Condensed ring PI3Kalpha inhibitor compound, pharmaceutical composition and application of fused ring PI3Kalpha inhibitor compound and pharmaceutical composition

Abstract

The invention provides a PI3Kalpha inhibitor compound as shown in a formula I, a pharmaceutical composition and application of the PI3Kalpha inhibitor compound and the pharmaceutical composition. The compound has good PI3Kalpha inhibitory activity, can be used for treating diseases related to PI3Kalpha, not only has good biological activity and good safety, but also improves transmembrane activity and drug bioavailability. # imgabs0 #

Description

[0001] The present invention claims the priority of the prior application filed with the State Intellectual Property Office of China on June 30, 2023, with patent application number 202310795287.0 and entitled “Fused-ring PI3Kα inhibitor compounds, pharmaceutical compositions and their applications”; the full text of the prior application is incorporated into the present invention by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical compounds, and specifically relates to fused-ring PI3Kα inhibitor compounds, pharmaceutical compositions and applications thereof. Background Art

[0003] Phosphatidylinositol 3-kinase (PI3K) is a unique and conserved family of intracellular lipid kinases that possess both phosphatidylinositol kinase activity and serine / threonine (Ser / Thr) kinase activity. The PI3K family includes 15 kinases, which can be divided into three major categories (class I, class II, and class III) based on their structure and substrate specificity.

[0004] The most widely studied of these is class I PI3K, which is a heterodimer consisting of a regulatory subunit p85 and a catalytic subunit p110. There are four types of catalytic subunits: α, β, δ, and γ. Among them, α, β, and δ correspond to p85α, p85β, or p55 regulatory subunits; while the γ type corresponds to p101 and p84 / 87 regulatory subunits. The regulatory subunit has an SH2 domain that can recognize the intracellular kinase domain of RTKs and trigger the activation of the catalytic subunit p110.

[0005] Usually, after class I PI3K is activated by tyrosine kinase or G protein-coupled receptor, it can catalyze PIP2 to generate PIP3 and trigger the activation of serine / threonine kinase AKT. AKT is regulated by PDK and mTOR2, and activation of AKT can promote cell cycle progression; in addition, activation of AKT can trigger the expression of a series of downstream molecules, thereby maintaining cell survival, promoting vascular survival, and promoting cell growth. Homologous phosphatase-tensin (PTEN), as a negative regulator of PI3K signal transduction, can dephosphorylate PIP3 and convert it into PIP2.

[0006] PI3K signaling is one of the most common abnormally activated pathways in cancer and is thought to be associated with a range of human cancers. Early studies have shown that pan-PI3K inhibitors LY294002 and Wortmannin can improve cancer cells' resistance to a variety of therapies, including chemotherapy, radiotherapy, and targeted therapy. In addition to targeting cancer cells, studies have also demonstrated the potential of PI3K inhibitors in cancer immunotherapy.

[0007] In the past two decades, the development of drugs related to the PI3K pathway has been a key research area, and some results have been achieved. Several PI3K inhibitors targeting individual isoforms have now been approved by regulatory authorities. These include inhibitors targeting leukocyte-enriched PI3Kδ, which is mainly found in B-cell malignancies, and alpelisib, a PI3Kα isoform selective inhibitor for the treatment of HR+ / HER2- / PIK3CA-mutated advanced metastatic breast cancer and the treatment of pro-overgrowth syndrome (PROS).

[0008] Unlike PI3Kδ and PI3Kγ, which are mainly expressed in hematopoietic cells, PI3Kα is expressed in most tissues. PI3Kα plays a core role in regulating the body's glucose homeostasis, and PI3Kα inhibition in patients usually causes hyperglycemia or hyperinsulinemia. Studies have also shown that high levels of insulin may have mitogenic and anti-apoptotic effects on cancer cells, thereby offsetting the anti-proliferative effects of PI3Kα inhibitors. Therefore, the development of PI3Kα inhibitors faces challenges in tolerability and safety.

[0009] Alpelisib has an equivalent inhibitory effect on mutant and wild-type PI3Kα. Although the drug is classified as a PI3Kα-specific drug, severe concentration-dependent side effects and drug resistance are often observed. Clinical studies have also shown that the incidence of adverse events (AEs) of Alpelisib ≥ grade 3 (mainly hyperglycemia) is high, which limits patients' tolerance and acceptance of the drug. At the same time, the sensitivity of Alpelisib depends on the PIK3CA mutation. Therefore, there is an urgent need for more accurate, more efficient, and better tolerated inhibitors against mutant PI3Kα to change the current treatment status and meet clinical needs.

[0010] PIK3CA is the gene encoding the PI3Kα catalytic subunit p110α protein and is the most commonly mutated gene in solid tumors. The most common hotspot mutations of the PIK3CA gene occur mainly in the kinase domain of exon 20 (H1047R) and the helical domain of exon 9 (E545K, E542K). These mutations have a greater impact on PI3Kα activity and have been shown to be oncogenic gain-of-function mutations. Among them, approximately 15% of breast cancers will have H1047R mutations, which are relatively uncommon in other tumors. Compared with PIK3CA wild-type patients, patients with PIK3CA-mutated HR+ / HER2- advanced breast cancer have a poorer prognosis, poor response to traditional treatment, and resistance to endocrine therapy and chemotherapy. Some small studies that mainly analyzed ER+ breast cancer tumors have shown that H1047R patients show reduced survival compared with tumors containing E545K.

[0011] Therefore, targeting PI3Kα mutations and developing inhibitors with enhanced selectivity for mutant PI3Kα may provide valuable treatment opportunities for breast cancer patients carrying this mutation, overcoming the problem of compensatory production of insulin or glucose after systemic PI3Kα inhibition. This will create an increased window for drug dosing, selectively inhibiting the pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα in tissues that control systemic metabolism. It is hoped that the scope of research on PI3Kα inhibitors will be expanded from HR+ / HER2- to HER2+ and TNBC, and from advanced to early stages, so that more patients can benefit. Summary of the invention

[0012] The present invention provides a compound represented by formula I and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof;

[0013]

[0014] in,

[0015] R1 and R2 are the same or different and are independently selected from H or C 1-12 Alkyl; or, R1, R2 and the carbon atom to which they are connected together form a C 3-12 Cycloalkane ring;

[0016] W is selected from O, S or NH;

[0017] X1, X2, X3 are the same or different and are independently selected from CR x or N;

[0018] Y1 and Y2 are the same or different and are independently selected from CR y or N;

[0019] Each R x are the same or different and are independently selected from H, halogen, CN, OH, unsubstituted or optionally substituted by one, two or more R x1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 Cycloalkyl; each R x1 are the same or different and are independently selected from H, halogen, CN, OH, C 1-6 Alkyl or C 1-6 Alkoxy;

[0020] Each R y are the same or different and are independently selected from H, halogen, CN, OH, unsubstituted or optionally substituted by one, two or more R y1 Substituted with the following groups: C1-12 Alkyl, C 1-12 Alkoxy or C 3-12 Cycloalkyl; each R y1 are the same or different and are independently selected from H, halogen, CN, OH, C 1-6 Alkyl or C 1-6 Alkoxy;

[0021] m is selected from 0, 1, 2 or 3;

[0022] Ring A is selected from C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring, C 3-14 Cycloalkane ring or 3-14 membered heterocyclic ring;

[0023] Each R a are the same or different and are independently selected from H, halogen, CN, oxo (=O), OH, unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, -N(R a11 )(R a12 )、-C(O)N(R a13 )(R a14 ) or -S(O)2-R a15 ; Each R a1 are the same or different and are independently selected from H, OH, CN, halogen, OH, C 1-6 Alkyl or C 1-6 Alkoxy; R a11 , R a12 , R a13 , R a14 , R a15 The same or different, independently selected from H or C 1-12 alkyl;

[0024] q is selected from 0, 1, 2, 3, 4 or 5;

[0025] Z is selected from O or NH;

[0026] Ring E is selected from C 6-10 Aromatic ring or 5-10 membered heteroaromatic ring;

[0027] Each R e are the same or different and are independently selected from H, halogen, CN, OH, COOH, unsubstituted or optionally substituted by one, two or more R e1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12Cycloalkyl, -C(O)NH2 or 5-10 membered heteroaryl; each R e1 are the same or different and are independently selected from H, halogen, CN, OH, C 1-6 Alkyl or C 1-6 Alkoxy;

[0028] p is selected from 0, 1, 2, 3, 4 or 5.

[0029] According to some embodiments, R1 and R2 are the same or different and are independently selected from H or C 1-6 Alkyl; or, R1, R2 and the carbon atom to which they are connected together form a C 3-6 Cycloalkane ring;

[0030] According to some embodiments, R1 and R2 are the same or different and are independently selected from H or methyl; or, R1 and R2 together with the carbon atom to which they are commonly attached form a cyclopropane ring.

[0031] According to some embodiments, W is selected from O or S; according to some embodiments, W is selected from O.

[0032] According to some embodiments, X1, X2, X3 are independently selected from CR x ;

[0033] According to some embodiments, each R x are the same or different and are independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0034] According to some embodiments, each R x are the same or different and are independently selected from H, F, Cl, CN, methyl, methoxy or cyclopropyl.

[0035] According to some embodiments, Y1 and Y2 are independently selected from CR y ;

[0036] According to some embodiments, each R y are the same or different and are independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0037] According to some embodiments, each R y are the same or different and are independently selected from H, F, Cl, CN, methyl, methoxy or cyclopropyl.

[0038] According to some embodiments, ring A is selected from a benzene ring, a 5-6 membered heteroaromatic ring, a C3-6 Cycloalkane ring or 4-8 membered heterocyclic ring;

[0039] According to some embodiments, ring A is selected from a benzene ring, a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, a thiophene ring, a furan ring, a pyrimidine ring, a pyridine ring, a cyclopropane ring, an azetidine ring, an azaspiro[3.3]heptane ring, a morpholine ring, a tetrahydropyrrole ring

[0040] According to some embodiments, Ring A is selected from

[0041] According to some embodiments, each R a are the same or different and are independently selected from H, CN, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -NHC 1-6 Alkyl, -C(O)(NHC 1-6 Alkyl) or -S(O)2-C 1-6 alkyl;

[0042] According to some embodiments, each R a are the same or different and are independently selected from H, F, Cl, CN, oxo (=O), methyl, methoxy, cyclopropyl, difluoromethyl, difluoromethoxy, mesyl, -NHCH3 or -C(O)NHCH3;

[0043] According to some embodiments, Selected from

[0044]

[0045] According to some embodiments, ring E is selected from a benzene ring or a 5-6 membered heteroaromatic ring;

[0046] According to some embodiments, ring E is selected from a benzene ring, a pyridine ring, an oxazole ring, a pyrazole ring, a furan ring, a thiophene ring, an imidazole ring or a thiazole ring.

[0047] According to some embodiments, each R e are the same or different and are independently selected from H, halogen, C 1-6 Alkyl, COOH, -C(O)NH2 or 5-membered heteroaryl;

[0048] According to some embodiments, each R eare the same or different and are independently selected from H, F, Cl, methyl, COOH, -C(O)NH2,

[0049] According to some embodiments, Selected from

[0050] According to some embodiments, the compound represented by Formula I has the structure shown below:

[0051]

[0052]

[0053] Among them, ring A, ring E, W, X1, X2, X3, Y1, Y 2、 R1, R2, R a , R e , R x , R y , m, p, q have the definitions described in the present invention, and n is selected from 0, 1, 2 or 3.

[0054] According to some embodiments, the compound represented by Formula I has the structure shown below:

[0055]

[0056] Among them, ring A, ring E, W, Y1, Y2, R1, R2, R a , R e , R x , R y , m, p, q have the definitions described in the present invention, and n is selected from 0, 1, 2 or 3.

[0057] According to some embodiments, the compound represented by Formula I has the structure shown below:

[0058]

[0059] Among them, ring A, ring E, Y1, Y2, R1, R2, R a , R e , R x , R y , m, p, q have the definitions described in the present invention, and n is selected from 0, 1, 2 or 3.

[0060] According to some embodiments, the compound represented by Formula I may have the structure shown below:

[0061]

[0062]

[0063]

[0064]

[0065]

[0066] The present invention further provides a pharmaceutical composition comprising the compound of formula I described in the present invention and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the pharmaceutical composition described in the present invention further comprises a therapeutically effective amount of the compound of formula I described in the present invention and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0068] The carrier in the pharmaceutical composition is "acceptable" in that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject being treated. One or more pharmaceutical excipients may be used for delivery of the active compound.

[0069] The present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of PI3Kα inhibitors.

[0070] The present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of a drug for preventing and / or treating cancer, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, skin cancer and / or benign overgrowth syndrome.

[0071] The present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of a drug for preventing and / or treating PIK3CA-associated overgrowth (PROS).

[0072] The present invention also provides a method for preventing and / or treating a PI3Kα-mediated disease or condition, which comprises administering to a patient in need of such treatment a therapeutically effective amount of at least one compound or pharmaceutical composition of the present invention alone, or, optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0073] According to some embodiments, the PI3Kα-mediated disease or symptom is selected from cancer, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, skin cancer and / or benign overgrowth syndrome;

[0074] According to some embodiments, the PI3Kα-mediated disease or condition is PIK3CA-associated overgrowth (PROS).

[0075] Beneficial Effects

[0076] The compounds provided by the present invention have good PI3Kα inhibitory activity and can be used for the treatment of diseases related to PI3Kα. The compounds of the present invention not only have good biological activity and good safety, but also improve transmembrane activity and drug bioavailability.

[0077] Definition and explanation of terms

[0078] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and / or claims of this application.

[0079] The term "optional" (or "optionally", "optionally") in the general formula definitions of the present application means the situation of being substituted by zero, one or more substituents, for example, "optionally substituted by one, two or more R" means that it may not be substituted by R (unsubstituted) or may be selectively substituted by one, two or more R.

[0080] "More" means three or more.

[0081] Unless otherwise specified, the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein. For example, the numerical range "1-12" is equivalent to recording each integer value in the numerical range "1-12", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0082] The term "C 1-12The term "alkyl" is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms. 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0083] The term "C 3-12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, preferably "C 3-10 Cycloalkyl", more preferably "C 3-8 The term "Cycloalkyl" 3-12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-12 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonanyl, 2,6-diazaspiro[3,4]octanyl, or a tricyclic hydrocarbon group such as adamantyl.

[0084] The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-10 The term "C 6-14 The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position.

[0085] The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-10 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, furthermore, may be benzo-fused. "Heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4- , 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8- 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbozolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-pyridinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9- 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]oxazolyl, 2-, 4- or 54H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3 1-, 2-, 3-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14 membered heteroaryl group is connected to other groups to form the compound of the present invention, it can be a carbon atom on the 5-14 membered heteroaryl ring connected to other groups, or it can be a heteroatom on the 5-14 membered heteroaryl ring connected to other groups. When the 5-14 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, the hydrogen bonded to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen bonded to the heteroatom on the heteroaryl ring may be substituted.

[0086] Unless otherwise defined, the term "3-14 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)2- states. For example, the "3-14 membered heterocyclyl" may be a 3-14 membered N-containing heterocyclyl (containing at least one N). Preferably, the heterocyclyl may be selected from a "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclyl may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). The heterocyclyl may include fused or bridged rings and spirocyclic rings. In particular, the heterocyclyl may include, but is not limited to, 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclic group may be bicyclic, for example but not limited to a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl. When the 3-14-membered heterocyclic group is connected to other groups to form the compounds of the present invention, the carbon atoms on the 3-14-membered heterocyclic group may be connected to other groups, or the heterocyclic atoms on the 3-14-membered heterocyclic group may be connected to other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl group may be connected to other groups. Or when the 3-14 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at the para position thereof may be connected to other groups.

[0087] The term "spirocyclic" refers to a ring system in which two rings share one ring-forming atom.

[0088] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0089] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0090] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0091] "Halo" means substituted with one or more halogens.

[0092] Those skilled in the art will appreciate that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form a base addition salt; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form an inner salt.

[0093] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of the polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0094] According to its molecular structure, the compounds of the present invention may be chiral, and therefore various enantiomeric forms may exist. Thus, these compounds may exist in racemic form or optically active form. The compounds of the present invention encompass isomers or mixtures, racemates in which each chiral carbon is in R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolution agent. Examples of suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in R and S forms. Chromatographic enantiomer resolution can also be advantageously carried out with the aid of optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0095] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0096] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0097] The term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. DETAILED DESCRIPTION

[0098] The technical solution of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included in the scope of protection intended by the present disclosure.

[0099] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0100] Example 1

[0101] 2-((1-(2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-9-oxo-9H-xanthen-4-yl)ethyl)amino)benzoic acid 001

[0102]

[0103] first step

[0104] 2-(2-Acetyl-4-methylphenoxy)-4-bromobenzonitrile 001b

[0105] At room temperature, 001a (10 g) and 4-bromo-2-fluorobenzonitrile (19.98 g) were added to the reaction bottle, followed by potassium carbonate (18.41 g), potassium iodide (552 mg), and finally N,N-dimethylformamide (100 mL), and the mixture was reacted at 100°C for 2 hours. The mixture was first diluted with water (200 mL), and then extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 x 50 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-50%) as the eluent to obtain the title compound 001b (12 g).

[0106] LC-MS: (ESI, m / z) = 329.85 [M+H] +

[0107] Step 2

[0108] 2-(2-Acetyl-4-methylphenoxy)-4-bromobenzoic acid 001c

[0109] At room temperature, add 001b (10g) and potassium hydroxide (16.99g) to the reaction bottle, then slowly add water (100mL) at 0℃, and react at 110℃ overnight. Wash with ethyl acetate (100mL) first, collect the aqueous phase, adjust the pH of the aqueous phase to 5-6 with dilute hydrochloric acid, and extract the aqueous phase with ethyl acetate (3x 100mL). Combine the organic phases, backwash with saturated sodium chloride solution (1x50 mL), and dry over anhydrous sodium sulfate. After filtering the obtained mixture, the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography under the following conditions: C18 chromatography column, mobile phase: water (0.05% trifluoroacetic acid) / acetonitrile (0-50%), to obtain the title compound 001c (600mg).

[0110] LC-MS: (ESI, m / z) = 348.90 [M+H] +

[0111] Step 3

[0112] 4-Acetyl-6-bromo-2-methyl-9H-xanthene-9-one 001d

[0113] At room temperature, 001c (550 mg) and 1.2-dichloroethane (4 mL) were added to the reaction flask, followed by trifluoromethanesulfonic acid (2 mL), and the mixture was reacted at 80°C for 1 hour. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 x 50 mL), and dried over anhydrous sodium sulfate. After the mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-50%) as the eluent to obtain the title compound 001d (280 mg).

[0114] LC-MS: (ESI, m / z) = 330.85 [M+H] +

[0115] Step 4

[0116] 4-Acetyl-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-9H-xanthene-9-one 001e

[0117] Under nitrogen protection, 001d (260 mg) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole (108 mg) were added to the reaction bottle, and then [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (42 mg) and potassium carbonate (144 mg) were added in sequence, and nitrogen was replaced three times. Finally, 1,4-dioxane (3 mL) and water (0.3 mL) were added and reacted at 60 ° C for 2 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3x50 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1x50 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (0-50%) as eluent to give the title compound 001e (160 mg) as a white solid.

[0118] LC-MS: (ESI, m / z) = 333.05 [M+H] +

[0119] Step 5

[0120] 4-(1-Hydroxyethyl)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-9H-xanthene-9-one 001f

[0121] At room temperature, 001e (140 mg) and methanol (2 mL) were added to the reaction flask, and then sodium borohydride (31 mg) was added at 0°C, and the reaction was continued at room temperature for 2 hours. Water (20 mL) was added to quench, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 x 30 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the eluent was ethyl acetate / petroleum ether (0-50%) to obtain the title compound 001f (120 mg).

[0122] LC-MS: (ESI, m / z) = 335.05 [M+H] +

[0123] Step 6

[0124] 4-(1-bromoethyl)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-9H-xanthene-9-one 001g

[0125] At room temperature, 001f (120 mg) and dichloromethane (2 mL) were added to the reaction flask, phosphorus tribromide (145 mg) was added at 0 ° C, and the reaction was carried out at 0 ° C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), diluted with water (20 mL), and extracted with dichloromethane (3x 20 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1x 20 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure to obtain the title compound 001g (100 mg).

[0126] LC-MS: (ESI, m / z) = 396.85 [M+H] +

[0127] Step 6

[0128] 2-((1-(2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-9-oxo-9H-xanthen-4-yl)ethyl)amino)benzoic acid 001

[0129] At room temperature, 001g (40mg) and 2-aminobenzoic acid (20mg) were added to the reaction bottle, and then N,N-dimethylformamide (1mL) was added, and the reaction was carried out at 80°C for 6 hours. The crude product was purified by high performance liquid chromatography (chromatographic column specifications: YMC Triart C18 column, 30*150,5um; mobile phase A: water (10mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60ml / min; gradient: 17% B to 39% B in 10 minutes) to obtain the title compound 001 (21.6mg).

[0130] LC-MS: (ESI, m / z) = 453.85 [M+H] +

[0131] 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.46(s,1H),8.17–8.13(m,2H),7.96(d,1H),7.87–7.79(m,2H),7.73–7.69(m ,1H),7.61(d,1H),7.13–7.04(m,1H),6.51–6.40(m,2H),5.34–5.22(m,1H),3.91(s,3H),2.36(s,3H),1.65(d,3H).

[0132] Biological evaluation

[0133] Test Example 1: The purpose of this test is to determine the inhibitory effect of the test compound on PI3Kα and PI3Kα(H1047R) using the ADP-Glo ​​luciferase luminescence detection method.

[0134] Test materials and instruments

[0135] A. Reagent Information

[0136]

[0137]

[0138] Experimental procedures

[0139] a. Preparation of reaction buffer

[0140] Take 10 ml as an example, prepare and use it on the day of the experiment:

[0141]

[0142] b. Compound Preparation

[0143] The test compound was prepared into a 100x concentration stock solution with DMSO, and the compound was graded diluted using a multi-channel electronic pipette. 50 nL of the test compound was transferred to a 384-well microvolume assay plate using the automated micropipette system Echo550.

[0144] Only 50 nL of 100% DMSO solution was added to the wells in the negative control and positive control areas.

[0145] c. Experimental steps

[0146] The PI3Kα and PI3Kα(H1047R) enzyme solutions and substrate mixed solutions were prepared using reaction buffer. The final concentrations of enzyme and substrate in the reaction solution were as follows:

[0147]

[0148]

[0149] After the compound transfer is completed, 2.5 μL of PI3Ks enzyme solution (compound wells and ZPE wells) or 2.5 μL of reaction buffer (HPE wells) is added to each well of the 384-well test plate as shown in the figure, centrifuged at 1000 rpm for 1 minute, and then the 384-well plate is placed in a constant temperature incubator and pre-incubated at 25°C for 10 minutes. After the incubation is completed, 2.5 μL of substrate mixed solution is added to each well to start the reaction (the total reaction volume is 5 μL), and the 384-well plate is placed in a constant temperature incubator and reacted at 25°C for 60 minutes. After the reaction, 5 μL of ADP-Glo ​​reagent (Promega, #V9102, thawed in advance and equilibrated to room temperature) was added to stop the reaction, and then incubated in a constant temperature incubator at 25°C for 60 minutes, and then 10 μL of Kinase Detection Substrate (Promega, #V9102, thawed in advance and equilibrated to room temperature) was added to each well, centrifuged and mixed, and then incubated in a constant temperature incubator at 25°C for 30 minutes. The fluorescence value was read on the Envision 2104 multi-function plate reader, and the reaction signal value read in each well was the raw data, and the raw data was used to analyze the half-inhibitory concentration of the compound on PI3K kinase.

[0150] Experimental Results

[0151] This experiment uses XLfit, a software developed by IDBS and integrated into the Microsoft Excel environment, to process and analyze test data. First, calculate the average reaction signals of the positive control wells and negative control wells respectively, and then use the formula "single-well inhibition rate = (negative control signal average value - single-well signal value) / (negative control signal average value - positive control signal average value) * 100%" to calculate the reaction inhibition rate percentage of each compound well. Then import the concentration and corresponding inhibition rate data into the XLfit software, use the Dose Response One Site 205 model in the software, and use the four-parameter method to fit the inhibition rate-concentration curve, and calculate the half-inhibitory concentration (IC 50 value).

[0152]

[0153] Experimental Conclusion

[0154] The above data show that the representative compounds of the present invention have good PI3Kα inhibitory activity.

[0155] The above is an exemplary description of the implementation of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above-mentioned implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of this application.

Claims

1. A compound of formula I and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt: in, R1 and R2 are the same or different and are independently selected from H or C 1-12 Alkyl; or, R1, R2 and the carbon atom to which they are connected together form a C 3-12 Cycloalkane ring; W is selected from O, S or NH; X1, X2, X3 are the same or different and are independently selected from CR x or N; Y1 and Y2 are the same or different and are independently selected from CR y or N; Each R x are the same or different and are independently selected from H, halogen, CN, OH, unsubstituted or optionally substituted by one, two or more R x1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 Cycloalkyl; each R x1 are the same or different and are independently selected from H, halogen, CN, OH, C 1-6 Alkyl or C 1-6 Alkoxy; Each R y are the same or different and are independently selected from H, halogen, CN, OH, unsubstituted or optionally substituted by one, two or more R y1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy or C 3-12 Cycloalkyl; each R y1 are the same or different and are independently selected from H, halogen, CN, OH, C 1-6 Alkyl or C 1-6 Alkoxy; m is selected from 0, 1, 2 or 3; Ring A is selected from C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring, C 3-14 Cycloalkane ring or 3-14 membered heterocyclic ring; Each R a are the same or different and are independently selected from H, halogen, CN, oxo (=O), OH, unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, -N(R a11 )(R a12 )、-C(O)N(R a13 )(R a14 ) or -S(O)2-R a15 ; Each R a1 are the same or different and are independently selected from H, OH, CN, halogen, OH, C 1-6 Alkyl or C 1-6 Alkoxy; R a11 , R a12 , R a13 , R a14 , R a15 The same or different, independently selected from H or C 1-12 alkyl; q is selected from 0, 1, 2, 3, 4 or 5; Z is selected from O or NH; Ring E is selected from C 6-10 Aromatic ring or 5-10 membered heteroaromatic ring; Each R e are the same or different and are independently selected from H, halogen, CN, OH, COOH, unsubstituted or optionally substituted by one, two or more R e1 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, -C(O)NH2 or 5-10 membered heteroaryl; each R e1 are the same or different and are independently selected from H, halogen, CN, OH, C 1-6 Alkyl or C 1-6 Alkoxy; p is selected from 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: R1 and R2 are the same or different and are independently selected from H or C 1-6 Alkyl; or, R1, R2 and the carbon atom to which they are connected together form a C 3-6 Cycloalkane ring; Preferably, R1 and R2 are the same or different and are independently selected from H or methyl; or, R1, R2 together with the carbon atom to which they are commonly attached form a cyclopropane ring; Preferably, W is selected from O or S; More preferably, W is selected from O.

3. The compound according to claim 1 or 2, and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: X1, X2, and X3 are independently selected from CR x ; Preferably, each R x are the same or different and are independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; Preferably, each R x are the same or different and are independently selected from H, F, Cl, CN, methyl, methoxy or cyclopropyl; Preferably, Y1 and Y2 are independently selected from CR y ; Preferably, each R y are the same or different and are independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; Preferably, each R y are the same or different and are independently selected from H, F, Cl, CN, methyl, methoxy or cyclopropyl.

4. The compound according to any one of claims 1 to 3 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from a benzene ring, a 5-6 membered heteroaromatic ring, a C 3-6 Cycloalkane ring or 4-8 membered heterocyclic ring; Preferably, ring A is selected from a benzene ring, a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, a thiophene ring, a furan ring, a pyrimidine ring, a pyridine ring, a cyclopropane ring, an azetidine ring, an azaspiro[3.3]heptane ring, a morpholine ring, a tetrahydropyrrole ring, Preferably, ring A is selected from Preferably, each R a are the same or different and are independently selected from H, CN, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -NHC 1-6 Alkyl, -C(O)(NHC 1-6 Alkyl) or -S(O)2-C 1-6 alkyl; Preferably, each R a are the same or different and are independently selected from H, F, Cl, CN, oxo (=O), methyl, methoxy, cyclopropyl, difluoromethyl, difluoromethoxy, mesyl, -NHCH3 or -C(O)NHCH3; Preferably, Selected from 5. The compound according to any one of claims 1 to 4 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: Ring E is selected from a benzene ring or a 5-6 membered heteroaromatic ring; Preferably, ring E is selected from a benzene ring, a pyridine ring, an oxazole ring, a pyrazole ring, a furan ring, a thiophene ring, an imidazole ring or a thiazole ring; Preferably, each R e are the same or different and are independently selected from H, halogen, C 1-6 Alkyl, COOH, -C(O)NH2 or 5-membered heteroaryl; Preferably, each R e are the same or different and are independently selected from H, F, Cl, methyl, COOH, -C(O)NH2, Preferably, Selected from 6. The compound according to any one of claims 1 to 5 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound has the structure shown below: Among them, ring A, ring E, W, X1, X2, X3, Y1, Y2, R1, R2, R a , R e , R x , R y , m, p, q have the definitions as described in any one of claims 1 to 5, and n is selected from 0, 1, 2 or 3; Preferably, the compound represented by formula I has the structure shown below: Among them, ring A, ring E, W, Y1, Y2, R1, R2, R a , R e , R x , R y , m, p, q have the definitions as described in any one of claims 1 to 5, and n is selected from 0, 1, 2 or 3; Preferably, the compound represented by formula I has the structure shown below: Among them, ring A, ring E, Y1, Y2, R1, R2, R a , R e , R x , R y , m, p, q have the definitions as described in any one of claims 1-5, and n is selected from 0, 1, 2 or 3.

7. The compound according to any one of claims 1 to 6 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound has the structure shown below:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or a pharmaceutically acceptable salt thereof.

9. Use of the compound according to any one of claims 1 to 7 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 8 in the preparation of a PI3Kα inhibitor; and / or, use in the preparation of a medicament for preventing and / or treating cancer, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, skin cancer and / or benign overgrowth syndrome; And / or, use in the preparation of a medicament for preventing and / or treating PIK3CA-related overgrowth (PROS).

10. A method for preventing and / or treating a disease or condition mediated by PI3Kα, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound according to any one of claims 1 to 7 and its racemate, stereoisomer, tautomer, isotope-labeled form, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8; Preferably, the PI3Kα-mediated disease or symptom is selected from cancer, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, skin cancer and / or benign overgrowth syndrome; Preferably, the PI3Kα-mediated disease or symptom is PIK3CA-associated overgrowth (PROS).

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