PI3Ka INHIBITOR COMPOUND, PHARMACEUTICAL COMPOSITION, AND USE THEREOF

Abstract

The present invention provides a PI3Kα inhibitor compound represented by formula (I), a pharmaceutical composition, and a use thereof. The compound has good PI3Kα inhibitory activity, can be used for treating PI3Kα-related diseases, has good biological activity and good safety, and improves trans-membrane activity and drug bioavailability.

Description

PI3Kα inhibitor compounds, pharmaceutical compositions and applications thereof

[0001] The present invention claims the priority of the prior application No. 202410274974.2 filed with the State Intellectual Property Office of China on March 11, 2024, entitled “PI3Kα inhibitor compounds, pharmaceutical compositions and their applications”; the priority of the prior application No. 202410619685.1 filed with the State Intellectual Property Office of China on May 17, 2024, entitled “PI3Kα inhibitor compounds, pharmaceutical compositions and their applications”; the priority of the prior application No. 202411017149.0 filed with the State Intellectual Property Office of China on July 26, 2024, entitled “PI3Kα inhibitor compounds, pharmaceutical compositions and their applications”. The present invention claims priority of the prior application for “PI3Kα inhibitor compounds, pharmaceutical compositions and their applications”; the prior application for patent application number 202411447943.9, filed with the State Intellectual Property Office of China on October 16, 2024, and entitled “PI3Kα inhibitor compounds, pharmaceutical compositions and their applications”; the prior application for patent application number 202510220124.9, filed with the State Intellectual Property Office of China on February 26, 2025, and entitled “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 in particular relates to PI3Kα inhibitor compounds, pharmaceutical compositions and applications thereof. Background Art

[0003] Phosphatidylinositol 3-kinases (PI3Ks) are a unique and conserved family of intracellular lipid kinases that possess both phosphatidylinositol kinase and serine / threonine (Ser / Thr) kinase activity. The PI3K family includes 15 kinases, which can be divided into three major classes (class I, class II, and class III) based on their structure and substrate specificity.

[0004] The most extensively studied class I PI3Ks are heterodimers composed of a regulatory subunit, p85, and a catalytic subunit, p110. There are four types of catalytic subunits: α, β, δ, and γ. The α, β, and δ classes correspond to the p85α, p85β, or p55 regulatory subunits, while the γ class corresponds to the p101 and p84 / 87 regulatory subunits. These regulatory subunits possess SH2 domains that recognize the intracellular kinase domain of RTKs and trigger activation of the catalytic subunit, p110.

[0005] Typically, upon activation by tyrosine kinases or G protein-coupled receptors, class I PI3K catalyzes the conversion of PIP2 to PIP3, triggering activation of the serine / threonine kinase AKT. AKT is regulated by PDK and mTOR2, and activation of AKT promotes cell cycle progression. Furthermore, AKT activation triggers the expression of a series of downstream molecules, thereby maintaining cell survival, promoting vascular survival, and promoting cell growth. The phosphatase-tensin homolog (PTEN), a negative regulator of PI3K signaling, dephosphorylates PIP3 to convert it to PIP2.

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

[0007] Over the past two decades, drug development related to the PI3K pathway has been a major research focus, with some success. Several PI3K inhibitors targeting individual isoforms have received regulatory approval. These include inhibitors targeting PI3Kδ, which is primarily enriched in leukocytes in B-cell malignancies, and alpelisib, a selective inhibitor of the PI3Kα isoform, for the treatment of HR+ / HER2- / PIK3CA-mutated advanced metastatic breast cancer and Proliferative Disorders (PROS) syndrome.

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

[0009] Alpelisib has equivalent inhibitory effects 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 grade ≥ 3 (mainly hyperglycemia) with Alpelisib 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 precise, more efficient, and better-tolerated inhibitors targeting mutant PI3Kα to change the current treatment status and meet clinical needs.

[0010] PIK3CA, the gene encoding the p110α protein, a catalytic subunit of PI3Kα, is the most commonly mutated gene in solid tumors. The most common hotspot mutations in the PIK3CA gene occur primarily in the kinase domain of exon 20 (H1047R) and the helical domain of exon 9 (E545K and E542K). These mutations significantly impact PI3Kα activity and have been shown to be oncogenic gain-of-function mutations. The H1047R mutation occurs in approximately 15% of breast cancers, while it is relatively uncommon in other tumors. Compared with patients with wild-type PIK3CA, patients with HR+ / HER2- advanced breast cancer harboring PIK3CA mutations have a poorer prognosis, poor response to conventional treatment, and resistance to endocrine therapy and chemotherapy. Small studies primarily analyzing ER+ breast and adenocarcinoma tumors have shown that patients with the H1047R mutation exhibit decreased survival compared to tumors harboring E545K.

[0011] Therefore, targeting PI3Kα mutations and developing inhibitors with enhanced selectivity for mutant PI3Kα may provide valuable therapeutic opportunities for breast cancer patients carrying this mutation, overcoming the problem of compensatory insulin or glucose production after systemic PI3Kα inhibition. This would create an increased window for drug dosing, selectively inhibiting the pathological signaling of mutant PI3Kα in cancer cells while sparing 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 earlier stages, thereby benefiting more patients. Summary of the Invention

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

[0013] wherein R1 and R2 are the same or different and are independently selected from H, deuterium, unsubstituted or optionally substituted by one, two or more R 11 Substituted with the following groups: C1-12 Alkyl, C 1-12 Alkyloxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, C 3-12 Cycloalkyl; each R 11 the same or different, independently selected from H, deuterium, halogen, CN, OH, C 1-12 alkyl;

[0014] Each R3 is the same or different and is independently selected from H, deuterium, halogen, CN, OH, unsubstituted or optionally substituted by one, two or more R 31 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkyloxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, N(R 32 )(R 33 ); each R 31 the same or different, independently selected from H, deuterium, halogen, CN, C 1-12 Alkyl, C 1-12 Alkyloxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, C 1-12 Acyl; R 32 、R 33 the same or different, independently selected from H, deuterium, C 1-12 Alkyl, S(=O)2R 311 、S(=O)(=NH)R 312 ; R 311 、R 312 the same or different, independently selected from H, deuterium, C 1-12 alkyl;

[0015] X1 is selected from N, NR x1 or CR x2 ; R x1 、R x2 the same or different, independently selected from H, deuterium, halogen, CN, C 1-12 alkyl;

[0016] X2 is selected from O or N;

[0017] Ring A is selected from C 3-12 Carbocyclic, 3-14 membered heterocyclic, C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring;

[0018] Each R athe same or different, independently selected from H, deuterium, halogen, CN, OH, C 1-12 Alkyl, C 1-12 Alkyloxy, C 3-12 Cycloalkyl, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, OH-C 1-12 alkyl;

[0019] Y1 is absent or selected from ether bond (-O-), carbonyl Unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 1-12 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-14 Cycloalkylene, 3-14 membered heterocycloalkylene, C 6-14 Arylene, 5-14 membered heteroarylene, imino (-NH-); each R b the same or different, independently selected from deuterium, OH, CN, halogen, NH2, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl, halogenated C 3-12 Cycloalkyl, -S(O)2-C 1-12 Alkyl, -C 1-12 Alkyl-CN;

[0020] L1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: C 1-12 Alkylene, C 1-12 Alkylene-C 3-14 Cycloalkylene, C 1-12 Alkylene-3-14 membered heterocycloalkylene; each R c the same or different, independently selected from deuterium, OH, CN, halogen, NH2, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl, halogenated C 3-12 Cycloalkyl, -S(O)2-C 1-12 Alkyl, -C 1-12 Alkyl-CN;

[0021] R4 is selected from CN, unsubstituted or optionally substituted by one, two or more R d Substituted with the following groups: C 3-12Carbocyclic ring, 3-14 membered heterocyclic ring, C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring; each R d the same or different, independently selected from deuterium, OH, CN, halogen, NH2, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl, halogenated C 3-12 Cycloalkyl, -S(O)2-C 1-12 Alkyl, -C 1-12 Alkyl-CN;

[0022] m is selected from 0, 1, 2, 3 or 4;

[0023] n is selected from 0, 1, 2, 3 or 4.

[0024] According to some embodiments, R1, R2 are the same or different and are independently selected from H, unsubstituted or optionally substituted by one, two or more R 11 Substituted with the following groups: C 1-6 Alkyl (such as methyl, ethyl, isopropyl, tert-butyl), halogenated C 1-6 Alkyl (such as trifluoromethyl, difluoromethyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl);

[0025] According to some embodiments, each R 11 The same or different, independently selected from halogen (such as F, Cl, Br), C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl);

[0026] According to some embodiments, R1 and R2 are the same or different and are independently selected from H or trifluoromethyl.

[0027] According to some embodiments, R1 is H and R2 is trifluoromethyl.

[0028] According to some embodiments, each R3 is the same or different and is independently selected from halogen, CN, unsubstituted or optionally substituted by one, two or more R 31 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkyloxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, N(R 32 )(R 33 );

[0029] According to some embodiments, each R 31 The same or different, independently selected from H, CN, C 1-6 Alkyl, C 1-6 acyl group;

[0030] According to some embodiments, each R 31 The same or different, independently selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl);

[0031] According to some embodiments, R 32 、R 33 The same or different, independently selected from H, C 1-6 Alkyl (such as methyl, ethyl, isopropyl, tert-butyl), -S(=O)2-C 1-6 Alkyl, -S(=O)(=NH)C 1-6 alkyl.

[0032] According to some embodiments, each R3 is the same or different and independently selected from F or methyl.

[0033] According to some embodiments, m is selected from 0, 1, 2 or 3.

[0034] According to some embodiments, m is 2 and R3 is F.

[0035] According to some embodiments, X1 is selected from N, NR x1 or CR x2 ; R x1 、R x2 The same or different, independently selected from H, halogen (such as F, Cl, Br), CN, C 1-6 Alkyl (eg, methyl, ethyl, isopropyl, tert-butyl).

[0036] According to some embodiments, X1 is selected from CR x2 ; R x2 Selected from H or methyl.

[0037] According to some embodiments, X1 is selected from CCH3.

[0038] According to some embodiments, X2 is selected from O.

[0039] According to some embodiments, Ring A is selected from C 3-8 Carbocyclic ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring.

[0040] According to some embodiments, ring A is selected from a benzene ring or a 5-6 membered heteroaromatic ring.

[0041] According to some embodiments, ring A is selected from a benzene ring, a pyrazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyridinone ring (such as a pyridin-2(1H)-one ring), a pyrimidinone ring (such as a pyrimidin-2(1H)-one ring), and a pyridazinone ring (such as a pyridazin-3(2H)-one ring).

[0042] According to some embodiments, Selected from

[0043] Among them, the “*” side is connected to the urea group, and the “#” side is connected to Y1.

[0044] According to some embodiments, each R a The same or different, independently selected from deuterium, halogen (such as F, Cl, Br), CN, OH, C 1-6 Alkyl (such as methyl, ethyl, isopropyl, tert-butyl), C 1-6 Alkyloxy (such as methoxy), C 3-6 Cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogenated C 1-6 Alkyl (such as trifluoromethyl, difluoromethyl), halogenated C 1-6 Alkyloxy, OH-C 1-6 alkyl;

[0045] According to some embodiments, each R a are the same or different and are independently selected from F, Cl, and methoxy.

[0046] According to some embodiments, each R a are the same or different and are independently selected from methoxy.

[0047] According to some embodiments, n is selected from 0 or 1.

[0048] According to some embodiments, Selected from

[0049] According to some embodiments, Y1 is absent or selected from an ether bond (-O-), a carbonyl group Unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 1-6 Alkylene (such as methylene, ethylene, n-propylene), C 3-6 Cycloalkylene (such as ), 3-6 membered heterocycloalkylene (such as ), imino group (-NH-).

[0050] According to some embodiments, R bSelected from OH, CN, halogen (such as F, Cl, Br), C 1-6 Alkyl (such as methyl, ethyl, isopropyl, tert-butyl), C 1-6 Alkoxy (such as methoxy), -S(O)2-C 1-6 Alkyl (e.g. -S(O)2-CH3).

[0051] According to some embodiments, R b is selected from F, Cl, Br, CN, OH, methoxy or methylsulfonyl.

[0052] According to some embodiments, L1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: C 1-4 Alkylene, C 1-4 Alkylene-C 3-6 Cycloalkylene, C 1-4 Alkylene-3-6 membered heterocycloalkylene.

[0053] According to some embodiments, L1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted groups: methylene,

[0054] According to some embodiments, L1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted groups: methylene,

[0055] According to some embodiments, L1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted methylene.

[0056] According to some embodiments, R c Selected from halogen, CN, C 1-6 Alkyl (such as methyl, ethyl, isopropyl, tert-butyl), C 3-6 Cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogenated C 1-6 Alkyl (eg, trifluoromethyl, difluoromethyl).

[0057] According to some embodiments, R c is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0058] According to some embodiments, R4 is selected from CN, unsubstituted or optionally substituted with one, two or more R d Substituted with the following groups: C 3-6 Carbocyclic or 3-8 membered heterocyclic ring; each R dthe same or different, independently selected from deuterium, OH, CN, halogen, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl.

[0059] According to some embodiments, R4 is selected from CN, cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, oxetanyl ring (such as ), tetrahydrofuranyl ring (such as ), tetrahydropyranyl ring (such as ).

[0060] According to some embodiments, R4 is CN.

[0061] According to some embodiments, Selected from

[0062] According to some embodiments, Selected from

[0063] According to some embodiments, Selected from

[0064] According to some embodiments, the compound represented by Formula I may have the structure shown below:

[0065] Among them, R1, R2, R3, X1, X2, Y1, L1, Ring A, R a , m, n have the definitions described herein;

[0066] X3 is selected from CH2, NH, or O;

[0067] Each R e the same or different, independently selected from deuterium, halogen, CN, OH, C 1-4 Alkyl (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl), C 1-4 Alkoxy (such as methoxy, ethoxy), C 3-6 Cycloalkyl (such as cyclopropyl), halogenated C 1-6 Alkyl (such as difluoromethyl, trifluoromethyl), halogenated C 1-6Alkyloxy (difluoromethoxy, trifluoromethoxy), hydroxyl C 1-6 Alkyl (such as hydroxymethyl, hydroxyethyl);

[0068] m1 is selected from 0, 1, 2 or 3; m2 is selected from 0, 1, 2 or 3; m1 and m2 are not 0 at the same time;

[0069] m3 is selected from 0, 1, 2 or 3.

[0070] According to some embodiments, the compound represented by Formula I may have the structure shown below:

[0071] Among them, Y1, L1, ring A, R a , n has the meaning given in this document;

[0072] X3 is selected from CH2, NH, or O;

[0073] Each R e the same or different, independently selected from deuterium, halogen, CN, OH, C 1-4 Alkyl (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl), C 1-4 Alkoxy (such as methoxy, ethoxy), C 3-6 Cycloalkyl (such as cyclopropyl), halogenated C 1-6 Alkyl (such as difluoromethyl, trifluoromethyl), halogenated C 1-6 Alkyloxy (difluoromethoxy, trifluoromethoxy), hydroxyl C 1-6 Alkyl (such as hydroxymethyl, hydroxyethyl);

[0074] m1 is selected from 0, 1, 2 or 3; m2 is selected from 0, 1, 2 or 3; m1 and m2 are not 0 at the same time;

[0075] m3 is selected from 0, 1, 2 or 3.

[0076] According to some embodiments, the compound represented by Formula I may have the structure shown below:

[0077] Wherein, Y1 and L1 have the definitions described herein.

[0078] According to some embodiments, the compound represented by Formula I may have the structure shown below:

[0079] The present invention also provides a method for preparing the compound represented by formula I, comprising the following steps:

[0080] Among them, R1, R2, R3, X1, X2, Y1, L1, Ring A, R a , m, n have the definitions described herein; Z is selected from a leaving group, such as a halogen (such as Cl), R is selected from C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-3 Alkyl-C 6-10 Aryl groups, such as phenyl, tolyl, and benzyl.

[0081] The present invention further provides a pharmaceutical composition comprising the compound of formula I described in the present invention and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt.

[0082] 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, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0083] 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.

[0084] The present invention further provides a pharmaceutical combination product comprising a compound of formula I described herein and its racemates, stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts, and one or more additional therapeutic agents.

[0085] The present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of PI3Kα inhibitors.

[0086] The present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt or pharmaceutical composition 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, head and neck cancer, colorectal cancer, skin cancer and / or benign overgrowth syndrome. In some embodiments, the breast cancer is selected from ER+ / HER2- breast cancer.

[0087] The present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, 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).

[0088] The present invention also provides a method for preventing and / or treating a disease or condition mediated by PI3Kα, 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.

[0089] According to some embodiments, the PI3Kα-mediated disease or condition is selected from cancer.

[0090] According to some embodiments, the PI3Kα-mediated disease or condition is PIK3CA-related overgrowth (PROS).

[0091] According to some embodiments, the present invention further provides a use of a drug combination in the preparation of a drug for preventing and / or treating cancer, wherein the drug combination comprises:

[0092] (a) the compound of formula I of the present invention and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt, or the pharmaceutical composition thereof; and

[0093] (b) one or more additional therapeutic agents.

[0094] In some embodiments, the additional therapeutic agent is selected from one or more of a CDK4 / 6 inhibitor, a selective estrogen receptor (ER) degrader, an AKT inhibitor, an mTOR inhibitor, and an HDAC inhibitor.

[0095] In some embodiments, the cancer is selected from lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, head and neck cancer, colorectal cancer, skin cancer, and / or benign overgrowth syndrome.

[0096] In some embodiments, the breast cancer is selected from ER+ / HER2- breast cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0097] Figure 1: Schematic diagram of the tumor growth curve in Test Example 3 (data points represent the average tumor volume within the group, and error bars represent standard errors). Beneficial effects

[0098] The compounds provided by the present invention have good PI3Kα inhibitory activity and can be used to treat diseases related to PI3Kα. The compounds of the present invention not only have good biological activity and good safety, but also have improved transmembrane activity and drug bioavailability.

[0099] Definitions and Explanations of Terms

[0100] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0101] The term "optional" (or "optionally", "optionally") in the general formula definitions of this 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 optionally substituted by one, two or more R.

[0102] "More" means three or more.

[0103] Unless otherwise indicated, numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-12" is equivalent to reciting each integer value in the numerical range "1-12", namely, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.

[0104] The term "C 1-12 "Alkyl" is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms, "C 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6The 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.

[0105] 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 Cycloalkyl". The term "C 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]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0106] The term "C 6-14 "Aryl" should be 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 can be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-10 Aryl". The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C10 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. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0107] 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, may additionally be benzofused. "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-quinolinyl, 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 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-oxo-1-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-oxo-1-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-oxo-1-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-oxo-1-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-oxo-1-carbazolyl, -phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 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-benzoisoquinolinyl, 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]-o-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

[0015] In some embodiments, the present invention further comprises carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 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- to 14-membered heteroaryl group is linked to other groups to form a compound of the present invention, the carbon atoms on the 5- to 14-membered heteroaryl ring may be linked to the other groups, or heteroatoms on the 5- to 14-membered heteroaryl ring may be linked to the other groups. When the 5- to 14-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, a hydrogen atom connected to a carbon atom on a heteroaryl ring may be substituted, or a hydrogen atom connected to a heteroatom on a heteroaryl ring may be substituted.

[0108] 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 can be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). The heterocyclyl can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclyl can include, but is not limited to, 4-membered rings such as azetidinyl, oxetane; 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 can be benzo-fused. The heterocyclic group may be bicyclic, such as, 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]pyrazin-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 linked to other groups to form the compounds of the present invention, the linking may be to a carbon atom of the 3-14-membered heterocyclic group or to a heterocyclic atom on the 3-14-membered heterocyclic group ring. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl group may be connected to the other group. 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 the other group.

[0109] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0110] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0111] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0112] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0113] "Halo" means substituted with one or more halogens.

[0114] The term "oxo" refers to a substituent in which a carbon atom, a nitrogen atom, or a sulfur atom is oxidized to form an oxy group (=O).

[0115] The term "alkylamino" refers to -NH-(alkyl) or -N-(alkyl)2, wherein alkyl is as defined above. Non-limiting examples of alkylamino include methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, and the like.

[0116] The term "alkyloxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0117] The terms "alkyleneoxy" and "oxyalkylene" refer to -alkylene-O- or -O-alkylene-, where alkylene represents a linear or branched saturated divalent hydrocarbon radical. The definition of "alkyl" with respect to the number of carbon atoms in "alkylene" applies as defined above. It will be understood by those skilled in the art that an alkyleneoxy or oxyalkylene group can be attached to the remainder of the molecule in which it is contained in any orientation, i.e., the two terms are used interchangeably.

[0118] The term "nitrogen oxide" refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound structure.

[0119] Unless otherwise specified, a heterocyclic group, heteroaryl group, or heteroarylene group includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include 1, 2, or more substituted or bonded forms thereof, including pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene, and pyridin-4-ylene; thienyl or thienylene group includes thien-2-yl, thien-2-ylene, thien-3-ylene, and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0120] Wavy lines intersecting chemical bonds Used to indicate the connection position between a group and other atoms in the molecular structure. Indicates connection with the 3-position of pyridyl. When the group connection position is not fixed, taking pyridyl as an example, The above-mentioned embodiment shows that the pyridyl group can be connected to any position on the pyridyl group. Unless otherwise specified, similar expressions in this application are interpreted the same as above.

[0121] In the chemical structure of the compound of the present invention, the bond Indicates that the configuration is not specified. Indicates the absolute configuration, that is, if there are stereoisomers in the chemical structure, the bond Can be or include both Two configurations.

[0122] In the present invention, the compounds referred to also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 32 P. 35 S. 18 F and 36Cl. Compounds of the invention, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention, for example, those incorporating radioactive isotopes (such as 3 H and 14 C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 H or D) substitution may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability and may therefore be preferred in certain circumstances. The presence of hydrogen in a substituent of the present invention without the separate listing of the term deuterium or tritium does not exclude deuterium or tritium, but rather may also include deuterium or tritium.

[0123] It will be appreciated by those skilled in the art 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 base addition salts; 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 internal salts.

[0124] 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 polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0125] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Thus, these compounds may exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon is in the R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well 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 resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, e.g., hexane / isopropanol / acetonitrile.

[0126] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0127] 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.

[0128] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit 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) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents 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) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses 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

[0129] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative 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 within the scope of protection intended by the present disclosure.

[0130] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0131] Synthesis of intermediate 001-1c

[0132] The first step (S,Z)-N-((5,7-difluoro-3-methylbenzofuran-2-yl)methylene)-2-methylpropane-2-sulfenamide 001-1e

[0133] Under nitrogen protection, at 80 ° C, a solution of 001-1d (3 g, refer to the synthesis steps in the patent "WO2022265993A1"), (S)-tert-butylsulfenamide (2.8 g) and tetraisopropyl titanate (13.1 g) in tetrahydrofuran (60 mL) was stirred overnight. The reaction mixture was quenched by adding a saturated sodium chloride solution (200 mL). Filtered, the filter cake was washed with ethyl acetate (100 mL), and the filtrate was extracted with ethyl acetate (3×100 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (100 mL), and dried over anhydrous sodium sulfate. After filtering the obtained mixture, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-18%) to give compound 001-1e (4.2 g).

[0134] LC-MS: (ES, m / z) = 300.00 [M+H] +

[0135] Step 2 (S)-N-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide 001-1f

[0136] Under nitrogen, tetrabutylammonium difluorotriphenylsilicate (7.2 g) was added to a solution of 001-1e (4 g) in tetrahydrofuran (80 mL) at room temperature. The temperature was lowered to -60°C and stirred for 1 hour. A solution of (trifluoromethyl)trimethylsilane (7.7 g) in tetrahydrofuran (20 mL) was slowly added dropwise. After stirring for 1 hour, the temperature was raised to -30°C and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (80 mL) at -30°C and extracted with ethyl acetate (3 × 80 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (100 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-38%) to obtain compound 001-1f (3.6 g).

[0137] LC-MS: (ES, m / z) = 370.20 [M+H] +

[0138] Step 3 (R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl-1-amine 001-1c

[0139] 001-1f (3.6 g) was dissolved in a solution of hydrochloric acid in 1,4-dioxane (40 mL, 4 M) at room temperature and stirred for 2 h. The reaction solution was then concentrated, and the resulting residue was dissolved in water and basified to pH 8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were backwashed with saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to yield compound 001-1c (2.4 g).

[0140] LC-MS: (ES, m / z)=249.30[M+H-17] +

[0141] Example 1 (R)-1-(1-(cyanomethyl)-1H-pyrazol-4-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea 001-1

[0142] The first step (1-(cyanomethyl)-1H-pyrazol-4-yl)carbamic acid phenyl ester 001-1b

[0143] Under nitrogen, phenyl chloroformate (134.81 mg) was added to a solution of 001-1a (100 mg) in tetrahydrofuran (5 mL) at room temperature. The reaction system was stirred at room temperature for 16 hours. The reaction solution was then dried to give compound 001-1b (160 mg, crude product). The crude product was used directly in the next step.

[0144] LCMS: (ESI, m / z): 243.1 [M+H] + ;

[0145] Step 2 (R)-1-(1-(cyanomethyl)-1H-pyrazol-4-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea 001-1

[0146] Under nitrogen, crude compound 001-1b (110.46 mg) and N,N-diisopropylethylamine (147.33 mg) were added to a solution of 001-1c (100 mg) in dimethyl sulfoxide (6 mL) at room temperature. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched by adding water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were backwashed with saturated brine (3 × 50 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters 2767 / QDA, Column: Xbridge C18 19 × 250 mm, 10 μm; mobile phase A: 0.03% ammonia / water, mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 51% to 55%) to afford compound 001-1 (42.37 mg).

[0147] LCMS: (ESI, m / z): 414.1 [M+H] +

[0148] 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H),7.88(s,1H),7.73(d,1H),7.50(s,1H),7.46-7.37(m,2H),6.09-5.98(m,1H),5.39(s,2H),2.30(s,3H).

[0149] Example 2 1-(1-(1-cyanoethyl)-1H-pyrazol-4-yl)-3-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea 004-1

[0150] The first step 2-(4-nitro-1H-pyrazol-1-yl)propionitrile 004-1b

[0151] Under nitrogen, 2-bromopropionitrile (4.74 g) and potassium carbonate (2.44 g) were added to a solution of 004-1a (2.0 g) in N,N-dimethylformamide (20 mL) at room temperature. The mixture was reacted at 80°C for 2 hours. The mixture was then cooled to room temperature, quenched with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford compound 004-1b (3 g, crude product), which was used directly in the next reaction.

[0152] MS:(ESI,m / z):167.1[M+H] + ;

[0153] Step 2 2-(4-amino-1H-pyrazol-1-yl)propionitrile 004-1c

[0154] To a solution of 004-1b (2 g) in methanol (10 mL) was added palladium on carbon (1.28 g) at room temperature, and the mixture was stirred at room temperature for 2 hours under a H2 atmosphere. The mixture was filtered through celite and washed with methanol (50 mL x 2). The residue was concentrated in vacuo and then purified by silica gel column chromatography (methanol / dichloromethane = (0-5%)) to give compound 004-1c (1.4 g).

[0155] MS:(ESI,m / z):137.2[M+H] +

[0156] Step 3 (1-(1-cyanoethyl)-1H-pyrazol-4-yl)phenylcarbamate 004-1d

[0157] Under nitrogen, phenyl chloroformate (241.67 mg) was added dropwise to a solution of 004-1c (200 mg) in tetrahydrofuran (10 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was dried to give compound 004-1d (330 mg, crude product), which was used directly in the next reaction.

[0158] MS:(ESI,m / z):257.1[M+H] +

[0159] Step 4 1-(1-(1-cyanoethyl)-1H-pyrazol-4-yl)-3-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea 004-1

[0160] Under nitrogen protection, crude compound 004-1d (92.3 mg) and N,N-diisopropylethylamine (96.93 mg) were added to a solution of 001-1c (100 mg) in dimethyl sulfoxide (3 mL) at room temperature and stirred at 50°C for 16 hours. The reaction mixture was then quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, backwashed with saturated brine (40 mL × 3), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by C18 reverse phase column (methanol / 0.1% aqueous ammonia solution, 3%-66%), and the resulting solution was concentrated and lyophilized to give compound 004-1 (20 mg).

[0161] LCMS: (ESI, m / z): 428.1[M+1] + ;

[0162] 1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),7.92(s,1H),7.74(d,1H),7.53(s,1H),7.46– 7.37(m,2H),6.09–5.98(m,1H),5.80–5.73(m,1H),2.30(s,3H),1.76–1.72(m,3H).

[0163] By enlarging the previous steps, 2.5 g of compound 004-1 was obtained, and 004-1 (2.5 g) was subjected to SFC chiral separation under the following conditions: column: CHIRALPAK AY; column size: 5.0 cm × 25 cm, 10 μm; mobile phase: n-hexane / EtOH = 85 / 15 (V / V); flow rate: 60 mL / min; wavelength: UV 254 nm; temperature: 35°C; the obtained solutions were concentrated and lyophilized to obtain compounds 004-1-1 (front peak, Rt = 6.146 min, 1.22 g) and 004-1-2 (back peak, Rt = 7.112 min, 1.25 g).

[0164] 004-1-1

[0165] LCMS: (ESI, m / z): 427.9 [M+1] + ;

[0166] 1 H NMR(400MHz,DMSO-d6)δ8.44(s,1H),7.92(s,1H),7.73(d,1H),7.53(s,1H),7.4 6–7.35(m,2H),6.08–5.98(m,1H),5.80–5.73(m,1H),2.30(s,3H),1.74(d,3H).

[0167] 004-1-2

[0168] LCMS: (ESI, m / z): 427.9 [M+1] + ;

[0169] 1 H NMR(400MHz,DMSO-d6)δ8.44(s,1H),7.92(s,1H),7.73(d,1H),7.53(s,1H),7.4 6–7.35(m,2H),6.08–5.98(m,1H),5.80–5.73(m,1H),2.29(s,3H),1.74(d,3H).

[0170] Example 3 (R)-1-(2-((cyanomethyl)amino)pyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea 049-1

[0171] Step 1 2-((5-nitropyrimidin-2-yl)amino)acetonitrile 049-1b

[0172] Under nitrogen, aminoacetonitrile (421.87 mg) was added dropwise to a solution of 049-1a (1 g) and N,N-diisopropylethylamine (5 mL) in dimethyl sulfoxide (10 mL) at room temperature. The mixture was then reacted at 80°C for 2 hours. The mixture was then quenched with water (50 mL) and extracted with ethyl acetate (40 mL x 2). The organic phase was backwashed with brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated in vacuo. Compound 049-1b (754 mg, crude product) was obtained. The crude product was used directly in the next reaction.

[0173] MS:(ESI,m / z):180.1[M+H] + ;

[0174] Step 2 2-((5-aminopyrimidin-2-yl)amino)acetonitrile 049-1c

[0175] To a solution of 049-1b (754 mg, crude product) in methanol (5 mL) was added palladium on carbon (44.80 mg) at room temperature, and the mixture was stirred at room temperature under a H2 atmosphere for 2 hours. The mixture was then filtered through a pad of celite and washed with methanol (50 mL x 2). The mixture was concentrated in vacuo. The resulting residue was purified by dry-phase chromatography on a silica gel column using methanol / dichloromethane (0-5%) to afford compound 049-1c (358 mg).

[0176] MS:(ESI,m / z):150.1[M+H] + ;

[0177] Step 3 (2-((cyanomethyl)amino)pyrimidin-5-yl)phenylcarbamate 049-1d

[0178] Under nitrogen, phenyl chloroformate (110.15 mg) was added dropwise to a solution of 049-1c (100 mg) in tetrahydrofuran (5 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was spin-dried to obtain compound 049-1d (180 mg, crude product), which was used directly in the next reaction.

[0179] MS:(ESI,m / z):270.1[M+H] + ;

[0180] Step 4 (R)-1-(2-((cyanomethyl)amino)pyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea 049-1

[0181] Under nitrogen, crude compound 049-1d (121.44 mg) and N,N-diisopropylethylamine (159.97 mg) were added to a solution of 001-1c (110 mg) in dimethyl sulfoxide (5 mL) at room temperature. The mixture was stirred at 50°C for 12 hours. The reaction mixture was then quenched with water (50 mL). The reaction mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were backwashed with saturated brine (50 mL x 3) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters 2767 / QDA, column: XBridge C18, 19*250 mm*10 μm; flow rate: 20 mL / min; mobile phase A: 0.03% NH3H2O / H2O, B: ACN; gradient: 51-51%) to afford compound 049-1 (87.78 mg).

[0182] LCMS: (ESI, m / z): 441.1 [M+H] + ;

[0183] 1 H NMR(400MHz,DMSO-d6)δ8.43(s,2H),8.42–8.40(m,1H),7.90(d,1H),7.59–7 .53(m,1H),7.46–7.37(m,2H),6.11–6.00(m,1H),4.24(d,2H),2.30(s,3H).

[0184] Example 4 (R)-1-(1-(1-(cyanomethyl)cyclopropyl)-1H-pyrazol-4-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea 007-1

[0185] The first step is ethyl 2-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)acetate 007-1b

[0186] Under argon protection, 007-1a (1 g) and DBU (1.64 g) were added to a solution of 4-nitro-1H-pyrazole (0.99 g) in acetonitrile (10 mL) at room temperature. The reaction system was stirred at 80°C for 3 hours. The reaction solution was then concentrated, and the resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-50%) to obtain compound 007-1b (1.7 g).

[0187] LCMS: (ESI, m / z): 240.2 [M+H]+;

[0188] Step 2 2-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)acetic acid 007-1c

[0189] Under argon, lithium hydroxide hydrate (0.45 g) was added to a solution of 007-1b (1.7 g) in tetrahydrofuran (16 mL) and water (4 mL) at room temperature. The reaction system was stirred at room temperature for 1 hour. Thin-layer chromatography (PE / EA = 9:1) monitored the formation of new spots. The mixture was diluted with water (30 mL) and then acidified with aqueous hydrochloric acid (2N, 2 mL). The mixture was then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 007-1c (1.3 g).

[0190] Step 3 2-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)acetyl chloride 007-1d

[0191] Under argon protection, thionyl chloride (5.37 g) was added to a toluene (15 mL) solution of 007-1c (1.3 g), and the mixture was stirred at 100 degrees for 3 hours. The mixture was then concentrated under reduced pressure to obtain 007-1d (1.3 g).

[0192] Step 4: 2-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)acetamide 007-1e

[0193] 007-1d (1.3 g) was dissolved in aqueous ammonia (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then quenched with saturated sodium bicarbonate (20 mL) and extracted with dichloromethane (30 mL x 3). The organic phase was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by dry-phase chromatography on a silica gel column using dichloromethane / methanol (0-8%) to afford 007-1e (0.76 g).

[0194] LCMS: (ESI, m / z): 211.1 [M+H]+;

[0195] Step 5 2-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)acetonitrile 007-1f

[0196] Under argon, triethylamine (2.1 g) and thionyl chloride (1.3 g) were slowly added to a solution of 007-1e (740 mg) in dichloromethane (10 mL) at -78°C and stirred for 16 hours. Thin-layer chromatography (DCM / MeOH = 9:1) monitored the formation of new spots. The reaction solution was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by dry-phase chromatography on a silica gel column using dichloromethane / methanol (0-5%) to afford 007-1f (650 mg).

[0197] Step 6 2-(1-(4-amino-1H-pyrazol-1-yl)cyclopropyl)acetonitrile 007-1g

[0198] Under argon, iron powder (580.84 mg) and ammonium chloride (556.30 mg) were added to a solution of 007-1f (200 mg) in methanol / water (9:1, 10 mL) at room temperature. The mixture was stirred at 70°C for 16 hours. The mixture was then filtered, and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by dry-phase silica gel column chromatography using dichloromethane / methanol (0-5%) to afford 007-1g (150 mg).

[0199] LCMS: (ESI, m / z): 163.2 [M+H] + ;

[0200] Step 7 (R)-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)phenylcarbamate 007-1h

[0201] Under nitrogen, phenyl chloroformate (209.1 mg) was added dropwise to a solution of 001-1c (300 mg) in tetrahydrofuran (10 mL) at room temperature, and the mixture was stirred at 25°C for 16 hours. The reaction solution was then spin-dried to give 007-1h (300 mg, crude product), which was used directly in the next reaction.

[0202] MS:(ESI,m / z):386.1[M+H] + ;

[0203] Step 8 (R)-1-(1-(1-(cyanomethyl)cyclopropyl)-1H-pyrazol-4-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea 007-1

[0204] Under argon, 007-1h (38.99 mg, crude) and triethylamine (35.67 mg) were added to a solution of 007-1g (15 mg) in dimethyl sulfoxide (2 mL) at room temperature. The mixture was stirred at 50°C for 16 hours. The reaction solution was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, backwashed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by dry method by silica gel column chromatography and purified with ethyl acetate / petroleum ether (0-50%) to give a crude product, which was then purified by prep-HPLC (Waters 2767 / QDA, column: XBridge C18, 19*250mm*10μm; mobile phase A: 0.03% NH4OH / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 52%-52%) to give 007-1 (22.23mg).

[0205] LCMS: (ESI, m / z): 454.2 [M+H] + ;

[0206] 1 H NMR(400MHz,Methanol-d4)δ7.83(s,1H),7.48(s,1H),7.22–7.18(m,1H),7.08–7.01(m, 1H),6.01–5.93(m,1H),3.01(s,2H),2.32(s,3H),1.38–1.33(m,2H),1.22–1.17(m,2H).

[0207] The compounds listed in Table 1 below were prepared using conditions similar to those in the above examples, and the structural characterization data of these compounds are listed in Table 1.

[0208] Table 1

[0209] Biological evaluation

[0210] 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.

[0211] Test materials and instruments

[0212] A. Reagent Information

[0213] B. Consumables Information

[0214] C. Instrument Information

[0215] Experimental procedures

[0216] a. Preparation of reaction buffer

[0217] Taking 10 ml as an example, prepare and use immediately on the day of the experiment:

[0218] b. Compound Preparation

[0219] The test compound was prepared into a 100x concentration stock solution with DMSO, and the compound was serially diluted using a multichannel electronic pipette. 50 nL of the test compound was transferred to a 384-well microvolume assay plate using the automated micropipette system Echo550. Only 50 nL of 100% DMSO solution was added to the wells in the negative control and positive control areas.

[0220] c. Experimental steps

[0221] PI3Kα and PI3Kα(H1047R) enzyme solutions and substrate mixture were prepared using reaction buffer. The final concentrations of enzyme and substrate in the reaction solution were as follows:

[0222] After compound transfer, 2.5 μL of PI3Ks enzyme solution (compound wells and ZPE wells) or 2.5 μL of reaction buffer (HPE wells) were added to each well of the 384-well assay plate as shown in the diagram. The plates were centrifuged at 1000 rpm for 1 minute, and then placed in a thermostatic incubator for 10 minutes at 25°C. After incubation, 2.5 μL of substrate mixture solution was added to each well to initiate the reaction (total reaction volume was 5 μL), and the 384-well plate was placed in a thermostatic incubator for 60 minutes at 25°C. After the reaction, 5 μL of ADP-Glo ​​reagent (Promega, #V9102, thawed and equilibrated to room temperature) was added to stop the reaction. After incubation at 25°C for 60 minutes, 10 μL of Kinase Detection Substrate (Promega, #V9102, thawed and equilibrated to room temperature) was added to each well. The mixture was centrifuged and then incubated at 25°C for 30 minutes. Fluorescence was read on an Envision 2104 multi-function plate reader. The reaction signal value for each well was used to analyze the half-inhibitory concentration of the compound on PI3K kinase.

[0223] Experimental results

[0224] 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 signal of the positive control well and the negative control well respectively, and then calculate the reaction inhibition rate percentage of each compound well according to 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%". Then import the concentration and corresponding inhibition rate data into 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 (IC50) of the compound. 50 The results are shown in Table 2.

[0225] Table 2

[0226] Experimental Conclusion

[0227] The above data show that the representative compounds of the present invention have good PI3Kα inhibitory activity.

[0228] Test Example 2: The purpose of this test is to determine the inhibitory effect of the test compound on SK-BR-3 (WT) and T47D (H1047R) using the ADP-Glo ​​luciferase luminescence detection method.

[0229] Materials and reagents

[0230] SK-BR-3 / T47D CTG Assay Experimental Procedure

[0231] 1) Preheat PBS, 0.25% trypsin, and cell culture medium in a 37°C water bath.

[0232] 2) Observe the cells under a microscope to assess the degree of cell confluence and confirm the absence of bacterial and fungal contamination.

[0233] 3) Remove the culture medium and wash the cells with 5 ml of PBS and aspirate. Add 2 ml of 0.25% trypsin / EDTA to a 100 mm dish. Place the dish in the incubator for several minutes, or until the cells detach. Add 5 ml of fresh cell culture medium, rinse the cells, and transfer them to a 15 ml centrifuge tube.

[0234] 4) The collected cells were centrifuged at 1000 rpm for 5 minutes.

[0235] 5) After centrifugation, discard the supernatant and resuspend the cell pellet in 5 mL of cell culture medium.

[0236] 6) Take 20 μL of resuspended cells and count them. Use a cell counter star to add 20 μL of cell suspension to 20 μL of dye to count the cells.

[0237] 7) Adjust the volume of the suspension using cell culture medium to achieve the desired cell concentration.

[0238] 8) According to the plate map, transfer 45 μL of cell suspension (see the table below for cell numbers) to each well of a 384-well microplate. As a positive control, add 45 μL of culture medium.

[0239] 9) Incubate the plate overnight at 37°C / 5% CO2.

[0240] Day 1:

[0241] 1) Dilute the compound. The stock concentration of the compound is 10 mM, and the starting concentration of the compound is 10 μM. Use a multichannel pipette to dilute the compound 3-fold (5 μL to 10 μL) to 10 concentration points.

[0242] 2) Dilute the compound to a final concentration of 10x the compound using growth medium. Add 2 ml of the compound at 1000x the final concentration to 198 ml of culture medium. DMSO% is used to achieve a concentration of 1%.

[0243] 3) Add 5uL of 10x compound prepared in culture medium to a 384-cell plate (1X).

[0244] 4) Centrifuge at 1000 rpm for 1 minute and place the cell plate in a cell culture incubator at 37°C and 5% CO2.

[0245] Day 8: Readings

[0246] 1) Add 25 μL / well of CTG reagent to the cell assay plate. Incubate on a shaker at 300 rpm for 10 minutes at room temperature, away from light.

[0247] 2) Read the luminescence signal on a plate reader (Envision) and calculate the half inhibitory concentration (IC 50 The results are shown in Table 3.

[0248] Experimental results

[0249] Table 3

[0250] Experimental Conclusions: The compounds of this invention exhibited strong activity in T47D cells and demonstrated good selectivity relative to the wild-type SK-BR-3 cell line. This indicates that the present invention, through structural optimization, significantly improved the activity and selectivity of these compounds, thereby reducing the clinical side effects associated with wild-type PI3Kα inhibition.

[0251] Test Example 3 Pharmacokinetic Study of the Test Compound in BALB / c Female Nude Mice

[0252] Experimental methods

[0253] On the day of administration, the test substance was prepared using a solvent formulation of 20% PEG400+10% VE-TPGS+70% HP-β-CD aqueous solution (10% HP-β-CD), and the administration solution was prepared and ready for use.

[0254] Animals: BALB / c female nude mice, 6-8 weeks old, weighing approximately 15-23 g. Ten mice (six plus extra mice) were provided by Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd.

[0255] The oral gavage PO dose was 100 mg / kg at a concentration of 10 mg / mL. Animals were fasted overnight with free access to water and returned to food 4 hours after administration.

[0256] Weigh the animals before dosing, calculate the dose based on body weight, and administer the drug once orally via gavage on the day of dosing. Venous blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after dosing. Approximately 0.03 mL of blood was collected per time point. Blood samples were anticoagulated with K2-EDTA in the tubes. Plasma was obtained by centrifugation within 1 hour of collection (centrifugation conditions: 6800 g, 6 minutes, 2-8°C). Samples were stored at -80°C until analysis.

[0257] Sample preparation for LC-MS / MS: 12 μL of plasma sample was protein precipitated with 240 μL of methanol containing 10 ng / mL internal standard (verapamil). The mixture was vortexed for 1 minute and then centrifuged at 4000 rpm for 10 minutes. 200 μL of the supernatant was transferred to a 96-well plate. 1 μL of the supernatant was subjected to LC-MS / MS analysis.

[0258] The concentration of the test substance in the plasma of BALB / c female nude mice was determined using a validated LC-MS / MS method.

[0259] Experimental results

[0260] The results are shown in Table 4 below.

[0261] Table 4

[0262] Experimental Conclusion

[0263] The compound of the present invention is effective in the C-terminal activity of BALB / c female nude mice. max , AUC is significantly better than that of STX-478. It can be seen that the present invention significantly improves the in vivo pharmacokinetic properties of this type of compound through structural optimization and enhances the drugability of the compound.

[0264] Test Example 4: Efficacy of the Test Compound in the xxT47D Subcutaneous Tumor Model Established in BALB / c Female Nude Mice

[0265] Cell Culture: Human breast cancer xxT47D cells (ER+ / HER2-) were cultured in vitro in an appropriate medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin, and 1.5 μg / mL blasticidin. Culture was performed in a 5% CO2 incubator at 37°C. When cell saturation reached 80%-90%, cells in the logarithmic growth phase were harvested, counted, and plated.

[0266] Animals: BALB / c female nude mice, 6-8 weeks old, weighing approximately 18-22 g. A total of 30 mice (18 plus surplus mice) were provided by Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0267] Animal husbandry: The experiment can only begin after the animals have been kept in the experimental environment for 3-7 days after arrival. The animals are kept in IVC (independent ventilation system) cages (6 per cage) in an SPF animal room. All cages, bedding and drinking water must be sterilized before use. All experimental personnel should wear protective clothing and latex gloves when operating in the animal room. The animal information card for each cage should indicate the number of animals in the cage, gender, strain, receipt date, dosing regimen, experimental number, group and start date of the experiment. Cages, feed and drinking water are changed twice a week. The breeding environment and lighting conditions are as follows:

[0268] √ Temperature: 20-26℃

[0269] Humidity: 40-70%

[0270] Feed ingredients: Feed meets the standards for laboratory animal food. Maximum contaminant levels are within controllable limits and are routinely inspected by the manufacturer. High-pressure sterilized drinking water is used.

[0271] Tumor inoculation: 2-3 days before inoculation, all mice were implanted with estrogen tablets (0.36mg / 60-day release 17β-Estradiol) subcutaneously. On the day of inoculation, 0.2mL (10×10 6xxT47D cells (+Matrigel) were subcutaneously inoculated on the right back of the mouse. When the average tumor volume reached 150-200mm 3 Dosing was initiated at approximately 4 hr. Animals were weighed and tumor volume was measured before dosing. Groups were randomly assigned based on tumor volume (randomized block design). The experimental groups and dosing schedule are shown in Table 5.

[0272] Table 5 Grouping and dosing regimen of in vivo efficacy animal experiment in xxT47D (ER+ / HER2-) subcutaneous tumor model

[0273] Note: 1. N: number of mice per group; 2. Blank control and compound solvent is 20% PEG400 + 10% VE-TPGS + 70% HP-β-CD aqueous solution (10% HP-β-CD)

[0274] Observation: The use and welfare of experimental animals will be conducted in accordance with the rules of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Animal health and mortality will be monitored daily. Routine examinations will include observation of tumor growth and the effects of drug treatment on the animals' daily behaviors, such as activity, food and water intake, weight change (twice weekly), physical signs, or other abnormalities. Group deaths and adverse reactions will be recorded based on the number of animals in each group.

[0275] Experimental indicators: The experimental indicators are used to examine whether tumor growth is inhibited, delayed, or cured. Tumor diameter is measured twice a week with a vernier caliper. The formula for calculating tumor volume is: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.

[0276] The tumor inhibition efficacy of a compound was evaluated using TGI (%) or relative tumor growth rate (T / C) (%). TGI (%) reflects the rate of tumor growth inhibition. TGI (%) is calculated as follows: TGI (%) = [1 - (average tumor volume of a treatment group at the end of dosing - average tumor volume of the treatment group at the start of dosing) / (average tumor volume of the vehicle control group at the end of treatment - average tumor volume of the vehicle control group at the start of treatment)] x 100%.

[0277] Tumor tissue was collected from each group 4 hours after administration for PK analysis, and plasma was collected at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h for PK analysis. The average drug concentration ratio in plasma and tumor tissue at the 4h time point was calculated.

[0278] The relative tumor proliferation rate T / C (%) is calculated as follows: T / C% = T RTV / C RTV ×100%(T RTV :RTV in treatment group; CRTV : RTV of negative control group). Relative tumor volume (RTV) was calculated based on the results of tumor measurement. The calculation formula is RTV=V t / V0, where V0 is the tumor volume measured at the time of group administration (i.e., d0), V t is the tumor volume at a certain measurement, T RTV with C RTV Get data for the same day.

[0279] After the experiment, the tumor weight was measured and T weight / C weight Percentage, T weight and C weight Represent the tumor weights of the drug-treated group and the vehicle control group, respectively.

[0280] Termination of the experiment: If the animal's health condition continues to deteriorate or the tumor volume exceeds 2,000 mm 3 If the animal is seriously ill or in pain, it must be euthanized. If the animal has any of the following conditions, notify the veterinarian and euthanize it:

[0281] √ Obvious weight loss, weight loss greater than 20%;

[0282] √ Not able to freely access food and water;

[0283] √The average tumor volume of the control group reached 2,000 mm 3 ;

[0284] √ The animal develops the following clinical manifestations and continues to deteriorate:

[0285] ○ Piloerection

[0286] ○Hunched back

[0287] ○ White ears, nose, eyes, or feet

[0288] Shortness of breath

[0289] ○ Twitching

[0290] ○Continuous diarrhea

[0291] Dehydration

[0292] ○ Slow movement

[0293] ○Voice

[0294] Data Analysis: T-tests were used for comparisons between two groups. One-way ANOVA was used for comparisons between three or more groups. Possible differences between different treatment groups were analyzed using two-way ANOVA. All data were analyzed using Graphpad Prism. A p value < 0.05 was considered significant.

[0295] Experimental results

[0296] 1) The PK and TGI results are shown in Table 6; the tumor growth curve results are shown in Figure 1.

[0297] Table 6

[0298] Based on the above results, it can be seen that the new structural compounds obtained by structural optimization of the present invention have a good effect of inhibiting tumor growth in the xxT47D subcutaneous tumor model established on BALB / c nude mice. Compared with STX-478 (100mpk), 001-1 has a significantly better tumor inhibitory effect (TGI) than STX-478 (1.03VS 0.85) at a lower dose (50mpk) and a lower systemic exposure (33149h*ng / mL Vs46003h*ng / mL). In summary, the compound 001-1 of the present invention has better in vivo efficacy than STX-478.

[0299] 2) The results of tumor-to-blood ratio are shown in Table 7.

[0300] Table 7

[0301] The tumor-to-blood ratio of the representative compound of the present invention is significantly better than that of STX-478 (2.66 vs 1.09). This shows that the present invention has significantly improved the tumor-to-blood ratio of this type of compound through structural optimization, resulting in a higher exposure in tumor tissue.

[0302] Other Notes

[0303] Unless otherwise specified, the structures of the control compounds used in the tests of the present invention are as follows, and the synthesis steps thereof are described in WO2022265993A1.

[0304] The above is an exemplary description of the implementation methods of the technical solutions disclosed herein. It should be understood that the scope of protection of the present disclosure is not limited to the above-mentioned implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present disclosure shall be included in the scope of protection of the claims of this application.

Claims

1. A compound of formula I and its racemate, stereoisomer, tautomer, 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, deuterium, unsubstituted or optionally substituted by one, two or more R 11 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkyloxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, C 3-12 Cycloalkyl; each R 11 the same or different, independently selected from H, deuterium, halogen, CN, OH, C 1-12 alkyl; Each R3 is the same or different and is independently selected from H, deuterium, halogen, CN, OH, unsubstituted or optionally substituted by one, two or more R 31 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkyloxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, N(R 32 )(R 33 ); each R 31 the same or different, independently selected from H, deuterium, halogen, CN, C 1-12 Alkyl, C 1-12 Alkyloxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, C 1-12 Acyl; R 32 、R 33 the same or different, independently selected from H, deuterium, C 1-12 Alkyl, S(=O)2R 311 、S(=O)(=NH)R 312 ; R 311 、R 312 the same or different, independently selected from H, deuterium, C 1-12 alkyl; X1 is selected from N, NR x1 or CR x2 ; R x1 、R x2 the same or different, independently selected from H, deuterium, halogen, CN, C 1-12 alkyl; X2 is selected from O or N; Ring A is selected from C 3-12 Carbocyclic ring, 3-14 membered heterocyclic ring, C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring; Each R a the same or different, independently selected from H, deuterium, halogen, CN, OH, C 1-12 Alkyl, C 1-12 Alkyloxy, C 3-12 Cycloalkyl, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, OH-C 1-12 alkyl; Y1 is absent or selected from ether bond (-O-), carbonyl Unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 1-12 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-14 Cycloalkylene, 3-14 membered heterocycloalkylene, C 6-14 Arylene, 5-14 membered heteroarylene, imino (-NH-); each R b the same or different, independently selected from deuterium, OH, CN, halogen, NH2, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl, halogenated C 3-12 Cycloalkyl, -S(O)2-C 1-12 Alkyl, -C 1-12 Alkyl-CN; L1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: C 1-12 Alkylene, C 1-12 Alkylene-C 3-14 Cycloalkylene, C 1-12 Alkylene-3-14 membered heterocycloalkylene; each R c the same or different, independently selected from deuterium, OH, CN, halogen, NH2, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl, halogenated C 3-12 Cycloalkyl, -S(O)2-C 1-12 Alkyl, -C 1-12 Alkyl-CN; R4 is selected from CN, unsubstituted or optionally substituted by one, two or more R d Substituted with the following groups: C 3-12 Carbocyclic ring, 3-14 membered heterocyclic ring, C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring; each R d the same or different, independently selected from deuterium, OH, CN, halogen, NH2, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl, halogenated C 3-12 Cycloalkyl, -S(O)2-C 1-12 Alkyl, -C 1-12 Alkyl-CN; m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt, wherein: R1 and R2 are the same or different and are independently selected from H, unsubstituted or optionally substituted by one, two or more R 11 Substituted with the following groups: C 1-6 Alkyl (such as methyl, ethyl, isopropyl, tert-butyl), halogenated C 1-6 Alkyl (such as trifluoromethyl, difluoromethyl), C 3-6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); Preferably, each R 11 The same or different, independently selected from halogen (such as F, Cl, Br), C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl); Preferably, R1 and R2 are the same or different and are independently selected from H or trifluoromethyl; Preferably, R1 is H, R2 is trifluoromethyl; Preferably, each R3 is the same or different and is independently selected from halogen, CN, unsubstituted or optionally substituted by one, two or more R 31 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkyloxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, N(R 32 )(R 33 ); Preferably, each R 31 The same or different, independently selected from H, CN, C 1-6 Alkyl, C 1-6 acyl group; Preferably, each R 31 The same or different, independently selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl); Preferably, R 32 、R 33 The same or different, independently selected from H, C 1-6 Alkyl (such as methyl, ethyl, isopropyl, tert-butyl), -S(=O)2-C 1-6 Alkyl, -S(=O)(=NH)C 1-6 alkyl; Preferably, each R3 is the same or different and is independently selected from F or methyl; Preferably, m is selected from 0, 1, 2 or 3; Preferably, m is 2 and R3 is F; Preferably, X1 is selected from N, NR x1 or CR x2 ; R x1 、R x2 The same or different, independently selected from H, halogen (such as F, Cl, Br), CN, C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl); Preferably, X1 is selected from CR x2 ; R x2 Selected from H or methyl; Preferably, X1 is selected from CCH3; Preferably, X2 is selected from O.

3. The compound according to claim 1 or 2, and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from C 3-8 Carbocyclic ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring; Preferably, ring A is selected from a benzene ring or a 5-6 membered heteroaromatic ring; Preferably, ring A is selected from a benzene ring, a pyrazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyridinone ring (such as a pyridin-2(1H)-one ring), a pyrimidinone ring (such as a pyrimidin-2(1H)-one ring), a pyridazinone ring (such as a pyridazin-3(2H)-one ring); Preferably, Selected from Among them, the "*" side is connected to the urea group, and the "#" side is connected to Y1; Preferably, each R a The same or different, independently selected from deuterium, halogen (such as F, Cl, Br), CN, OH, C 1-6 Alkyl (such as methyl, ethyl, isopropyl, tert-butyl), C 1-6 Alkyloxy (such as methoxy), C 3-6 Cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogenated C 1-6 Alkyl (such as trifluoromethyl, difluoromethyl), halogenated C 1-6 Alkyloxy, OH-C 1-6 alkyl; Preferably, each R a The same or different, independently selected from F, Cl, methoxy; Preferably, each R a are the same or different and are independently selected from methoxy; Preferably, n is selected from 0 or 1; Preferably, Selected from 4. The compound according to any one of claims 1 to 3, and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: Y1 is absent or selected from ether bond (-O-), carbonyl Unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 1-6 Alkylene (such as methylene, ethylene, n-propylene), C 3-6 Cycloalkylene (such as ), 3-6 membered heterocycloalkylene (such as ), imino (-NH-); Preferably, R b Selected from OH, CN, halogen (such as F, Cl, Br), C 1-6 Alkyl (such as methyl, ethyl, isopropyl, tert-butyl), C 1-6 Alkoxy (such as methoxy), -S(O)2-C 1-6 Alkyl (e.g. -S(O)2-CH3); Preferably, R b is selected from F, Cl, Br, CN, OH, methoxy or methylsulfonyl; Preferably, L1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: C 1-4 Alkylene, C 1-4 Alkylene-C 3-6 Cycloalkylene, C 1-4 Alkylene-3-6 membered heterocycloalkylene; Preferably, L1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted groups: methylene, Preferably, L1 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted groups: methylene, Preferably, L1 is selected from unsubstituted or optionally substituted with one, two or more R c substituted methylene; Preferably, R c Selected from halogen, CN, C 1-6 Alkyl (such as methyl, ethyl, isopropyl, tert-butyl), C 3-6 Cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogenated C 1-6 Alkyl (e.g., trifluoromethyl, difluoromethyl); Preferably, R c is selected from F, Cl, Br, CN, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Preferably, R4 is selected from CN, unsubstituted or optionally substituted with one, two or more R d Substituted with the following groups: C 3-6 Carbocyclic or 3-8 membered heterocyclic ring; each R d the same or different, independently selected from deuterium, OH, CN, halogen, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl; Preferably, R4 is selected from CN, cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, oxetanyl ring (such as ), tetrahydrofuranyl ring (such as ), tetrahydropyranyl ring (such as )。 Preferably, R4 is CN.

5. The compound according to any one of claims 1 to 4, and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: Selected from Preferably, Selected from Preferably, Selected from 6. The compound according to any one of claims 1 to 5, and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound has the structure shown below: Among them, R1, R2, R3, X1, X2, Y1, L1, Ring A, R a , m, n have the definitions described herein; X3 is selected from CH2, NH, or O; Each R e the same or different, independently selected from deuterium, halogen, CN, OH, C 1-4 Alkyl (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl), C 1-4 Alkoxy (such as methoxy, ethoxy), C 3-6 Cycloalkyl (such as cyclopropyl), halogenated C 1-6 Alkyl (such as difluoromethyl, trifluoromethyl), halogenated C 1-6 Alkyloxy (difluoromethoxy, trifluoromethoxy), hydroxyl C 1-6 Alkyl (such as hydroxymethyl, hydroxyethyl); m1 is selected from 0, 1, 2 or 3; m2 is selected from 0, 1, 2 or 3; m1 and m2 are not 0 at the same time; m3 is selected from 0, 1, 2 or 3. Preferably, the compound represented by formula I may have the structure shown below: Among them, Y1, L1, ring A, R a , n has the meaning given in this document; X3 is selected from CH2, NH, or O; Each R e the same or different, independently selected from deuterium, halogen, CN, OH, C 1-4 Alkyl (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl), C 1-4 Alkoxy (such as methoxy, ethoxy), C 3-6 Cycloalkyl (such as cyclopropyl), halogenated C 1-6 Alkyl (such as difluoromethyl, trifluoromethyl), halogenated C 1-6 Alkyloxy (difluoromethoxy, trifluoromethoxy), hydroxyl C 1-6 Alkyl (such as hydroxymethyl, hydroxyethyl); m1 is selected from 0, 1, 2 or 3; m2 is selected from 0, 1, 2 or 3; m1 and m2 are not 0 at the same time; m3 is selected from 0, 1, 2 or 3. Preferably, the compound represented by formula I may have the structure shown below: Wherein, Y1 and L1 have the definitions described herein.

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

8. A method for preparing the compound according to any one of claims 1 to 7, comprising the following steps: Among them, R1, R2, R3, X1, X2, Y1, L1, Ring A, R a , m, n have the definitions described herein; Z is selected from a leaving group, such as a halogen (such as Cl), R is selected from C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-3 Alkyl-C 6-10 Aryl groups, such as phenyl, tolyl, and benzyl.

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

10. Use of the compound according to any one of claims 1 to 7 and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 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, head and neck cancer, colorectal cancer, skin cancer and / or benign overgrowth syndrome; preferably, the breast cancer is selected from ER+ / HER2- breast cancer; And / or, use in the preparation of a medicament for preventing and / or treating PIK3CA-related overgrowth (PROS).

11. A method for preventing and / or treating a disease or condition mediated by PI3Kα, 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, N-oxide, solvate, polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 9; Preferably, the PI3Kα-mediated disease or condition is selected from cancer, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, head and neck cancer, colorectal cancer, skin cancer and / or benign overgrowth syndrome; Preferably, the breast cancer is selected from ER+ / HER2- breast cancer; Preferably, the PI3Kα-mediated disease or condition is PIK3CA-associated overgrowth (PROS).

12. A pharmaceutical combination comprising a compound of formula I according to any one of claims 1 to 7, and its racemates, stereoisomers, tautomers, N-oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts, and one or more additional therapeutic agents.

13. Use of a drug combination in the preparation of a drug for preventing and / or treating cancer, the drug combination comprising: (a) a compound of formula I according to any one of claims 1 to 7, and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 9; and (b) one or more additional therapeutic agents.

14. The pharmaceutical combination product according to claim 12 or the use according to claim 13, characterized in that The therapeutic agent is selected from one or more of CDK4 / 6 inhibitors, selective estrogen receptor (ER) degraders, AKT inhibitors, mTOR inhibitors, and HDAC inhibitors.

15. The use according to claim 13, characterized in that The cancer is selected from lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, head and neck cancer, colorectal cancer, skin cancer and / or benign overgrowth syndrome; preferably, the breast cancer is selected from ER+ / HER2- breast cancer.