PI3Kalpha inhibitor and application thereof

Abstract

The present invention relates to selective PI3K [alpha] allosteric inhibitors. Specifically, the compound disclosed by the invention has a structure as shown in a formula (I), the definitions of all groups and substituent groups are described in the specification, and the compound has excellent selective activity on mutant PI3Kalpha. The invention also discloses a preparation method of the compound and an application of the compound in an anti-tumor aspect. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a class of compounds used as PI3Kα inhibitors, and stereoisomers, deuterated substances, pharmaceutically acceptable salts, solvates or prodrugs thereof, to pharmaceutical compositions comprising such compounds and salts, and to uses thereof, and to applications thereof in regulating PI3Kα activity or treating PI3Kα-related diseases. Background Art

[0002] Phosphatidylinositol 3-kinases (PI3Ks) are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositol or phospholipid inositol. They play a key role in many fundamental biological processes, including proliferation, survival, differentiation, and metabolism. PI3Ks are currently divided into class IA, class IB, class II, and class III. Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are usually activated by tyrosine kinases or G protein-coupled receptors to produce PIP3, which binds to downstream effectors such as Akt / PDK1, mTOR, Tec family kinases, and effectors in the Rho family GTPases pathway. Class II and class III PI3Ks play a key role in intracellular transport by synthesizing PI(3)P and PI(3,4)P2. Among them, the class IA family consists of three subtypes: α, β, and δ. The class IB family includes only the γ subtype. Among the different PI3K subfamily proteins, PI3Kα is a heterodimer containing a p110α catalytic subunit and a p85α regulatory subunit. The gene encoding the p110α subunit, PIK3CA, is mutated at a rate of nearly 30% in human cancers, including colorectal cancer, glioblastoma, and gastric cancer. Importantly, overactivation of PI3Kα is directly associated with resistance to current therapeutic drugs and poor prognosis.

[0003] Mutations in the gene encoding PI3Kα occur primarily as point mutations in several hot spots in the helical and kinase domains, such as E542K, E545K, and H1047R. These mutations have been shown to be oncogenic gain-of-function mutations. Due to the high incidence of PI3Kα mutations, targeting this pathway may provide valuable therapeutic opportunities. Other PI3K isoforms such as PI3Kδ or PI3Kγ are primarily expressed in hematopoietic cells, whereas PI3Kα and PI3Kβ are constitutively expressed.

[0004] Due to the central role of PI3Kα in regulating glucose homeostasis, PI3K inhibition often results in hyperglycemia and / or hyperinsulinemia in patients. High levels of circulating insulin may promote cancer cell mitosis and / or anti-apoptosis, thereby attenuating the anti-proliferative effects of PI3K inhibitors.

[0005] In the setting of PI3Kα mutant cancers, one approach to overcome the problem of insulin and / or glucose replacement after systemic inhibition of PI3Kα is to develop inhibitors that are more selective for mutant PI3Kα than wild-type PI3Kα. This would create a larger window for drug doses to selectively inhibit the pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα in host tissues that controls systemic metabolism, thereby limiting toxicity and allowing higher doses and more complete inhibition of the drug target.

[0006] Currently, PI3Kα inhibitors are almost equivalent in wild-type and mutant forms. Since the PI3Kα mutation site is far away from the active site, selective inhibitors of the mutation have been difficult to develop. Therefore, inhibitors targeting allosteric binding pockets near known mutations (such as H1047R, E542K, E545K) may provide a new way to selectively inhibit PI3Kα. Therefore, targeting the allosteric binding pockets of PI3Kα mutations may in turn provide valuable therapeutic targets for drug development. Summary of the invention

[0007] The object of the present invention is to provide a compound represented by formula (I), a preparation method thereof and use thereof in selective PI3Kα inhibitor drugs.

[0008] The first aspect of the present invention provides a compound, characterized in that the compound is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof,

[0009]

[0010] in:

[0011] X1 is N, O;

[0012] X2 and X3 are each independently selected from the following group: N, C;

[0013] X4 is N or CR;

[0014] Ring B is: a 5-7 membered heterocycloalkyl group containing 1 N atom and 0-3 heteroatoms selected from N, O or S, which is optionally substituted by one or more R5;

[0015] Ring A is selected from the following group: C 6-10 Aryl, 5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; wherein the C 6-10 Aryl, 5-8 membered heteroaryl is optionally substituted by m R6;

[0016] R1 is selected from the group consisting of H, deuterium, halogen, -CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy;

[0017] R, R2, R3 are each independently selected from the following group: H, halogen, -CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl;

[0018] R4 is selected from the following group: -L-(C 1-6 Alkyl), -LC 6-10 Aryl, -L-(5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), -L-(saturated or partially saturated C 3-8 -(saturated or partially saturated 4-8 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S); wherein the C 1-6 Alkyl, C 6-10 Aryl, 5-8 membered heteroaryl, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted by n R7;

[0019] Each R5 is independently selected from the group consisting of H, deuterium, halogen, -CN, oxo (=O), C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;

[0020] Each R6 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -SO2R8, -S(O)(NR8)R9, -SO2NR8R9, -P(O)R8R9;

[0021] Each R7 is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo (=O), -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、-L1-(C 1-6 Alkyl), -L1-(saturated or partially saturated C 3-10 Cycloalkyl), -L1-(C 6-10 aryl), -L1-(saturated or partially saturated 3-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S), -L1-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), wherein the C 1- 6 alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, -SO2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8R9,

[0022] Alternatively, the two R7 atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, C 6-10 aryl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, or 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、C 1-6 Alkyl, C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S;

[0023] L and L1 are each independently a bond or are selected from the following group: C 1-6 Alkylene, 1-6 membered heteroalkylene containing 1-4 heteroatoms selected from N, O or S, -NR8-, -O-, -C(O)-, -C(O)NR8-, -C(O)O-, -NR8C(O)-, -(SO2)-, -SO2NR8-, -NR8SO2-, -NR8SO2NR9-, -S(O)(NR8)-;

[0024] Each R8, R9, R 10 Each independently selected from the following group: H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 aryl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with 0-6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl;

[0025] Alternatively, R8, R9 and the heteroatom to which they are connected together form a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S; or, R9, R 10 Together with the heteroatoms to which it is attached, it forms a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S;

[0026] is a single bond or a double bond;

[0027] Each m and n is independently selected from: 0, 1, 2, 3, 4, 5.

[0028] In another preferred embodiment, X4 is CR.

[0029] In another preferred embodiment, R is selected from the following group: H, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 3-5 Cycloalkyl, halogenated C 3-5 Cycloalkyl.

[0030] In another preferred embodiment, R is selected from the following group: H, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 alkyl.

[0031] In another preferred embodiment, R is H.

[0032] In another preferred embodiment, X4 is CH.

[0033] In another preferred embodiment, the compound has a structure selected from the following group:

[0034]

[0035] in:

[0036] X1 is N, O;

[0037] X2 and X3 are each independently selected from the following group: N, C;

[0038] Y1, Y2, Y3, and Y4 are each independently selected from the following group: O, C(R5)2, CHR5, C(=O), S(=O), S(=O)2, and NR5;

[0039] Ring A is selected from the following group: phenyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; wherein the phenyl, 5-6 membered heteroaryl is optionally substituted by m R6;

[0040] R1 is selected from the group consisting of H, deuterium, halogen, -CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy;

[0041] R2 and R3 are each independently selected from the following group: H, halogen, -CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 3-5 Cycloalkyl, halogenated C 3-5 Cycloalkyl;

[0042] R4 is selected from the following group: -L-(C 1-6 alkyl), -L-phenyl, -L-(5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), -L-(saturated or partially saturated C 3-6 -(saturated or partially saturated 4-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S); wherein the C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted by n R7;

[0043] Each R5 is independently selected from the group consisting of H, deuterium, halogen, -CN, oxo (=O), halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 3-5 Cycloalkyl, halogenated C 3-5 Cycloalkyl, 3-5 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;

[0044] Each R6 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-3 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -SO2R8, -S(O)(NR8)R9, -SO2NR8R9, -P(O)R8R9;

[0045] Each R7 is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo (=O), -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、-L1-(C 1-6 Alkyl), -L1-(saturated or partially saturated C 3-10 Cycloalkyl), -L1-(C 6-10 aryl), -L1-(saturated or partially saturated 3-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S), -L1-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, -SO2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8R9,

[0046] Alternatively, the two R7 atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, C 6-10 aryl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, or 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、C 1-6 Alkyl, C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S;

[0047] L and L1 are each independently a bond or are selected from the following group: C 1-6 Alkylene, 1-6 membered heteroalkylene containing 1-4 heteroatoms selected from N, O or S, -NR8-, -O-, -C(O)-, -C(O)NR8, -C(O)O-, -NR8C(O)-, -(SO2)-, -SO2NR8-, -NR8SO2-, -NR8SO2NR9-;

[0048] Each R8, R9, R 10 Each independently selected from the following group: H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 aryl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with 0-6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl;

[0049] Alternatively, R8, R9 and the heteroatom to which they are connected together form a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S; or, R9, R 10 Together with the heteroatoms to which it is attached, it forms a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S;

[0050] is a single bond or a double bond;

[0051] Each m and n is independently selected from: 0, 1, 2, 3, 4, 5.

[0052] In another preferred embodiment, X2 and X3 are both C, or one of X2 and X3 is N and the other is C.

[0053] In another preferred embodiment, Y1, Y2, Y3, and Y4 are each independently selected from the following group: O, C(R5)2, CHR5, and C(=O).

[0054] In another preferred embodiment, Y1, Y2, Y3, and Y4 are each independently selected from the following group: O, CH2, CHR5, and C(=O).

[0055] In another preferred embodiment, one of Y1, Y2, Y3, and Y4 is O, CHR5, or C(═O), and the others are CH2.

[0056] In another preferred embodiment, each R5 is independently selected from the following group: H, deuterium, halogen, -CN, oxo (=O), C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 3-5 Cycloalkyl, halogenated C 3-5 Cycloalkyl, 3-5 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S.

[0057] In another preferred embodiment, each R5 is independently selected from the following group: H, deuterium, halogen, oxo (=O), C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy.

[0058] In another preferred embodiment, each R5 is independently selected from the following group: H, deuterium, halogen, oxo (=O), C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3alkyl.

[0059] In another preferred embodiment, the compound has a structure selected from the following group:

[0060]

[0061] Wherein, R1, R2, R3, R4, Y1, Y2, Y3, Y4, and Ring A are as defined herein; Structure Contains the following configurations: In another preferred embodiment, the compound has a structure selected from the following group:

[0062]

[0063]

[0064] wherein R1, R2, R3, R4, R5, and Ring A are as defined herein, and p is 0, 1, 2, 3, or 4;

[0065] structure Contains the following configurations:

[0066] In another preferred embodiment, ring A is selected from the following group: C 6-10 Aryl, 5-6 membered heteroaryl containing 1 N atom and 0-3 heteroatoms selected from N, O or S, wherein the phenyl, 5-6 membered heteroaryl is optionally substituted by m R6.

[0067] In another preferred embodiment, ring A is selected from the following group: phenyl, 5-6 membered heteroaryl containing 1-4 N heteroatoms, wherein the phenyl, 5-6 membered heteroaryl is optionally substituted by m R6.

[0068] In another preferred embodiment, ring A is selected from the following group: phenyl, pyridyl, thienyl, furyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, wherein the group is optionally substituted by m R6.

[0069] In another preferred embodiment, ring A is selected from the following group: phenyl, pyridyl, wherein the phenyl, pyridyl is optionally substituted by m R6.

[0070] In another preferred embodiment, each R6 is independently selected from the group consisting of H, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R8, -C(O)OR8, -C(O)NR8R9.

[0071] In another preferred embodiment, each R6 is independently selected from the following group: H, deuterium, halogen, -C(O)R8, -C(O)OR8, -C(O)NR8R9.

[0072] In another preferred embodiment, each R6 is independently selected from the following group: H, deuterium, halogen, -C(O)OR8.

[0073] In another preferred embodiment, each R6 is independently selected from the following group: H, deuterium, halogen, -C(O)OH.

[0074] In another preferred embodiment, R1 is selected from the group consisting of H, deuterium, halogen, -CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy.

[0075] In another preferred embodiment, R1 is selected from the group consisting of H, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy.

[0076] In another preferred embodiment, R1 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl.

[0077] In another preferred embodiment, R1 is C 1-3 Alkyl, for example methyl, ethyl, n-propyl or isopropyl.

[0078] In another preferred embodiment, R1 is R configuration or S configuration.

[0079] In another preferred embodiment, R1 is a methyl group in R configuration.

[0080] In another preferred embodiment, R, R2, and R3 are independently selected from the following groups: H, halogen, -CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 3-5 Cycloalkyl, halogenated C 3-5 Cycloalkyl.

[0081] In another preferred embodiment, R2 and R3 are each independently selected from the following group: H, halogen, C 1-6 Alkyl, halogenated C1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C3 cycloalkyl, halogenated C3 cycloalkyl.

[0082] In another preferred embodiment, R2 is selected from the following group: H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C3 cycloalkyl, halogenated C3 cycloalkyl, R3 is H.

[0083] In another preferred embodiment, R2 is selected from the following group: H, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, R3 is H.

[0084] In another preferred embodiment, R2 is selected from the following group: H, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, R3 is H.

[0085] In another preferred embodiment, ring A has a structure selected from the following group:

[0086]

[0087] wherein each R6 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated

[0088] C 1-6 Alkyl, deuterated C 1-3 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R6, -C(O)OR6, -

[0089] C(O)NR6R7, -SO2R6, -S(O)(NR6)R7, -SO2NR6R7, -P(O)R6R7;

[0090] m is selected from: 0, 1, 2, 3, 4, 5.

[0091] In another preferred embodiment, ring A has a structure selected from the following group:

[0092]

[0093] In another preferred embodiment, ring A has a structure selected from the following group:

[0094]

[0095] In another preferred embodiment, R4 has a structure selected from the following group:

[0096]

[0097]

[0098] Wherein, L and L1 are each independently a bond or are selected from the following group: C 1-6 Alkylene, -C(O)-, -C(O)NH-, -C(O)O-, -(SO2)-, -SO2NH-;

[0099] Each R7 is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo (=O), -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、-L1-(C 1-6 Alkyl), -L1-(saturated or partially saturated C 3-10 Cycloalkyl), -L1-(C 6-10 aryl), -L1-(saturated or partially saturated 3-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S), -L1-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, -SO2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8R9,

[0100] Alternatively, the two R7 atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, C 6-10 aryl, a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S, or a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、C 1-6 Alkyl, C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S;

[0101] n is selected from: 0, 1, 2, 3, 4, 5.

[0102] In another preferred embodiment, each R7 is independently selected from the following group: hydrogen, deuterium, halogen, oxo (=O), -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -L1-(C 1-6 Alkyl), -L1-(saturated or partially saturated C3-10 Cycloalkyl), -L1-(C 6-10 aryl), -L1-(saturated or partially saturated 3-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S), -L1-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl.

[0103] In another preferred embodiment, each R7 is independently selected from the following group: hydrogen, deuterium, halogen, oxo (=O), -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, -L1-(C 1-6 alkyl), wherein the C 1-6 The alkyl group is optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl.

[0104] In another preferred embodiment, each R7 is independently selected from the following group: hydrogen, deuterium, halogen, oxo (=O), -CN, -OH, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -L1-(C 1-6 alkyl), wherein the C 1-6 The alkyl group is optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy.

[0105] In another preferred embodiment, each of R8, R9, R 10 Each independently selected from the following group: H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted by 0-6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy.

[0106] In another preferred embodiment, each of R8, R9, R 10 Each independently selected from the following group: H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-4 Cycloalkyl, 3-4 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted by 0-6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy.

[0107] In another preferred embodiment, each of R8, R9, R 10 Each independently selected from the following group: H, C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0108] In another preferred embodiment, the compound has a structure selected from the following group:

[0109]

[0110] wherein R1, R2, R3, R4, Y1, Y2, and Y3 are as defined herein;

[0111] X5 is CR6 or N;

[0112] Each R6 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-3 Alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, -C(O)R6, -C(O)OR6, -C(O)NR6R7, -SO2R6, -S(O)(NR6)R7, -SO2NR6R7, -P(O)R6R7;

[0113] m is selected from: 0, 1, 2, 3, 4.

[0114] In another preferred embodiment, X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , L, L1, Ring A, and Ring B are each independently the corresponding groups of compounds C1-C2 in the examples.

[0115] In another preferred embodiment, the compound is selected from the following group:

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125] The second aspect of the present invention provides a pharmaceutical composition comprising a safe and effective amount of one or more compounds described in the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

[0126] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, for a use selected from the group consisting of:

[0127] 1) Preparation of selective PI3Kα inhibitors;

[0128] 2) Preparation of drugs for regulating PI3Kα activity or treating PI3Kα-related diseases.

[0129] In another preferred embodiment, the PI3Kα has one or more mutations selected from the following group: H1047R, E542K, E545K.

[0130] In another preferred embodiment, the PI3Kα-related disease is cancer or tumor.

[0131] In another preferred embodiment, the cancer or tumor is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid, unknown primary cancer, cardiac (heart) tumor, atypical teratoma / rhabdoid tumor, primary central nervous system lymphoma, cervical cancer, bile duct cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia ( CML), colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, fungal disease, S-cell lymphoma, syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, sensory blastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid, malignant gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma, kidney cancer, laryngeal cancer, white Blood disease, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic carcinoma, metastatic squamous neck carcinoma, midline duct carcinoma with nut gene alteration, oral cancer, multiple endocrine neoplasms syndrome, multiple myeloma / plasma cell neoplasms, myelodysplastic syndrome, myelodysplastic tumors, myeloproliferative tumors, chronic myeloproliferative tumors, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma Tumors, sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell tumor, multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood vascular tumors, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, skin squamous cell carcinoma, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic cancer, thyroid cancer, tracheobronchial tumors, renal pelvis and ureteral transitional cell carcinoma, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, Wilms' tumor.

[0132] In another preferred embodiment, the cancer is endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophageal gastric cancer, neurothecoma, head and neck squamous cell carcinoma, melanoma, esophageal gastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenal cortical carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymoma, pheochromocytoma, other neuroepithelial tumors, thyroid cancer, leukemia or encapsulated glioma.

[0133] In another preferred embodiment, the cancer is breast cancer, prostate cancer or brain cancer.

[0134] The fourth aspect of the present invention provides a method for preventing and / or treating PI3Kα activity or treating PI3Kα-related diseases, the method comprising administering the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, deuterated form, solvate or prodrug thereof to a subject in need thereof.

[0135] In another preferred embodiment, the subject is a human or non-human mammal, such as rats, mice, rabbits, pigs, dogs, sheep, etc.

[0136] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0137] After long-term and in-depth research, the inventor unexpectedly prepared a class of compounds with excellent PI3Kα mutation selective inhibitory activity and a preparation method thereof. Specifically, through structural optimization, the inventor obtained a class of compounds with excellent PI3Kα mutation selective inhibitory activity. On this basis, the inventor completed the present invention.

[0138] the term

[0139] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0140] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0141] In the present invention, “C 1-6 "Alkyl" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like. Preferably, C 1-3Alkyl. Other similar terms have similar meanings.

[0142] In the present invention, the term "C 1-6 "Alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy. Preferably, C 1-3 Alkoxy. Other similar terms have similar meanings.

[0143] In the present invention, the term "deuterated C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms in a straight or branched chain, wherein the hydrogen atoms on the carbon atoms are optionally replaced by one, more or all of them by deuterium, such as -CD3, -CH2CD3, -CH(CH3)CD3, etc. The term "deuterated C 1-3 "Alkyl" has the same meaning.

[0144] In the present invention, the term "deuterated C 1-6 "Alkoxy" refers to an alkoxy group having a straight or branched chain of 1 to 6 carbon atoms in which one, more or all of the hydrogen atoms on the carbon atoms are optionally replaced by deuterium, such as -OCD3, -OCH2CD3, -OCH(CH3)CD3, etc. The term "deuterated C 1-3 "Alkoxy" has the same meaning.

[0145] In the present invention, the term "C 1-6 “Heteroalkyl” refers to a straight or branched alkyl group having 1 to 6 carbon atoms containing 1 to 4 heteroatoms selected from N, O or S, including but not limited to methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, -CH2OH, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, and the like.

[0146] In the present invention, the term "C 1-6 “Alkylene” refers to a straight or branched alkylene structure comprising 1 to 6 carbon atoms, including, but not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH(CH3)CH2 CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-. Other similar terms have similar meanings.

[0147] In the present invention, the term "saturated or partially saturated C 3-10 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including: 5-10Spirocycloalkyl, C 5-10 Bridged cycloalkyl, C 3-8 Monocyclic alkyl, C 4-12 Cycloalkyl, wherein some of the carbon atoms on the ring can form an unsaturated structure with the adjacent carbon atoms in the form of double bonds, includes but is not limited to:

[0148] The term "saturated or partially saturated C 3-6 "Cycloalkyl" has a similar meaning.

[0149] In the present invention, the term "saturated or partially saturated 3-12 membered heterocycloalkyl" refers to a cyclic alkyl group containing 1-4 heteroatoms selected from N, O or S, which may be a saturated ring or a partially unsaturated ring, including: a 5-12 membered spirocycloalkyl group containing 1-4 heteroatoms selected from N, O or S, a 5-12 membered bridged cycloalkyl group containing 1-4 heteroatoms selected from N, O or S, a 3-8 membered monocycloalkyl group containing 1-4 heteroatoms selected from N, O or S, a 4-12 membered cycloalkyl group containing 1-4 heteroatoms selected from N, O or S, including but not limited to:

[0150]

[0151] The terms "4-6 membered heterocycloalkyl" and "5-7 membered heterocycloalkyl" have the same meaning.

[0152] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning. 6-10 "Aryl" refers to an aromatic structure having 6-10 carbon atoms without heteroatoms, including: monocyclic aromatic groups, bicyclic C 8-10 Aryl; including but not limited to: etc. The aryl group may be optionally substituted or unsubstituted. The part connected to the parent is an aromatic ring.

[0153] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning, referring to a monocyclic or polycyclic heteroaromatic group containing 1 to 4 heteroatoms selected from N, O or S. For example, "5-10 membered heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O or S and 1 to 9 carbon atoms, which includes: 5-6 membered monocyclic heteroaryl, 8-10 membered polycyclic heteroaryl. Among them, "5-6 membered monocyclic heteroaryl" includes, but is not limited to: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.; "8-10 membered polycyclic heteroaryl" includes, but is not limited to:

[0154] The heteroaryl group may be optionally substituted or unsubstituted, wherein the portion attached to the parent group is an aromatic ring.

[0155] In the present invention, the term "halo" means substituted with halogen.

[0156] In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is a combination that is stable or chemically feasible. The substituents include, but are not limited to, deuterium, halogen, hydroxyl, cyano, amino, alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-10 Cycloalkyl, haloalkylamino, 3-10 membered heterocyclic group, aryl, heteroaryl, C 2-10 Acyl, C 2-10 Ester group, C 2-6 Alkynyl, C 2-6 Alkenyl, etc.

[0157] In the present invention, the term "0-6" means 0, 1, 2, 3, 4, 5 or 6. Other similar terms have similar meanings.

[0158] In the present invention, the term "one or more" refers to 1, 2, 3, 4, 5 or 6. Other similar terms have similar meanings.

[0159] It should be understood that when a group is present in multiple different positions of a compound at the same time, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the following group:" has the same meaning as the term "each independently selected from the following group:" and the term "independently selected from the following group:".

[0160] Compound

[0161] The present invention provides a compound, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof,

[0162]

[0163] Wherein, R1, R2, R3, R4, X1, X2, X3, Ring A and Ring B are as defined above.

[0164] In another preferred embodiment, in the compound, any one of R1, R2, R3, R4, X1, X2, X3, ring A and ring B is independently a corresponding specific group in the specific compound.

[0165] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0166] Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0167] The compounds of the present invention also include prodrugs of the compounds shown in formula (I). The term "prodrug" includes a compound that may be biologically active or inactive, and when taken by an appropriate method, it undergoes metabolism or chemical reactions in the human body and is converted into a class of compounds of formula (I), or a salt or solution composed of a compound of formula (I). The prodrug includes (but is not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and the like forms of the compound.

[0168] The term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0169] It should be understood that the specific preparation method of the compound of formula (I) of the present invention does not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combination can be easily performed by a person skilled in the art to which the present invention belongs.

[0170] Typically, the compounds of the present invention can be prepared by the process described in the examples, wherein the raw materials and reagents used can be purchased from commercial sources unless otherwise specified.

[0171] Pharmaceutical compositions and methods of administration

[0172] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds and a pharmaceutically acceptable carrier.

[0173] Since the compounds of the present invention have excellent anti-tumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0174] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0175] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0176] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0177] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0178] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0179] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0180] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0181] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0182] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0183] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0184] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0185] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0186] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0187] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0188] Compared with the prior art, the present invention has the following main advantages:

[0189] (1) The compound has excellent activity selective for PI3Kα mutation.

[0190] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0191] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0192] Example Synthesis Route

[0193] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is defined as follows. Compounds marked with (or) or (rel) are single enantiomers with arbitrarily specified absolute stereochemistry (e.g., based on chiral SFC elution described in the Examples section). Compounds marked with (&) or (rac) are mixtures of enantiomers with relative stereochemistry as shown in the text. Compounds marked with (abs) are single enantiomers with absolute stereochemistry as shown in the text.

[0194] Synthesis of intermediates

[0195] Synthesis of intermediate int1:

[0196] The synthetic route and experimental process are as follows:

[0197]

[0198] 1. Synthesis of compound int1-2:

[0199] In a 100 ml single-mouth bottle, int1-1 (2 g, 1 eq), sodium carbonate (4.2 g, 2 eq), water (20 mL), 1,4-dioxane (60 mL) were added, the temperature was lowered to 0 °C, Fmoc-Cl (5.7 g, 1.1 eq) was added, the temperature was naturally raised to room temperature, stirred for 4 h, and diluted with saturated brine (200 mL). Extracted with ethyl acetate, the organic phases were combined, dried, and concentrated to obtain 6.7 g of product.

[0200] 2. Synthesis of compound int1-3:

[0201] Int1-2 (5g 1eq), toluene (100ml), 2-amino-3-bromo-5-fluorobenzoic acid (4.7g 1.3eq), thionyl chloride (2.58g 1.4eq) were added to a 100mL three-necked flask, stirred at 80℃ for 1h, heated to 120℃, stirred for 3h, and after the reaction was completed, the product was directly purified by column to obtain 2.2g, 1 H NMR(DMSO-d6,400MHz)δ8.22(s,1H),7.94–7.86(m,2H),7.75(s,1H),7.69–7.62(m,2H),7.34(qd, J=7.9,7.3,1.2Hz,4H),4.68–4.38(m,4H),4.33(t,J=6.2Hz,1H),4.14–3.96(m,2H),3.69(s,2H).

[0202] 3. Synthesis of compound int1-4:

[0203] Int1-3 (2.2g 1eq), dioxane (30ml), tributyl (1-ethoxyethylene) tin (1.82g 1.2eq), Pd (PPh3) 2Cl2 (0.59g 0.2eq) were added to the reaction bottle and reacted at 80°C for 3h under nitrogen protection. After the reaction, the reaction system was cooled to room temperature, 100ml of 2M hydrochloric acid was added and stirred for 30min, and then 100ml of saturated potassium fluoride solution was added and stirred for 30min, and then saturated sodium bicarbonate was added to adjust the pH value to near neutral, extracted with ethyl acetate, dried and concentrated, and purified by column chromatography to obtain 1.7g of the product.

[0204] 4. Synthesis of compound int1-5:

[0205] In a 500mL single-mouth bottle, add the above int1-4 (1.7g 1eq), methanol (3mL), and dichloromethane (30ml), cool to 0℃, add NaBH4 (0.2g 1.5eq), and stir at 0℃ for 1h. The reaction is complete after liquid mass monitoring, add saturated ammonium chloride (10ml), stir for 30min, extract with dichloromethane (20ml x 3), dry, concentrate, and purify by column to obtain 1.22g of the product. 1 H NMR(400MHz, Methanol-d4)δ7.74(d,J=9.3Hz,3H),7.62(t,J=7.1Hz,3H),7.38–7.23(m,4H),5.67(s,1H),4 .62(s,2H),4.29(d,J=23.7Hz,2H),4.02(s,1H),3.79(d,J=44.0Hz,1H),3.60(s,1H),1.50(d,J=6.3Hz,3H).

[0206] 5. Synthesis of compound int1:

[0207] In a 25mL three-necked flask, add int1-5 (1.22g, 1eq) and dichloromethane (60mL), protect with nitrogen, cool to 0℃, add phosphorus tribromide (1ml) dropwise, stir for 16h, react, concentrate to obtain 2.2g crude product, which is directly used for the next step. 1 HNMR(400MHz,Chloroform-d)δ7.88(d,J=7.9Hz,1H),7.77(s,3H),7.58(s,2H),7.45–7.29(m,4H),6.30(d,J=7.3H z,1H),4.60(q,J=21.5,21.0Hz,4H),4.27(t,J=6.0Hz,1H),4.17–4.02(m,2H),3.68(s,2H),2.06(d,J=13.4Hz,3H).

[0208] Synthesis of intermediate int2:

[0209] The synthetic route and experimental process are as follows:

[0210]

[0211] In a 100mL three-necked flask, int2-1 (300mg, 1.0eq), DHP (234mg, 2eq), dichloromethane (50ml), and then p-toluenesulfonic acid (64mg, 0.2eq) were added and reacted at room temperature for 1h under nitrogen protection. After the reaction was completed, the mixture was washed with saturated sodium chloride aqueous solution, extracted with dichloromethane, concentrated, and purified to obtain 300mg of the product.

[0212] Example 1

[0213] Compounds of the present invention

[0214]

[0215] The synthetic route and experimental process are as follows:

[0216]

[0217] 1. Synthesis of compound C1-1:

[0218] In a 100mL three-necked flask, add the above int1 (2.2g), dry N,N-dimethylformamide (60mL), tert-butyl anthranilate (2.9g, 6eq), and react at 80°C for 8h under nitrogen protection. After the reaction is complete, add saturated ammonium chloride, extract with ethyl acetate, and dry and concentrate to obtain 1.7g of crude product.

[0219] 2. Synthesis of Compound C1-2

[0220] C1-1 (1.7 g, 1.0 eq), diethylamine (5 ml), and dichloromethane (50 ml) were added to a 100 mL three-necked flask and reacted at room temperature for 8 h under nitrogen protection. After the reaction was completed, the mixture was washed with saturated aqueous ammonium chloride solution, extracted with dichloromethane, concentrated, and purified by column chromatography to obtain 258 mg of the product. 1H NMR(400MHz,Chloroform-d)δ8.30(d,J=6.2Hz,1H),7.86(dd,J=8.0,1.7Hz,1H),7.75(dd ,J=8.2,3.0Hz,1H),7.48(dd,J=9.2,3.0Hz,1H),7.08(ddd,J=8.7,7.1,1.7Hz,1H),6.51( ddd,J=8.1,7.0,1.1Hz,1H),6.28(d,J=8.4Hz,1H),5.50(t,J=6.5Hz,1H),4.17(s,2H),4. 04(td,J=5.6,1.4Hz,2H),3.34(q,J=7.6,6.7Hz,2H),1.63(s,9H).1.60(d,J=6.7Hz,3H).

[0221] 3. Synthesis of Compound C1-3

[0222] C1-2 (100 mg, 1.0 eq), Pd2(dba)3 (41.73 mg 0.2 eq), RuPhos (42.75 mg 0.4 eq), potassium tert-butoxide (77.4 mg 3 eq), int2 (112 mg 2 eq), toluene (5 ml) were added to a 20 mL sealed bottle and reacted at 100°C for 0.5 h. After the reaction was completed, the mixture was filtered, concentrated, and purified by column chromatography to obtain 60 mg of the product.

[0223] 4. Synthesis of Compound C1-4

[0224] C1-3 (110 mg, 1.0 eq), dichloromethane (5 mL), and trifluoroacetic acid (2.5 ml) were added to a 50 mL three-necked flask and reacted at 40°C for 6 h. After the reaction was completed, the mixture was concentrated and purified by TLC plate to obtain 72 mg of the product.

[0225] 5. Synthesis of Compounds C1 and C2

[0226] Compound C1-4 was separated by chiral preparative chromatography using the following chiral separation conditions: Instrument: Agilent 1260 Infinity II, Chromatographic column: phenomenex 5μm Amylose-1 (250×21.2mm), mobile phase: n-hexane: isopropanol = 7:3, column temperature: 25°C. Separation:

[0227] C1 (peak time 8.2min) 9.54mg 1H NMR(400MHz,DMSO-d6)δ12.71(s,1H),11.86(s,1H),8.60(s,1H),7.88–7.78(m,1H) ,7.68(dd,J=8.4,3.0Hz,1H),7.56(d,J=8.6Hz,1H),7.42(s,1H),7.18(d,J=8.1Hz, 1H),6.51(t,J=7.5Hz,1H),6.42(d,J=8.6Hz,1H),5.44(d,J=7.1Hz,1H),4.43(s,2H ),3.94(q,J=5.4Hz,2H),3.58(t,J=5.7Hz,2H),2.03(s,3H),1.59(d,J=6.6Hz,3H),

[0228] C2 (peak time 16.2min) 2mg 1 H NMR(400MHz,DMSO-d6)δ12.73(s,1H),11.88(s,1H),8.61(s,1H),7.86–7.77(m,1H) ,7.66(dd,J=8.4,3.0Hz,1H),7.54(d,J=8.6Hz,1H),7.42(s,1H),7.18(d,J=8.1Hz, 1H),6.51(t,J=7.5Hz,1H),6.40(d,J=8.6Hz,1H),5.41(d,J=7.1Hz,1H),4.43(s,2H ), 3.94 (q, J = 5.4Hz, 2H), 3.58 (t, J = 5.7Hz, 2H), 2.03 (s, 3H), 1.59 (d, J = 6.6Hz, 3H).

[0229] The invention provides a series of compounds with PI3KαH1047R mutation activity and selectivity, and a synthesis method thereof, which have broad application prospects.

[0230] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound, characterized in that The compound is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, in: X1 is N, O; X2 and X3 are each independently selected from the following group: N, C; X4 is N or CR; Ring B is: a 5-7 membered heterocycloalkyl group containing 1 N atom and 0-3 heteroatoms selected from N, O or S, which is optionally substituted by one or more R5; Ring A is selected from the following group: C 6-10 Aryl, 5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; wherein the C 6-10 Aryl, 5-8 membered heteroaryl is optionally substituted by m R6; R1 is selected from the group consisting of H, deuterium, halogen, -CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy; R, R2, R3 are each independently selected from the following group: H, halogen, -CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl; R4 is selected from the following group: -L-(C 1-6 Alkyl), -LC 6-10 Aryl, -L-(5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), -L-(saturated or partially saturated C 3-8 -(saturated or partially saturated 4-8 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S); wherein the C 1-6 Alkyl, C 6-10 Aryl, 5-8 membered heteroaryl, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted by n R7; Each R5 is independently selected from the group consisting of H, deuterium, halogen, -CN, oxo (=O), C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S; Each R6 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -SO2R8, -S(O)(NR8)R9, -SO2NR8R9, -P(O)R8R9; Each R7 is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo (=O), -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、-L1-(C 1-6 Alkyl), -L1-(saturated or partially saturated C 3-10 Cycloalkyl), -L1-(C 6-10 aryl), -L1-(saturated or partially saturated 3-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S), -L1-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, -SO2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8R9, Alternatively, the two R7 atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, C 6-10 aryl, a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S, or a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、C 1-6 Alkyl, C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; L and L1 are each independently a bond or are selected from the following group: C 1-6 Alkylene, 1-6 membered heteroalkylene containing 1-4 heteroatoms selected from N, O or S, -NR8-, -O-, -C(O)-, -C(O)NR8-, -C(O)O-, -NR8C(O)-, -(SO2)-, -SO2NR8-, -NR8SO2-, -NR8SO2NR9-, -S(O)(NR8)-; Each R8, R9, R 10 Each independently selected from the following group: H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 aryl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with 0-6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl; Alternatively, R8, R9 and the heteroatom to which they are connected together form a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S; or, R9, R 10 Together with the heteroatoms to which it is attached, it forms a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S; is a single bond or a double bond; Each m and n is independently selected from: 0, 1, 2, 3, 4, 5.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, characterized in that: The compound has a structure selected from the group consisting of: in: X1 is N, O; X2 and X3 are each independently selected from the following group: N, C; Y1, Y2, Y3, and Y4 are each independently selected from the following group: O, C(R5)2, CHR5, C(=O), S(=O), S(=O)2, and NR5; Ring A is selected from the following group: phenyl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; wherein the phenyl, 5-6 membered heteroaryl is optionally substituted by m R6; R1 is selected from the group consisting of H, deuterium, halogen, -CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy; R2 and R3 are each independently selected from the following group: H, halogen, -CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 3-5 Cycloalkyl, halogenated C 3-5 Cycloalkyl; R4 is selected from the following group: -L-(C 1-6 alkyl), -L-phenyl, -L-(5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), -L-(saturated or partially saturated C 3-6 -(saturated or partially saturated 4-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S); wherein the C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted by n R7; Each R5 is independently selected from the group consisting of H, deuterium, halogen, -CN, oxo (=O), halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 3-5 Cycloalkyl, halogenated C 3-5 Cycloalkyl, 3-5 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S; Each R6 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-3 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -SO2R8, -S(O)(NR8)R9, -SO2NR8R9, -P(O)R8R9; Each R7 is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo (=O), -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、-L1-(C 1-6 Alkyl), -L1-(saturated or partially saturated C 3-10 Cycloalkyl), -L1-(C 6-10 aryl), -L1-(saturated or partially saturated 3-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S), -L1-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, -SO2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8R9, Alternatively, the two R7 atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, C 6-10 aryl, a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S, or a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、C 1-6 Alkyl, C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; L and L1 are each independently a bond or are selected from the following group: C 1-6 Alkylene, 1-6 membered heteroalkylene containing 1-4 heteroatoms selected from N, O or S, -NR8-, -O-, -C(O)-, -C(O)NR8, -C(O)O-, -NR8C(O)-, -(SO2)-, -SO2NR8-, -NR8SO2-, -NR8SO2NR9-; Each R8, R9, R 10 Each independently selected from the following group: H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 aryl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with 0-6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl; Alternatively, R8, R9 and the heteroatom to which they are connected together form a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S; or, R9, R 10 Together with the heteroatoms to which it is attached, it forms a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S; is a single bond or a double bond; Each m and n is independently selected from: 0, 1, 2, 3, 4, 5.

3. The compound according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, characterized in that: The compound has a structure selected from the group consisting of: wherein R1, R2, R3, R4, Y1, Y2, Y3, Y4, and Ring A are as defined in claim 2; structure Contains the following configurations:

4. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, characterized in that: Ring A has a structure selected from the group consisting of: wherein each R6 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-3 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R6, -C(O)OR6, - C(O)NR6R7, -SO2R6, -S(O)(NR6)R7, -SO2NR6R7, -P(O)R6R7; m is selected from: 0, 1, 2, 3, 4, 5.

5. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, characterized in that: R4 has a structure selected from the group consisting of: Wherein, L and L1 are each independently a bond or are selected from the following group: C 1-6 Alkylene, -C(O)-, -C(O)NH-, -C(O)O-, -(SO2)-, -SO2NH-; Each R7 is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo (=O), -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、-L1-(C 1-6 Alkyl), -L1-(saturated or partially saturated C 3-10 Cycloalkyl), -L1-(C 6-10 aryl), -L1-(saturated or partially saturated 3-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S), -L1-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, -SO2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8R9, Alternatively, the two R7 atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, C 6-10 aryl, a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S, or a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、C 1-6 Alkyl, C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; n is selected from: 0, 1, 2, 3, 4, 5.

6. The compound according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, characterized in that: The compound has a structure selected from the group consisting of: wherein R1, R2, R3, R4, Y1, Y2, and Y3 are as defined in claim 2; X5 is CR6 or N; Each R6 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-3 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R6, -C(O)OR6, -C(O)NR6R7, -SO2R6, -S(O)(NR6)R7, -SO2NR6R7, -P(O)R6R7; m is selected from: 0, 1, 2, 3, 4.

7. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, characterized in that: The compound is selected from the group consisting of:

8. A pharmaceutical composition, characterized in that The invention comprises a safe and effective amount of one or more compounds according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

9. Use of the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, characterized in that: For use selected from the group consisting of: 1) Preparation of selective PI3Kα inhibitors; 2) Preparation of drugs for regulating PI3Kα activity or treating PI3Kα-related diseases.

10. The use according to claim 9, characterized in that The PI3Kα-related disease is cancer or tumor.

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