the "alkyl" and "alkoxy" groups have the meanings as described above in the present invention, examples of such include but are not limited to hydroxymethyl, 1-hydroxyethyl, hydroxypropyl, 1,2-dihydroxypropyl, hydroxymethoxy, 1-hydroxyethoxy, etc.

[0072] The terms "halogen", "halogen atom" or "halo atom" include fluorine, chlorine, bromine, and iodine.

[0073] The term "heterocyclic group" can be a carbon-based or heteroatom-based group. The "heterocyclic group" also includes groups formed by the fusion of a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Heterocycles include but are not limited to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, thioxanyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazinyl, 4-methoxypiperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepinyl, diazepinyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinylimidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazane, 1,1-dioxo-2-yl, quinuclidinyl, and N-pyridylurea. And the heterocyclic group can be substituted or unsubstituted, wherein the substituents can be but are not limited to oxo(=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), carboxyalkoxy, etc.

[0074] The terms "fused bicyclic", "fused ring", "fused bicyclic group" or "fused ring group" refer to a saturated or unsaturated fused ring system, which relates to a non-aromatic bicyclic system. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain an aromatic ring or heteroaromatic ring (however, aromatic groups can be substituents thereon). Each ring in the fused bicyclic is either a carbocyclic ring or a heterocycloaliphatic ring. Examples of such include, but are not limited to, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 7-azabicyclo[2.2.1]heptyl, fused bicyclo[3.3.0]octyl, fused bicyclo[3.1.0]hexyl, 1,2,3,4,4a,5,8,8a-octahydronaphthyl, all of which are included in the fused bicyclic system. And the fused bicyclic group may be substituted or unsubstituted, where the substituents may be, but are not limited to, halogen, hydroxy, amino, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, etc.

[0075] The term "fused heterobicyclic group" refers to a saturated or unsaturated fused ring system, which relates to a non-aromatic bicyclic system. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain an aromatic ring or heteroaromatic ring (however, aromatic groups can be substituents thereon). And at least one ring system contains one or more heteroatoms, where each ring system contains a 3- to 7-membered ring, i.e., containing 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2. Examples of such include, but are not limited to, hexahydro-2H-[1,4]dioxino[2,3-c]pyrrolyl, etc. And the fused heterobicyclic group may be substituted or unsubstituted, where the substituents may be, but are not limited to, halogen, hydroxy, amino, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, etc.

[0076] Compared with the prior art, the technical effects of the present invention are reflected in:

[0077] (1) The present invention obtains a novel benzoxazole-based PI3Kα selective inhibitor compound.

[0078] (2) The compounds of the present invention can all effectively inhibit the PI3Kα kinase, and multiple compounds have PI3Kα inhibitory activity superior to that of the positive control TAK-117.

[0079] (3) The compounds of this type in the present invention have a novel structure, relatively small molecular weight, conform to the rule of drug-likeness, have significant anti-tumor activity, and can potentially be used for the treatment of related tumors.

[0080] (4) The compounds of the present invention have positive and predictable clinical application values for anti-proliferative diseases, especially anti-tumor, and have good development prospects.

[0081] (5) The compounds of the present invention are characterized by low cost, good efficacy and low toxicity. The intermediate products in the synthesis process of the compounds of the present invention have high yields, reducing resource waste and thus being beneficial to cost reduction. Detailed implementation manners

[0082] The technical solutions of the present invention will be further limited below in conjunction with specific implementation manners, but the scope of protection is not limited only to the descriptions made.

[0083] Unless otherwise indicated, all temperatures in the following described examples are in degrees Celsius. Reagents were purchased from commercial suppliers such as Alfa Aesar Chemical Company, J&K Scientific Ltd., Aladdin Reagent Co., Ltd., Beijing Coupling Technology Co., Ltd., etc. and were used without further purification unless otherwise indicated. General reagents were obtained from Shantou Xilong Chemical Factory, Guangzhou Chemical Reagent Factory, Tianjin Zhiyuan Chemical Reagent Co., Ltd. and Qingdao Ocean Chemical Factory, etc.

[0084] In the following described examples, the chromatographic column used is a silica gel column, and the silica gel (200 - 300 mesh) was purchased from Qingdao Ocean Chemical Factory. Nuclear magnetic resonance spectra were recorded in CDC13 or DMSO-d6 as solvents (in ppm), using TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets occur, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The coupling constant is expressed in Hertz (Hz).

[0085] In the following described examples, the low-resolution mass spectrometry (MS) data was determined by a spectrometer of Agilent 6120 series LC-MS equipped with a G1311B quaternary pump and G1316B TCC (column temperature maintained at 30 °C), with a G1329B autosampler and G1315C DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.

[0086] In the embodiments described below, the injection volume is determined by the sample concentration; the flow rate is 0.5 mL / min; the HPLC peaks are recorded and read at UV-Vis wavelengths of 210 nm and 254 nm. The mobile phase is isopropanol / n-hexane (40:60).

[0087] For the convenience of description, some raw materials will be described by their abbreviations in the embodiments described below. The corresponding explanations of these abbreviations and their full names are as follows: DCM is CH2Cl2, that is, dichloromethane; CDC13 is deuterated chloroform; PE is petroleum ether; both EtOAc and EA are ethyl acetate; both MeOH and CH3OH are methanol; Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium; DIPEA is N,N-diisopropylethylamine; DMSO-d6 is hexadeuterodimethyl sulfoxide; DME is ethylene glycol dimethyl ether; Na2SO4 is sodium sulfate.

[0088] Example 1: (R)-N-(1-amino-1-oxopropan-2-yl)-6-(2-aminobenz[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide, the structural formula is as follows:

[0089]

[0090] The synthesis method includes the following steps:

[0091] Step 1: Synthesis of 5-bromobenz[d]oxazol-2-amine

[0092] The structural formula of 5-bromobenz[d]oxazol-2-amine:

[0093]

[0094] Weigh the raw material 2-amino-4-bromophenol (16.04 mmol) and put it into a 250 mL eggplant-shaped flask, add MeOH to dissolve it, add cyanogen bromide (19.25 mmol) under stirring, stir and react at room temperature, monitor the reaction by TLC until it is completed, concentrate the reaction solution under reduced pressure in vacuo, quench it with an aqueous NaHCO3 solution, extract it with water and EA (3 × 100 mL), dry it over anhydrous Na2SO4, and concentrate it under reduced pressure in vacuo to obtain a dark yellow solid, which can be obtained by washing it with EA multiple times. Yellow solid, yield: 88.13%. HRMS(ESI) calcd. for C7H6BrN2O [M+H]+: 212.9585, found: 212.9588;

[0095] Step 2: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benz[d]oxazol-2-amine

[0096] Structural formula of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine:

[0097]

[0098] 5-Bromobenzo[d]oxazol-2-amine (10.37 mmol), bis(pinacolato)diboron (12.45 mmol), potassium acetate (31.14 mmol), Pd(dppf)Cl2 (1.03 mmol) were successively added into a 100 mL eggplant-shaped flask, dissolved with 1,4-dioxane, the reaction was purged with nitrogen, refluxed at 100 °C overnight, monitored by TLC until the raw materials reacted completely, nitrogen was removed, water and EA (3 × 50 mL) were added to the reaction mixture for extraction, dried over anhydrous Na2SO4, concentrated under reduced pressure in vacuo to obtain a yellow solid, and the product was obtained by washing with EA multiple times. Yellow solid, yield: 78.63%. HRMS(ESI) calcd. for C 13 H 18 BN2O3[M+H]+: 261.1332, found: 261.1456;

[0099] Step 3: Synthesis of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate

[0100] Structural formula of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate:

[0101]

[0102] 2-Amino-5-bromopyridine (6.66 mmol) and ethyl 2-chloro-3-oxopropionate (6.66 mmol) were weighed and placed into a 100 mL eggplant-shaped flask, dissolved with acetonitrile, the reaction was purged with nitrogen, refluxed at 80 °C overnight, monitored by TLC until the raw materials reacted completely, nitrogen was removed, water and EA (3 × 50 mL) were added to the reaction mixture for extraction, dried over anhydrous Na2SO4, concentrated under reduced pressure in vacuo to obtain a yellow oil, purified by silica gel column chromatography (PE:EA = 10:1) to obtain a white solid, yield: 89.14%. HRMS(ESI) calcd. for C 10 H 10 BrN2O2[M+H]+: 268.9847, found: 268.9854.

[0103] Step 4: Synthesis of 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid

[0104] Structural formula of 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid:

[0105]

[0106] Ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (4.47 mmol) and lithium hydroxide hydrate (13.43 mmol) were successively added to a 100 mL eggplant-shaped flask, dissolved in MeOH / THF / H2O (4:1:1), stirred at room temperature for 1 h, and monitored by TLC until the reaction of the raw materials was completed. Then, it was concentrated under reduced pressure in vacuo. 1N HCl was added to adjust the pH to 1-2, and a large amount of solid precipitated. It was filtered by suction under reduced pressure, and the filter cake was taken to obtain the product. White solid, yield: 88.65%. HRMS(ESI) calcd. for C8H4BrN2O2[M+H]-: 238.9534, found: 238.9532.

[0107] Step 5: Synthesis of (R)-N-(1-amino-1-oxopropan-2-yl)-6-bromoimidazo[1,2-a]pyridine-3-carboxamide

[0108] (R)-N-(1-amino-1-oxopropan-2-yl)-6-bromoimidazo[1,2-a]pyridine-3-carboxamide structural formula:

[0109]

[0110] 6-Bromoimidazo[1,2-a]pyridine-3-carboxylic acid (2.08 mmol), D-alaninamide (3.12 mmol), TCFH (2.5 mmol), and NMI (7.28 mmol) were successively added to a 100 mL eggplant-shaped flask, dissolved in acetonitrile, the reaction was purged with nitrogen, stirred at room temperature overnight, and monitored by TLC until the reaction of the raw materials was completed. Then, it was concentrated under reduced pressure in vacuo. Water and EA (3×50 mL) were added to the reaction mixture for extraction, dried over anhydrous Na2SO4, and concentrated under reduced pressure in vacuo to obtain a white floc. It was filtered by suction under reduced pressure and washed with DCM several times to obtain the product. White solid, yield: 88.08%. HRMS(ESI) calcd. for C 11 H 12 BrN4O2[M+H]+: 311.0065, found: 311.0078.

[0111] Step 6: Synthesis of (R)-N-(1-amino-1-oxopropan-2-yl)-6-(2-aminobenzoxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide

[0112] (R)-N-(1-amino-1-oxopropan-2-yl)-6-(2-aminobenzoxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide structural formula:

[0113]

[0114] (R)-N-(1-Amino-1-oxopropan-2-yl)-6-bromoimidazo[1,2-a]pyridine-3-carboxamide (0.48 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (0.48 mmol), sodium carbonate (1.45 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.048 mmol) were successively added to a 100 mL eggplant-shaped flask, dissolved in 1,4-dioxane, the reaction was purged with nitrogen, refluxed at 100 °C overnight, monitored by TLC until the raw materials were completely reacted, the nitrogen was removed, water and EA (3 × 50 mL) were added to the reaction mixture for extraction, dried over anhydrous Na2SO4, concentrated in vacuo under reduced pressure to obtain a yellow oil, purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a white solid, yield: 69.14%. HRMS(ESI) calcd. for C 18 H 17 N6O3[M+H]+: 365.1284, found: 365.1288.

[0115] Example 2: Methyl 2-(6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamido)butyrate, the structural formula is as follows:

[0116]

[0117] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with methyl 2-aminobutyrate, and other steps and operations are the same as in Example 1; the product obtained in step 6 is a white solid, yield: 49.84%. HRMS(ESI) calcd. for C 20 H 20 N5O4[M+H]+: 394.1437, found: 394.1456.

[0118] Example 3: N-(1-Amino-1-oxobutan-2-yl)-6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide, the structural formula is as follows:

[0119]

[0120] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with 2-aminobutanamide, and other steps and operations are the same as in Example 1; the product obtained in step 6 is a white solid, yield: 38.84%. HRMS(ESI) calcd. for C 19 H 19N6O3[M+H]+: 379.1440, found: 379.1444。

[0121] Example 4: Methyl 2-(6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamido)-2-methylpropionate, the structural formula is as follows:

[0122]

[0123] Synthesis method: In step 6 of Example 1, replace the substituted heterocyclic fragment with methyl 2-amino-2-methylpropionate, and other steps and operations are the same as in Example 1; the product obtained in step 6 is a white solid, yield: 45.84%. HRMS(ESI) calcd. for C 20 H 20 N5O4[M+H]+: 394.1437, found: 394.1456。

[0124] Example 5: N-(1-Amino-2-methyl-1-oxopropan-2-yl)-6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide, the structural formula is as follows:

[0125]

[0126] Synthesis method: In step 6 of Example 1, replace the substituted heterocyclic fragment with 2-amino-2-methylpropanamide, and other steps and operations are the same as in Example 1; the product obtained in step 6 is a white solid, yield: 48.84%. HRMS(ESI) calcd. for C 19 H 19 N6O3[M+H]+: 379.1440, found: 379.1444。

[0127] Example 6: Methyl (6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carbonyl)-L-alaninate, the structural formula is as follows:

[0128]

[0129] Synthesis method: In step 6 of Example 1, replace the substituted heterocyclic fragment with methyl L-alaninate, and other steps and operations are the same as in Example 1; the product obtained in step 6 is a white solid, yield: 48.84%. HRMS(ESI) calcd. for C 19 H 18 N5O4[M+H]+: 379.1281, found: 379.1444。

[0130] Example 7: (6-(2-Aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carbonyl)-L-alanine, with the structural formula as follows:

[0131]

[0132] Synthesis method: In step 6 of Example 1, replace the substituted heterocyclic fragment with L-alanine, and keep other steps and operations the same as in Example 1; the product obtained in step 6 is a white solid, yield: 48.84%. HRMS(ESI) calcd. for C 18 H 16 N5O4[M+H]-: 364.1124, found: 364.1444.

[0133] Example 8: (S)-N-(1-Amino-1-oxopropan-2-yl)-6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide, with the structural formula as follows:

[0134]

[0135] Synthesis method: In step 6 of Example 1, replace the substituted heterocyclic fragment with L-alaninamide, and keep other steps and operations the same as in Example 1; the product obtained in step 6 is a white solid, yield: 45.84%. HRMS(ESI) calcd. for C 18 H 17 N6O3[M+H]+: 365.1284, found: 365.1288.

[0136] Example 9: (6-(2-Aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)methanone, with the structural formula as follows:

[0137]

[0138] Synthesis method: In step 6 of Example 1, replace the substituted heterocyclic fragment with (4aR,7aS)-hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole, and keep other steps and operations the same as in Example 1; the product obtained in step 6 is a white solid, yield: 45.84%. HRMS(ESI) calcd. for C 21 H 20 N5O4[M+H]+: 406.1437, found: 406.1445.

[0139] Example 10: ((6-(2-Aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl))((4aR,7aR)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)methanone), the structural formula is as follows:

[0140]

[0141] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with (4aR,7aR)-hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole, and the other steps and operations are the same as in Example 1; The product obtained in step 6 is a white solid, yield: 45.84%. HRMS(ESI) calcd. for C 21 H 20 N5O4[M+H]+: 406.1437, found: 406.1445.

[0142] Example 11: N-(2-Amino-2-oxo-1-phenylethyl)-6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide, the structural formula is as follows:

[0143]

[0144] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with 2-amino-2-phenylacetamide, and the other steps and operations are the same as in Example 1; The product obtained in step 6 is a white solid, yield: 55.84%. HRMS(ESI) calcd. for C 23 H 19 N6O3[M+H]+: 427.1440, found: 427.1445.

[0145] Example 12: (S)N-(2-Amino-2-oxo-1-phenylethyl)-6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide, the structural formula is as follows:

[0146]

[0147] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with (S)2-amino-2-phenylacetamide, and the other steps and operations are the same as in Example 1; The product obtained in step 6 is a white solid, yield: 55.84%. HRMS(ESI) calcd. for C 23 H 19 N6O3[M+H]+: 427.1440, found: 427.1445.

[0148] Example 13: (R) N-(2-Amino-2-oxo-1-phenylethyl)-6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide, with the structural formula as follows:

[0149]

[0150] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with (R) 2-amino-2-phenylacetamide, and the other steps and operations are the same as in Example 1; The product obtained in step 6 is a white solid, yield: 55.84%. HRMS(ESI) calcd. for C 23 H 19 N6O3[M + H]+: 427.1440, found: 427.1445.

[0151] Example 14: (S)-N-(1-Amino-3-(4-fluorophenyl)-1-oxopropan-2-yl)-6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide, with the structural formula as follows:

[0152]

[0153] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with (S)-2-amino-3-(4-fluorophenyl)propanamide, and the other steps and operations are the same as in Example 1; The product obtained in step 6 is a white solid, yield: 34.67%. HRMS(ESI) calcd. for C 24 H 20 FN6O3[M + H]+: 459.1503, found: 459.1445.

[0154] Example 15: (S,E)-N-(2-Amino-1-(4-hydroxyphenyl)-2-oxoethyl)-1-(2-(2-aminobenzo[d]oxazol-5-yl)prop-1-en-1-yl)-1H-imidazole-5-carboxamide, with the structural formula as follows:

[0155]

[0156] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with (S) 2-amino-3-(4-hydroxyphenyl)acetamide, and the other steps and operations are the same as in Example 1; The product obtained in step 6 is a white solid, yield: 52.84%. HRMS(ESI) calcd. for C 23 H 19 N6O4[M + H]+: 443.1390, found: 443.1445.

[0157] Example 16: N-(1-amino-1-oxo-3-phenylpropan-2-yl)-6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide, with the structural formula as follows:

[0158]

[0159] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with 2-amino-3-phenethyl-propanamide, and other steps and operations are the same as in Example 1; The product obtained in step 6 is a white solid, yield: 23.76%. HRMS(ESI) calcd. for C 24 H 21 N6O3[M+H]+: 441.1597, found: 441.1445.

[0160] Example 17: (S)-N-(1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)-6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide, with the structural formula as follows:

[0161]

[0162] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with L-tyramide, and other steps and operations are the same as in Example 1; The product obtained in step 6 is a white solid, yield: 53.84%. HRMS(ESI) calcd. for C 24 H 21 N6O4[M+H]+: 457.1546, found: 457.1445.

[0163] Example 18: (6-(2-aminobenzo[d]oxazol-6-yl)imidazo[1,2-a]pyridin-3-yl)(2-(hydroxymethyl)morpholino)methanone, with the structural formula as follows:

[0164]

[0165] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with hydroxymethylmorpholine, and other steps and operations are the same as in Example 1; The product obtained in step 6 is a white solid, yield: 41.12%. HRMS(ESI) calcd. for C 20 H 20 N5O4[M+H]+: 394.1437, found: 394.1445.

[0166] Example 19: (6-(2-Aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-(dimethylamino)piperidin-1-yl)methanone, with the structural formula as follows:

[0167]

[0168] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with 4-(dimethylamino)piperidine, and other steps and operations are the same as in Example 1; The product obtained in step 6 is a white solid, yield: 55.84%. HRMS(ESI) calcd. for C 22 H 25 N6O2[M+H]+: 405.1961, found: 405.1945.

[0169] Example 20: (6-(2-Aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(piperazin-1-yl)methanone, with the structural formula as follows:

[0170]

[0171] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with piperazine, and other steps and operations are the same as in Example 1; The product obtained in step 6 is a white solid, yield: 55.84%. HRMS(ESI) calcd. for C 19 H 19 N6O2[M+H]+: 363.1491, found: 363.1445.

[0172] Example 21: 1-(6-(2-Aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carbonyl)pyrrolidine-2-carboxamide, with the structural formula as follows:

[0173]

[0174] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with prolinamide, and other steps and operations are the same as in Example 1; The product obtained in step 6 is a white solid, yield: 55.84%. HRMS(ESI) calcd. for C 20 H 19 N6O3[M+H]+: 391.1440, found: 391.1445.

[0175] Example 22: (6-(2-Aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(3-methoxypyrrolidin-1-yl)methanone, with the structural formula as follows:

[0176]

[0177] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with 3-methoxypyrrolidine, and the other steps and operations are the same as those in Example 1; the product obtained in step 6 is a white solid, yield: 55.84%. HRMS(ESI) calcd. for C 20 H 20 N5O3[M + H]+: 378.1488, found: 378.1445.

[0178] Example 23: (6-(2-Aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(3-(dimethylamino)pyrrolidin-1-yl)methanone, the structural formula is as follows:

[0179]

[0180] Synthesis method: Replace the substituted heterocyclic fragment in step 6 of Example 1 with 3-(dimethylamino)pyrrolidine, and the other steps and operations are the same as those in Example 1; the product obtained in step 6 is a white solid, yield: 55.84%. HRMS(ESI) calcd. for C 21 H 23 N6O2[M + H]+: 391.1804, found: 391.1845.

[0181] Example 24: 5-(2-((4aR,7aR)-Hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinoxalin-6-yl)benzo[d]oxazol-2-amine, the structural formula is as follows:

[0182]

[0183] The synthesis method comprises the following steps:

[0184] Step 1: Synthesis of 6-bromoquinoxalin-2-ol

[0185] The structural formula of 6-bromoquinoxalin-2-ol:

[0186]

[0187] In a 100 mL eggplant-shaped flask, quinoxalin-2-ol (13.7 mmol), concentrated sulfuric acid (14 mL), Ag2SO4 (6.8 mmol) and Br2 (13.6 mmol) were added successively and stirred at room temperature for 15 h. After monitoring the reaction of the raw materials by TLC until completion, the mixture was filtered to remove AgBr, the solid was washed with sulfuric acid, the combined filtrate was poured onto ice, the white solid was collected by filtration, washed with water, ethanol and ether, and then dried to obtain the product. White solid, yield: 80.13%. HRMS(ESI) calcd. for C8H6BrN2O [M+H]+: 224.9585, found: 224.9556;

[0188] Step 2: Synthesis of 6-bromo-2-chloroquinoxaline

[0189] Structural formula of 6-bromo-2-chloroquinoxaline:

[0190]

[0191] DMF (3 mL) was added to a well-stirred suspension of 6-bromo-quinoxalin-2-ol (5.28 mmol) in phosphorus oxychloride (4.5 mL). The temperature was slowly raised to 80 °C and HCl was vigorously evolved. The temperature was slowly raised to 120 °C and maintained for 1.5 h. The dark residue was poured onto ice containing NaHCO3 and the temperature was maintained below 15 °C for neutralization. The solid was filtered, washed with water and the solid was dissolved in dichloromethane. It was dried with anhydrous Na2SO4 and filtered through diatomaceous earth. The solvent was removed under vacuum to obtain 6-bromo-2-chloro-quinoxaline. White solid, yield: 58.71%. HRMS(ESI) calcd. for C8H5BrClN2 [M+H]+: 242.9246, found: 242.9556;

[0192] Step 3: Synthesis of (4aR,7aR)-6-(6-bromoquinoxalin-2-yl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole

[0193] (4aR)-6-(6-bromoquinoxalin-2-yl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole structural formula:

[0194]

[0195] 6-Bromo-2-chloroquinoxaline (3.3 mmol) and (4aR,7aR)-hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole (9.9 mmol) were successively added to a 100 mL eggplant-shaped flask, dissolved in DMSO, purged with nitrogen, stirred at 80 °C for 15 h. After monitoring the reaction of the starting materials by TLC until completion, nitrogen was removed, and the mixture was extracted with water and EA (3×100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure in vacuo to obtain a dark yellow solid. The product was obtained by silica gel column chromatography (PE:EA = 2:1). White solid, yield: 60.13%. HRMS(ESI) calcd. for C 14 H 15 BrN3O2[M+H]+: 336.0269, found: 336.0278;

[0196] Step 4: Synthesis of 5-(2-((4aR,7aR)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinoxalin-6-yl)benzo[d]oxazol-2-amine

[0197] Structural formula of 5-(2-((4aR,7aR)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinoxalin-6-yl)benzo[d]oxazol-2-amine:

[0198]

[0199] (4aR)-6-(6-Bromoquinoxalin-2-yl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole (8.3 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (8.3 mmol), sodium carbonate (24.9 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.83 mmol) were successively added to a 100 mL eggplant-shaped flask, dissolved in 1,4-dioxane, purged with nitrogen, and refluxed at 100 °C overnight. After monitoring the reaction of the starting materials by TLC until completion, nitrogen was removed, and water and EA (3×50 mL) were added to the reaction mixture for extraction, dried over anhydrous Na2SO4, and concentrated under reduced pressure in vacuo to obtain a yellow oil. The product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a white solid, yield: 41.09%. HRMS(ESI) calcd. for C 21 H 20 N5O3[M+H]+: 390.1488, found: 390.1489;

[0200] Example 25: 5-(2-((4aR,7aS)-Hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinoxalin-6-yl)benzo[d]oxazol-2-amine, with the structural formula as follows:

[0201]

[0202] Synthesis method: Replace the substituted heterocyclic fragment in Step 3 of Example 24 with (4aR,7aS)-hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole, and the other steps and operations are the same as in Example 24; the product obtained in Step 4 is a yellow solid, yield: 32.26%. HRMS(ESI) calcd. for C 21 H 20 N5O3[M + H]+: 390.1488, found: 390.1489;

[0203] Example 26: 5-(3-((4aR,7aS)-Hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinoxalin-6-yl)benzo[d]oxazol-2-amine, with the structural formula as follows:

[0204]

[0205] The synthesis method includes the following steps:

[0206] Step 1: Synthesis of 7-bromoquinoxalin-2-ol

[0207] Structural formula of 7-bromoquinoxalin-2-ol:

[0208]

[0209] Weigh the raw material 4-bromobenzene-1,2-diamine (10.7 mmol) and put it into a 250 mL eggplant-shaped flask, add acetonitrile to dissolve it, add glyoxylic acid ethyl ester (10.7 mmol) under stirring, reflux and react overnight at 80 °C. Monitor the reaction of the raw materials by TLC. After the reaction is completed, add water and EA (3 × 50 mL) to extract, dry with anhydrous Na2SO4, and concentrate under reduced pressure in vacuo to obtain a yellow solid, which can be obtained as the product by washing with EA multiple times. White solid, yield: 88.63%. HRMS(ESI) calcd. for C8H6BrN2O[M + H]+: 224.9585, found: 224.9556;

[0210] Step 2: Synthesis of 7-bromo-2-chloroquinoxaline

[0211] Structural formula of 7-bromo-2-chloroquinoxaline:

[0212]

[0213] Weigh 7-bromoquinoxalin-2-ol (5.3 mmol) and put it into a 100 mL eggplant-shaped flask. Dissolve it with acetonitrile. Add phosphorus oxychloride (6.9 mmol), DIPEA (10.6 mmol) and NMM (4.24 mmol) at 0 °C. React for 10 min in an ice bath, then transfer it to 80 °C and react overnight. Monitor the reaction of the raw materials by TLC. After the reaction is completed, add water and EA (3×50 mL) to the reaction mixture for extraction. Dry it with anhydrous Na2SO4 and concentrate it under reduced pressure to obtain a yellow oil. The product can be obtained by silica gel column chromatography. White solid, yield: 81.13%. HRMS(ESI) calcd. for C8H5BrClN2[M+H]+: 242.9246, found: 242.9556;

[0214] Step 3: Synthesis of 6-(4aR,7aS)-(7-bromoquinoxalin-2-yl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole

[0215] Structural formula of 6-(4aR,7aS)-(7-bromoquinoxalin-2-yl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole:

[0216]

[0217] Add 6-bromo-2-chloroquinoxaline (3.3 mmol), (4aR,7aS)-hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole (9.9 mmol) and TEA (19.8 mmol) into a 100 mL eggplant-shaped flask in sequence. Dissolve it with DMF and react overnight at 100 °C. Monitor the reaction of the raw materials by TLC. After the reaction is completed, add water and EA (3×50 mL) to the reaction mixture for extraction. Dry it with anhydrous Na2SO4 and concentrate it under reduced pressure to obtain a yellow oil. The product can be obtained by silica gel column chromatography. Yellow solid, yield: 71.36%. HRMS(ESI) calcd. for C 14 H 15 BrN3O2[M+H]+: 336.0269, found: 336.0278;

[0218] Step 4: Synthesis of 5-(3-((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinoxalin-6-yl)benzo[d]oxazol-2-amine

[0219] Structural formula of 5-(3-((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinoxalin-6-yl)benzo[d]oxazol-2-amine:

[0220]

[0221] In a 100 mL eggplant-shaped flask, 6-(4aR,7aS)-(7-bromoquinoxalin-2-yl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole (8.3 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (8.3 mmol), sodium carbonate (24.9 mmol), and tetrakis(triphenylphosphine)palladium (0.83 mmol) were successively added, dissolved in 1,4-dioxane, the reaction was purged with nitrogen, refluxed at 100 °C overnight, monitored by TLC until the raw materials reacted completely, the nitrogen was removed, water and EA (3 × 50 mL) were added to the reaction mixture for extraction, dried over anhydrous Na2SO4, and concentrated in vacuo under reduced pressure to obtain a yellow oil, which was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a yellow solid, yield: 37.29%. HRMS(ESI) calcd. for C 21 H 20 N5O3[M+H]+: 390.1488, found: 390.1489;

[0222] Example 27: 5-(4-((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinazolin-6-yl)benzo[d]oxazol-2-amine, the structural formula is as follows:

[0223]

[0224] The synthesis method includes the following steps:

[0225] Step 1: Synthesis of 6-bromoquinazolin-4-ol

[0226] The structural formula of 6-bromoquinazolin-4-ol:

[0227]

[0228] Weigh the raw material 2-amino-5-bromobenzoic acid (10.0 mmol) and put it into a 250 mL eggplant-shaped flask, dissolve it in acetic acid, add formamidine hydrochloride (10.0 mmol) under stirring, stir and react at 120 °C, monitor the reaction by TLC until it is complete, add an aqueous solution of NaHCO3 to quench, extract with water and EA (3 × 100 mL), dry over anhydrous Na2SO4, and concentrate in vacuo under reduced pressure to obtain a dark yellow solid, which can be obtained by washing with EA multiple times. Yellow solid, yield: 68.13%. HRMS(ESI) calcd. for C7H6BrN2O[M+H]+: 224.9585, found: 224.9588;

[0229] Step 2: Synthesis of 6-Bromo-4-chloroquinazoline

[0230] Structural formula of 6-Bromo-4-chloroquinazoline:

[0231]

[0232] Weigh 6-bromoquinazolin-4-ol (5.3 mmol) and put it into a 100 mL eggplant-shaped flask. Dissolve it with acetonitrile. Add phosphorus oxychloride (6.9 mmol), DIPEA (10.6 mmol) and NMM (4.24 mmol) at 0 °C. React for 10 min under an ice bath, then transfer it to 80 °C and react overnight. Monitor the reaction of the raw materials by TLC. After the reaction is completed, add water and EA (3 × 50 mL) to the reaction mixture for extraction, dry it with anhydrous Na2SO4, and concentrate it under reduced pressure to obtain a yellow oil. The product can be obtained by silica gel column chromatography. White solid, yield: 75.68%. HRMS(ESI) calcd. for C8H5BrClN2 [M+H]+: 242.9246, found: 242.9556;

[0233] Step 3: Synthesis of (4aR,7aS)-6-(6-Bromoquinazolin-4-yl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole

[0234] (4aR,7aS)-6-(6-Bromoquinazolin-4-yl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole's structural formula:

[0235]

[0236] Add 6-bromo-4-chloroquinazoline (3.3 mmol), (4aR,7aS)-hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole (9.9 mmol), and TEA (19.8 mmol) into a 100 mL eggplant-shaped flask in sequence. Dissolve it with DMF and react overnight at 100 °C. Monitor the reaction of the raw materials by TLC. After the reaction is completed, add water and EA (3 × 50 mL) to the reaction mixture for extraction, dry it with anhydrous Na2SO4, and concentrate it under reduced pressure to obtain a yellow oil. The product can be obtained by silica gel column chromatography. White solid, yield: 80.62%. HRMS(ESI) calcd. for C 14 H 15 BrN3O2 [M+H]+: 336.0269, found: 336.0278;

[0237] Step 4: Synthesis of 5-(4-((4aR,7aS)-Hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinazolin-6-yl)benzo[d]oxazol-2-amine

[0238] Structural formula of 5-(4-((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinazolin-6-yl)benzo[d]oxazol-2-amine:

[0239]

[0240] (4aR,7aS)-6-(6-Bromoquinazolin-4-yl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole (8.3 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (8.3 mmol), sodium carbonate (24.9 mmol), and tetrakis(triphenylphosphine)palladium (0.83 mmol) were successively added to a 100 mL eggplant-shaped flask, dissolved in 1,4-dioxane, the reaction was purged with nitrogen, refluxed at 100 °C overnight, monitored by TLC until the raw materials reacted completely, the nitrogen was removed, water and EA (3 × 50 mL) were added to the reaction mixture for extraction, dried over anhydrous Na2SO4, and concentrated in vacuo under reduced pressure to obtain a yellow oil, which was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a yellow solid, yield: 41.04%. HRMS(ESI) calcd.for C 21 H 20 N5O3[M+H]+: 390.1488, found: 390.1489;

[0241] Example 28: (S)-2-((6-(2-Aminobenzo[d]oxazol-5-yl)quinazolin-4-yl)amino)propanamide, the structural formula is as follows:

[0242]

[0243] Synthesis method: Replace the substituted heterocyclic fragment in step 3 of Example 27 with L-alaninamide, and the other steps and operations are the same as in Example 27; the intermediate obtained in step 4 is a yellow solid, yield: 46.47%. HRMS(ESI) calcd.for C 18 H 17 N6O2[M+H]+: 349.1350, found: 349.1378;

[0244] Example 29: (S)-2-((7-(2-Aminobenzo[d]oxazol-5-yl)quinoxalin-2-yl)amino)propanamide, the structural formula is as follows:

[0245]

[0246] Synthesis method: Replace the substituted heterocyclic fragment in step 3 of Example 26 with L-alaninamide, and the other steps and operations are the same as those in Example 26; the product obtained in step 4 is a yellow solid, yield: 45.47%. HRMS(ESI) calcd. for C 18 H 17 N6O2[M+H]+: 349.1350, found: 349.1398;

[0247] Example 30: 2-((6-(2-Aminobenzo[d]oxazol-5-yl)quinazolin-4-yl)amino)acetamide, the structural formula is as follows:

[0248]

[0249] Synthesis method: Replace the substituted heterocyclic fragment in step 3 of Example 27 with glycine amide, and the other steps and operations are the same as those in Example 27; the intermediate obtained in step 4 is a yellow solid, yield: 45.47%. HRMS(ESI) calcd. for C 17 H 15 N6O2[M+H]+: 335.1178, found: 335.1178;

[0250] Example 31: 2-((7-(2-Aminobenzo[d]oxazol-5-yl)quinoxalin-2-yl)amino)acetamide, the structural formula is as follows:

[0251]

[0252] Synthesis method: Replace the substituted heterocyclic fragment in step 3 of Example 26 with glycine amide, and the other steps and operations are the same as those in Example 26; the product obtained in step 4 is a yellow solid, yield: 42.40%. HRMS(ESI) calcd. for C 17 H 15 N6O2[M+H]+: 335.1178, found: 335.1178;

[0253] Example 32: 2-((6-(2-Aminobenzo[d]oxazol-5-yl)quinoxalin-2-yl)amino)acetamide, the structural formula is as follows:

[0254]

[0255] Synthesis method: Replace the substituted heterocyclic fragment in step 3 of Example 24 with glycine amide, and the other steps and operations are the same as those in Example 24; the intermediate obtained in step 4 is a yellow solid, yield: 45.90%. HRMS(ESI) calcd. for C 17 H 15N6O2[M+H]+: 335.1178, found: 335.1178.

[0256] The beneficial effects and applications of the compounds represented by the general formula (I) of the present invention are illustrated by the following experiments.

[0257] In vitro PI3Kα kinase inhibition test:

[0258] The compounds of the present invention inhibit the activity of PI3Kα kinase, thereby inhibiting the transduction of cell signaling pathways and affecting the cell cycle and cell proliferation. The inhibitory effect of such compounds on PI3Kα kinase is evaluated by the following Lance Ultra fluorescence test method.

[0259] Detection principle: The Lance Ultra fluorescence test is a homogeneous non-radioactive detection method. It quantitatively determines the activity of purified kinase by detecting the content of ATP in the system after the kinase reaction. The determination of ATP content is quantified by the light intensity generated after the oxidation of beetle luciferin catalyzed by Mg 2+ , ATP and oxygen. A certain amount of ATP is added to the reaction system. The kinase reaction consumes ATP, and the remaining ATP can react with the firefly luciferase in the Kinase Glo reagent to emit light, so that the amount of the remaining ATP can be quantitatively detected, and the activity of the reaction kinase can be indirectly determined.

[0260] Detection method: First, prepare 1× kinase buffer, which contains 50 mM HEPES, pH 7.5, 1 mM EGTA, 0.01% Tween-20; dissolve the compound with 100% DMSO and perform gradient dilution. Transfer 10 nL of the diluted compound to the detection plate. At the same time, prepare a Control group without the compound and a blank control group without kinase. Add 1× kinase buffer to PI3Kα to prepare a kinase solution, and take 5 μL and add it to the detection plate and vortex to mix evenly. Additionally, prepare 1× kinase reaction buffer containing 4E-BP1 (Thr 37 / 46, PE) polypeptide and ATP substrate, take 5 μL and add it to the well plate to start the reaction. After reacting at room temperature for 1 h, add 10 μL of PBS buffer containing EDTA and Eu-anti-P-4E-BP1 (Thr 37 / 46, PE) antibody to the well plate and incubate at room temperature for 60 min. Read the well plate and statistically analyze the data to calculate the inhibition rate of the compound on PI3Kα kinase. Substitute the inhibition rate and the corresponding concentration into

[0261] GraphPad Prism software for curve fitting, and calculate the IC 50 value.

[0262] Cell viability assay:

[0263] The Cell Counting Kit (CCK-8) method was used to evaluate the inhibitory activity of compounds on cell proliferation. The half-maximal inhibitory concentration (IC 50 value) was determined through single-concentration primary screening of activity and multi-concentration measurement.

[0264] Principle of cytotoxicity detection (CCK-8 method): The CCK-8 reagent contains WST–8, which is reduced by dehydrogenases in the mitochondria of cells to a highly water-soluble yellow formazan product under the action of the electron carrier 1-methoxy-5-methylphenazinium sulfate (1-MethoxyPMS). The amount of formazan produced is proportional to the number of living cells.

[0265] Experimental method:

[0266] (1) Cell seeding: The cells were prepared into a single-cell suspension with a culture medium containing 10% fetal bovine serum. 90 μL of adherent cells at 5×10 4 / mL and 9×10 4 / mL of suspension cells were seeded into each well of a 96-well plate and pre-cultured for 24 h under the conditions of 5% CO2 and 37 °C.

[0267] (2) Addition of test sample solution: 10 μL of the sample solution was added to each well. For primary screening of activity, 1 concentration was set for each sample, with 3 replicates; for IC50 determination, 8 concentrations (including 0 concentration) were set, and 3 replicates were set for each concentration. The plate was placed in an incubator and cultured for 48 h. A blank group (Blank), a control group (Control), and a drug group (Drug) were set up in the experiment.

[0268] (3) Color development: For adherent cells, the old culture medium and drug solution were aspirated (for suspension cells, 10 μL of the CCK-8 solution stock solution was directly added). 100 μL of the CCK-8 solution diluted tenfold was added to each well and further cultured at 37 °C and 5% CO2 for 1 - 4 h (operate in the dark and observe in real time).

[0269] (4) Detection: The absorbance at 450 nm was measured using a microplate reader, and the original data results were recorded.

[0270] (5) The original data was standardized using Excel software. For primary screening, the cell proliferation inhibition rate was calculated through the OD value of each well (formula = (ODControl - ODDrug) / (ODControl - ODBlank) × 100%), and the inhibition rate was statistically analyzed. IC 50 was calculated using GraphPad Prism 8 (version 8.0.2, GraphPad Software Inc), and the experimental results were expressed as ±SD.

[0271] (6) Positive control: Doxorubicin hydrochloride (Dox).

[0272] The results of the kinase assay are shown in Table 1. From the activity data in Table 1 below, it can be seen that the compounds described in the present invention can effectively inhibit the PI3Kα kinase and have good inhibitory activity against it. That is, the inhibitory activity (IC 50 ) of most compounds against the PI3Kα kinase is at the nanomolar level (1 - 999 nM). Compared with the Phase II clinical candidate drug TAK-117, many compounds in the present invention have better PI3Kα inhibitory activity than the positive control TAK-117. For example, in Examples 1, 2, 4, 5, 8, 11, 13, 14, 18, 20, 21, 26, and 27, especially in Examples 9, 26, and 27, their IC50 values are as high as 7.0 nM, 2.5 nM, and 5.5 nM respectively. To further verify the selectivity of the compounds for PI3Kα, the compounds with excellent kinase activity in Examples 9, 26, and 27 were selected for testing the inhibitory activity of each subtype kinase of PI3K. The results are shown in Table 2. Compared with TAK-117, Examples 9, 26, and 27 all have good selectivity for PI3Kα. Among them, the selectivity of PI3Kα in Example 9 is about 100 times higher than that of other subtypes, especially with excellent selectivity for PI3Kβ. The selectivity of PI3Kα in Example 26 is about 200 times higher than that of other subtypes, and it has selectivity for PI3Kα among the other three subtypes. Example 27 has general selectivity, and the activities of the four subtypes are equivalent. Further, the compounds with excellent kinase activity in Examples 9 and 26 were selected to test the cell activity. The anti-proliferation activity results are shown in Table 3. It is obvious that compound 26 shows higher anti-cancer activity than TAK-117 against multiple cancer cell lines, while compound 9 only shows anti-cancer activity equivalent to that of TAK-117. It should be noted that the compounds with high inhibitory activity against the PI3Kα kinase also show high anti-cancer activity against multiple cancer cell lines. Especially in these cells, such as MKN-45, HCT116, HeLa, K-562, 5637, GBC-SD, MCF-7, HepG2, CAL-62, A-375, and 293, their anti-cancer cell proliferation activities are better than those of TAK-117. Especially for HepG2 human liver cancer cells, the anti-proliferation activity is as high as 80.32%, which is about 5 times better than the proliferation activity of the positive drug TAK-117. The above results indicate that the compounds described in the present invention have positive and predictable anti-proliferative diseases, especially anti-tumor clinical application value, and have good development prospects.

[0273] Table 1 In vitro inhibitory activity of target compounds against PI3Kα kinase

[0274]

[0275] Table 2 Activity of selected compounds against class I PI3Ks

[0276]

[0277] Table 3 Antiproliferative activity of target compounds against various cancer cells

[0278]

[0279] Finally, it should be pointed out that the above embodiments are only representative examples of the present invention. Obviously, the technical solution of the present invention is not limited to the above embodiments, and there are many variations. All variations that can be directly derived or associated with the content disclosed by ordinary technicians in this field should be considered as the protection scope of the present invention.

Claims

1. A benzheterocyclic compound as a PI3Kα kinase inhibitor, characterized in that, Its specific structure is any one of the following six: (R)-N-(1-amino-1-oxopropan-2-yl)-6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide, and the structural formula is as follows: (6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)methanone, and the structural formula is as follows: (6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((4aR,7aR)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)methanone, and the structural formula is as follows: 5-(3-((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinoxalin-6-yl)benzo[d]oxazol-2-amine, and the structural formula is as follows: 5-(4-((4aR,7aS)-hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)quinazolin-6-yl)benzo[d]oxazol-2-amine, and the structural formula is as follows: 2-((7-(2-aminobenzo[d]oxazol-5-yl)quinoxalin-2-yl)amino)acetamide, and the structural formula is as follows:

2. A preparation method of the benzheterocyclic compound according to claim 1, characterized in that, Using 2-amino-4-bromophenol (A) as the raw material, the raw material (A) undergoes a cyclization reaction with cyanogen bromide to obtain intermediate (B), and intermediate (B) undergoes a Suzuki coupling reaction with bis(pinacolato)diboron to obtain intermediate (C). The specific reaction formula is as follows: Intermediate (C) is connected with different bromine-containing substituent fragments through a Suzuki coupling reaction to obtain the benzheterocyclic compound described in claim 1.

3. A selective PI3Kα kinase inhibitor, characterized in that, It includes the benzheterocyclic compound in claim 1 or its stereoisomer or a pharmaceutically acceptable salt.

4. A pharmaceutical composition, characterized in that, It contains the benzheterocyclic compound in claim 1 or its stereoisomer or a pharmaceutically acceptable salt.

5. Use of the benzheterocyclic compound according to claim 1, the selective PI3Kα kinase inhibitor according to claim 3, and the pharmaceutical composition according to claim 4 in the preparation of a drug for preventing and / or treating and / or adjuvantly treating diseases related to proliferative diseases, metabolic diseases, and neurological diseases caused by overactivation of PI3Kα kinase.

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