PI3kα inhibitor and use thereof

Abstract

A PI3Kα inhibitor and the use thereof. The inhibitor has a structure as shown in formula (I), has a good selective inhibitory activity on mutant PI3Kα, and can be used for preparing anti-tumor drugs.

Description

A PI3Kα inhibitor and its use 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 compounds, pharmaceutically acceptable salts, solvates or prodrugs thereof, pharmaceutical compositions comprising such compounds and salts, and uses thereof, as well as their applications 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 phosphatidylinositol. 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 typically 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 GTPase 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 various PI3K subfamily proteins, PI3Kα is a heterodimer composed of the p110α catalytic subunit and the p85α regulatory subunit. The gene encoding the p110α subunit, PIK3CA, is mutated in nearly 30% of human cancers, including colorectal cancer, glioblastoma, and gastric cancer. Importantly, overactivation of PI3Kα is directly associated with resistance to current therapeutic agents and poor prognosis.

[0003] Mutations in the gene encoding PI3Kα primarily occur as point mutations within several hotspots within the helical and kinase domains, such as E542K, E545K, and H1047R. These mutations have been shown to be oncogenic gain-of-function mutations. Given the high prevalence of PI3Kα mutations, targeting this pathway may offer valuable therapeutic opportunities. Other PI3K isoforms, such as PI3Kδ and 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 leads to 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 overcoming the problem of insulin and / or glucose substitution following systemic PI3Kα inhibition is to develop inhibitors that are more selective for mutant PI3Kα than for wild-type PI3Kα. This would create a larger window of opportunity for drug dosing to selectively inhibit the pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα, which controls systemic metabolism in host tissues. This would limit toxicity, allowing for higher dosing and more complete inhibition of the drug target.

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

[0007] Summary of the Invention

[0008] The object of the present invention is to provide a compound represented by formula (I), a preparation method thereof, and use thereof as a selective PI3Kα inhibitor drug.

[0009] The first aspect of the present invention provides a compound, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof,

[0010] in:

[0011] X1 is selected from the following group: N, O, S, NR 11 、C(R 11 ) q ;

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

[0013] X4 is N or CR;

[0014] X5 is selected from the group consisting of: absent, O, and NR 51 、C 1-6 Alkylene, C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene containing 1-4 heteroatoms selected from N, O or S, wherein the C 1-6 Alkylene, C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene are optionally substituted by 1, 2, 3, 4, 5 or 6 R 52 replace;

[0015] X6 is selected from the group consisting of: absent, NR 61 、C 1-6 Alkylene, wherein the C 1-6 The alkylene group is optionally substituted with 1, 2, 3, 4, 5 or 6 R 62 replace;

[0016] X7 is selected from the following group: C=O, C=S, CR 71 ;

[0017] Ring B is: a 5-7 membered heterocycloalkyl group containing 1 N atom and 0-3 heteroatoms selected from N, O or S, optionally substituted by one or more R5;

[0018] Ring A is selected from the group consisting of: C 6-10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, 5-10 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; wherein the C 6-10 Aryl, 5-10 membered heteroaryl is optionally substituted with m R6;

[0019] R, R2, R3, R 11 、R 52 、R 62 Each independently selected from the group consisting of H, deuterium, halogen, oxo (=O), -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, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, deuterated C 3-6 Cycloalkyl;

[0020] Alternatively, R together with R2 and the atom to which it is attached forms C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; wherein the C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 or 6 R6;

[0021] Alternatively, R2 and R3 together with the atoms to which they are attached form a C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; wherein the C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 or 6 R6;

[0022] R 51 、R 61Each independently selected from the group consisting of: H, -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, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl;

[0023] R 71 Selected from the group consisting of: H, halogen, -CN, -NO2, 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, -C(O)R8;

[0024] R4 is selected from the group consisting of: -L-(C 1-6 Alkyl), -LC 6-10 Aryl, -L-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), -L-(saturated or partially saturated C 3-8 cycloalkyl), -L-(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, 5-10 membered heteroaryl, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted by n R7;

[0025] 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;

[0026] 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 1-6Alkoxy, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -SO2R8, -S(O)(NR8)R9, -SO2NR8R9, -P(O)R8R9;

[0027] 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,

[0028] Alternatively, two R7 together with the atoms to which they are attached form a C 3-6 Cycloalkyl, C 6-10aryl, 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 6-10 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, -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;

[0029] L and L1 are each independently a bond or selected from the group consisting of: C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, 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)-, wherein the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 1-6 membered heteroalkylene optionally substituted with 0-6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NR8R9, =NR8;

[0030] 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, C6-10 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 1-6 Alkylamino, halogenated C 1-6 Alkylamino, C 1-6 Alkylthio, halo C 1-6 Alkylthio, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, halogenated C 3-6 Cycloalkyl, halogenated 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S;

[0031] Alternatively, R8, R9 and the heteroatom to which they are attached together form a 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocycloalkyl 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 1-6 Alkylamino, halogenated C 1-6 Alkylamino, C 1-6 Alkylthio, halo C 1-6 Alkylthio, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, halogenated C 3-6 Cycloalkyl, halogenated 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S;

[0032] Or, R9, R 10 The heteroatoms to which it is attached form a 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocycloalkyl is 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 1-6Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, C 1-6 Alkylthio, halo C 1-6 Alkylthio, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, halogenated C 3-6 Cycloalkyl, halogenated 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S;

[0033] each are each independently a single bond or a double bond;

[0034] Each m, n, and q are independently selected from the following group: 0, 1, 2, 3, 4, and 5.

[0035] In another preferred embodiment, the compound has a structure selected from the following group:

[0036] wherein X4, X5, X6, R2, R3, R4, Ring A, and Ring B are as defined above;

[0037] X1 is selected from the following group: N, CR 11 ;

[0038] R 11 Selected from the group consisting of: H, 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, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl;

[0039] R 71 Selected from the group consisting of: H, halogen, -CN, -NO2, 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, -C(O)R8;

[0040] R8 is selected from the group consisting of H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C3-6 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 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.

[0041] In another preferred embodiment, the compound has a structure selected from the following group:

[0042] structure Select from the following configurations:

[0043] Among them, X4, X5, X6, R2, R3, R4, R5, R 71 , Ring A, and p are as defined above;

[0044] R 52 、R 62 Each independently selected from the group consisting of H, halogen, oxo (=O), -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, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl;

[0045] R 51 、R 61 Each independently selected from the group consisting of: H, -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, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl.

[0046] In another preferred embodiment, the compound has a structure selected from the following group:

[0047] wherein X1, X2, X3, X4, X6, R2, R3, R4, Ring A and Ring B are as defined above.

[0048] In another preferred embodiment, the compound has a structure selected from the following group:

[0049] structure Select from the following configurations:

[0050] wherein X4, X6, R2, R3, R4, R5, Ring A, and p are as defined above;

[0051] R 62 Selected from the group consisting of: H, halogen, oxo (=O), -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, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3- 6-cycloalkyl;

[0052] R 61 Selected from the following group: H, -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, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl.

[0053] In another preferred embodiment, the compound has a structure selected from the following group:

[0054] Among them, X1, X2, X3, X4, X6, R2, R3, R4, R 51 , Ring A, and Ring B are as defined above.

[0055] In another preferred embodiment, the compound has a structure selected from the following group:

[0056] structure Select from the following configurations:

[0057] wherein X4, X6, R2, R3, R4, R5, Ring A, and p are as defined above;

[0058] R 51 、R 61 Each independently selected from the group consisting of: H, -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, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl;

[0059] R 62 Selected from the group consisting of: H, halogen, oxo (=O), -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, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3- 6-cycloalkyl.

[0060] In another preferred embodiment, the compound is a compound of formula (I-a), or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof,

[0061] in:

[0062] X1 is selected from the following group: N, O, C (R 11 ) q ;

[0063] X2 and X3 are each independently selected from the following group: N, C;

[0064] X4 is N or CR;

[0065] Ring B is: a 5-7 membered heterocycloalkyl group containing 1 N atom and 0-3 heteroatoms selected from N, O or S, optionally substituted by one or more R5;

[0066] Ring A is selected from the group consisting of: 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;

[0067] R1 is selected from the group consisting of H, deuterium, halogen, -CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6Alkyl, C 1- 6 alkoxy, halogenated C 1-6 alkoxy;

[0068] R, R2, R3, R 11 Each independently selected from the group consisting of: 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;

[0069] R4 is selected from the group consisting of: -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 cycloalkyl), -L-(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;

[0070] 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;

[0071] 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;

[0072] 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,

[0073] Alternatively, two R7 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 0-6 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;

[0074] L and L1 are each independently a bond or selected from the group consisting of: 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)-;

[0075] 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;

[0076] 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;

[0077] is a single bond or a double bond;

[0078] Each m, n, and q are independently selected from the following group: 0, 1, 2, 3, 4, and 5.

[0079] In another preferred embodiment, ring A is selected from the following group: C 6-10 Aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; wherein the C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with m R6.

[0080] 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(O)R8, -C(O)OR8, -SO2R8.

[0081] 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.

[0082] In another preferred embodiment, X6 is selected from the following group: NR 61 、C 1-6 Alkylene.

[0083] In another preferred embodiment, R 51 、R 61 Each independently selected from the following group: H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl.

[0084] In another preferred embodiment, X5 is C 1-6 Alkylene, wherein the C 1-6 The alkylene group is optionally substituted with 1, 2, 3, 4, 5 or 6 R 52 replace.

[0085] In another preferred embodiment, each of R, R2, R3, R 11 、R 52 、R 62 Each independently selected from the group consisting of H, deuterium, halogen, C 1-6Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl.

[0086] In another preferred embodiment, X4 is CR.

[0087] 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.

[0088] 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.

[0089] In another preferred embodiment, R is H.

[0090] In another preferred embodiment, X4 is CH.

[0091] In another preferred embodiment, X1 is selected from the following group: N, O, C(R 11 ) q .

[0092] In another preferred embodiment, X1 is selected from the following group: N, O.

[0093] In another preferred embodiment, X2 and X3 are each independently selected from the following group: N, C.

[0094] In another preferred embodiment, X7 is selected from the following group: C═O, C═S.

[0095] In another preferred embodiment, 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.

[0096] In another preferred embodiment, each R5 is independently selected from the following group: H, deuterium, halogen, oxo (=O), C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl.

[0097] In another preferred embodiment, R4 is selected from the following group: -L-(C 1-6 Alkyl), -LC 6-10 Aryl, -L-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), -L-(saturated or partially saturated C3-8 cycloalkyl), -L-(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, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 4-8 membered heterocycloalkyl are optionally substituted with n R7.

[0098] In another preferred embodiment, L and L1 are each independently a bond or selected from the following group: C 1-6 Alkylene, -NR8-, -O-, -C(O)-, -C(O)NR8-, -C(O)O-, -NR8C(O)-, -(SO2)-, -SO2NR8-, -NR8SO2-, -NR8SO2NR9-, -S(O)(NR8)-.

[0099] In another preferred embodiment, L and L1 are each independently a bond or selected from the following group: C 1-6 Alkylene, -C(O)-, -C(O)NR8-, -C(O)O-, -NR8C(O)-, -(SO2)-, -SO2NR8-, -NR8SO2-, -NR8SO2NR9-, -S(O)(NR8)-.

[0100] In another preferred embodiment, each R7 is independently selected from the following group: hydrogen, deuterium, halogen, oxo (=O), -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, -C(O)NR8R9, -NR8C(O)R9, -SO2R8, -NR8SO2R9, -SO2NR8R9, wherein the C 1-6 The alkyl group is optionally substituted with 0 to 6 substituents selected from the group consisting of: -OH, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0101] Alternatively, two R7 together with the atoms to which they are attached form a C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S.

[0102] In another preferred embodiment, the compound has a structure selected from the following group:

[0103] in:

[0104] X1 is selected from the following group: N, O, C (R 11 ) q ;

[0105] X2 and X3 are each independently selected from the following group: N, C;

[0106] Y1, Y2, Y3, and Y4 are each independently selected from the group consisting of O, C(R5)2, CHR5, C(=O), S(=O), S(=O)2, and NR5;

[0107] Ring A is selected from the group consisting of a phenyl group, a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S; wherein the phenyl group, the 5-6 membered heteroaryl group is optionally substituted by m R6;

[0108] 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;

[0109] R2, R3, R 11 Each independently selected from the group consisting of: 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;

[0110] R4 is selected from the group consisting of: -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 cycloalkyl), -L-(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-membered cycloalkyl, 4-6-membered heterocycloalkyl is optionally substituted by n R7;

[0111] Each R5 is independently selected from the group consisting of 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 3-5Cycloalkyl, 3-5 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;

[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 C 1-6 Alkoxy, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -SO2R8, -S(O)(NR8)R9, -SO2NR8R9, -P(O)R8R9;

[0113] 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 3-6Cycloalkyl, 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,

[0114] Alternatively, two R7 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 6-10 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, -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;

[0115] L and L1 are each independently a bond or selected from the group consisting of: 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-;

[0116] 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 6-10Aryl, 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;

[0117] 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;

[0118] is a single bond or a double bond;

[0119] Each m, n, and q are independently selected from the group consisting of: 0, 1, 2, 3, 4, and 5.

[0120] In another preferred embodiment, X2 and X3 are both C, or one of X2 and X3 is N and the other is C.

[0121] In another preferred embodiment, X2 is C and X3 is N.

[0122] 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).

[0123] In another preferred embodiment, Y1, Y2, Y3, and Y4 are each independently selected from the following group: O, CH2, CHR5, and C(=O).

[0124] In another preferred embodiment, Y1, Y2, Y3, and Y4 are each independently selected from the group consisting of CH2 and CHR5. In another preferred embodiment, one of Y1, Y2, Y3, and Y4 is O, CHR5, or C(═O), and the others are CH2.

[0125] 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 C3-5 Cycloalkyl, 3-5 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S.

[0126] 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.

[0127] 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.

[0128] In another preferred embodiment, the compound has a structure selected from the following group:

[0129] Among them, R1, R2, R3, R4, R 11 , Y1, Y2, Y3, Y4, and Ring A are as defined herein; Structure Contains the following configurations:

[0130] In another preferred embodiment, the structure Contains the following configurations:

[0131] In another preferred embodiment, the compound has a structure selected from the following group:

[0132] Among them, R1, R2, R3, R4, R5, R 11 , Ring A is as defined herein, and p is 0, 1, 2, 3 or 4;

[0133] structure Contains the following configurations:

[0134] 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.

[0135] 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.

[0136] 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.

[0137] In another preferred embodiment, ring A is selected from the following group: phenyl, pyridyl, wherein the phenyl and pyridyl are optionally substituted by m R6.

[0138] 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.

[0139] 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, -SO2R8.

[0140] In another preferred embodiment, each R6 is independently selected from the following group: H, deuterium, halogen, -C(O)OR8, -SO2R8.

[0141] In another preferred embodiment, each R6 is independently selected from the following group: H, deuterium, halogen, -C(O)OH.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] In another preferred embodiment, R1 is C 1-3 Alkyl, for example methyl, ethyl, n-propyl or isopropyl.

[0146] In another preferred embodiment, R1 is R configuration or S configuration.

[0147] In another preferred embodiment, R1 is a methyl group in R configuration.

[0148] 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.

[0149] In another preferred embodiment, R2 and R3 are each independently selected from the following groups: 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] In another preferred embodiment, ring A has a structure selected from the group consisting of:

[0154] 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)R8, -C(O)OR8, -C(O)NR8R9, -SO2R8, -S(O)(NR8)R9, -SO2NR8R9, -P(O)R8R9;

[0155] Each R8 and R9 are as defined above; m is selected from the group consisting of: 0, 1, 2, 3, 4, 5.

[0156] In another preferred embodiment, ring A has a structure selected from the group consisting of:

[0157] In another preferred embodiment, ring A has a structure selected from the group consisting of:

[0158] In another preferred embodiment, R4 has a structure selected from the group consisting of:

[0159] Wherein, L and L1 are each independently a bond or selected from the following group: C 1-6 Alkylene, -C(O)-, -C(O)NH-, -C(O)O-, -(SO2)-, -SO2NH-;

[0160] 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 1-6Alkyl), -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,

[0161] Alternatively, two R7 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 6-10 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, -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;

[0162] Each R8, R9, R 10 As defined above; n is selected from the group consisting of 0, 1, 2, 3, 4, and 5.

[0163] 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 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.

[0164] 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 C1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl.

[0165] 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 alkyl 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.

[0166] 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 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.

[0167] 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 with 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.

[0168] In another preferred embodiment, each of R8, R9, R 10 Each independently selected from the following group: H, C1-6 Alkyl, halogenated C 1-6 alkyl.

[0169] In another preferred embodiment, the compound has a structure selected from the following group:

[0170] wherein R1, R2, R3, R4, Y1, Y2, and Y3 are as defined herein;

[0171] X8 is CR6 or N;

[0172] 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;

[0173] m is selected from the following group: 0, 1, 2, 3, 4.

[0174] 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.

[0175] In another preferred embodiment, the compound is selected from the following group:

[0176] In another preferred embodiment, the compound is selected from the following group:

[0177] 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 form, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

[0178] The third aspect of the present invention provides a use of the compound according to 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:

[0179] 1) Preparation of selective PI3Kα inhibitors;

[0180] 2) Preparation of drugs for regulating PI3Kα activity or treating PI3Kα-related diseases.

[0181] In another preferred embodiment, the PI3Kα has one or more mutations selected from the following group: H1047R, E542K, and E545K.

[0182] In another preferred embodiment, the PI3Kα-related disease is cancer or tumor.

[0183] In another preferred embodiment, the cancer or tumor is selected from the group consisting of acute lymphoblastic 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 tumor, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, esophagus cancer, 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, leukemia Blood diseases, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic carcinoma, metastatic squamous neck cancer, midline duct cancer with nut gene alteration, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasms, myelodysplastic syndrome, myelodysplastic neoplasms, myeloproliferative neoplasms, chronic myeloproliferative neoplasms, nasal cavity 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 tumor (islet cell tumor), 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, squamous cell carcinoma of the skin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic cancer, thyroid cancer, tracheobronchial tumors, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, Wilms' tumor.

[0184] 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, neurilemmoma, 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.

[0185] In another preferred embodiment, the cancer is breast cancer, prostate cancer or brain cancer.

[0186] The fourth aspect of the present invention provides a method for preventing and / or treating PI3Kα activity or treating PI3Kα-related diseases, which comprises administering to a subject in need thereof the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, deuterated form, solvate or prodrug thereof.

[0187] In another preferred embodiment, the subject is a human or non-human mammal, such as rats, mice, rabbits, pigs, dogs, sheep, etc.

[0188] 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 described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0189] After extensive and in-depth research, the inventors unexpectedly developed a class of compounds with excellent PI3Kα mutation-selective inhibitory activity and a method for their preparation. Specifically, through structural optimization, the inventors obtained a class of compounds with excellent PI3Kα mutation-selective inhibitory activity. Based on this, the inventors completed the present invention.

[0190] the term

[0191] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0192] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0193] 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.

[0194] In the present invention, the term "C 1-6 "Alkoxy" refers to a straight or branched chain 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.

[0195] In the present invention, the term "deuterated C 1-6 "Alkyl" refers to an alkyl group having a straight or branched chain of 1 to 6 carbon atoms, wherein the hydrogen atoms on the carbon atoms are optionally replaced by one, more or all of them are replaced by deuterium, such as -CD3, -CH2CD3, -CH(CH3)CD3, etc. The term "deuterated C 1-3 "Alkyl" has the same meaning.

[0196] In the present invention, the term "deuterated C 1-6 "Alkoxy" refers to an alkoxy group comprising a linear or branched carbon atom of 1 to 6 carbon atoms in which one, more or all of the hydrogen 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.

[0197] In the present invention, the term "C 1-6 "Heteroalkyl" refers to a straight or branched chain 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, etc.

[0198] 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.

[0199] 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: C 5-10Spiroalkyl, C 5-10 Bridged cycloalkyl, C 3-8 Monocyclic alkyl, C 4-12 Cycloalkyl groups, wherein some of the carbon atoms on the ring can form unsaturated structures with adjacent carbon atoms in the form of double bonds, include but are not limited to:

[0200] etc. The term "saturated or partially saturated C 3-6 "Cycloalkyl" has a similar meaning.

[0201] 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, and non-limitingly including:

[0202] The terms "4- to 6-membered heterocycloalkyl" and "5- to 7-membered heterocycloalkyl" have the same meaning.

[0203] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning. 6-10 "Aryl" refers to an aromatic structure containing 6-10 carbon atoms without heteroatoms, including: monocyclic aromatic groups, bicyclic C 8-10 Aryl; including but not limited to: The aryl group may be optionally substituted or unsubstituted. The portion connected to the parent group is an aromatic ring.

[0204] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning, and refers to a monocyclic or polycyclic heteroaromatic group containing 1-4 heteroatoms selected from N, O or S. For example, a "5-10 membered heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O or S and 1-9 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: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.; "8-10 membered polycyclic heteroaryl" includes, but is not limited to:

[0205] Heteroaryl groups may be optionally substituted or unsubstituted, wherein the portion attached to the parent group is an aromatic ring.

[0206] In the present invention, the term "halo" means substituted with halogen.

[0207] 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.

[0208] In the present invention, the term "0-6" refers to 0, 1, 2, 3, 4, 5 or 6. Other similar terms have similar meanings.

[0209] In the present invention, the term "one or more" refers to 1, 2, 3, 4, 5 or 6. Other similar terms have similar meanings.

[0210] It should be understood that when a group is present simultaneously at multiple different positions in a compound, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the group:" has the same meaning as the term "each independently selected from the group:" or the term "independently selected from the group:".

[0211] Compound

[0212] The present invention provides a compound, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof,

[0213] wherein R2, R3, R4, X1, X2, X3, X4, X5, X6, X7, Ring A, and Ring B are as defined above.

[0214] In another preferred embodiment, in the compound, any one of R2, R3, R4, X1, X2, X3, X4, X5, X6, X7, Ring A, and Ring B is independently a corresponding specific group in the specific compound.

[0215] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed with 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.

[0216] Another preferred salt is a salt of the compound of the present invention formed with 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.

[0217] The compounds of the present invention also include prodrugs of the compounds represented by formula (I). The term "prodrug" includes compounds that may be biologically active or inactive, and that, when administered by appropriate methods, undergo metabolic or chemical reactions in the human body to transform into a compound of formula (I), or a salt or solution composed of a compound of formula (I). Such prodrugs include (but are not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino, carbamate, azo, phosphoramide, glucoside, ether, acetal, and other forms of the compounds.

[0218] 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.

[0219] 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 combinations can be easily performed by those skilled in the art to which the present invention belongs.

[0220] 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.

[0221] Pharmaceutical compositions and methods of administration

[0222] 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.

[0223] 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.

[0224] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0225] "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, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0226] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0227] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0228] 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 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.

[0229] Solid dosage forms such as tablets, dragees, 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 opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0230] 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, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0231] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0232] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0233] Compositions for parenteral injection may comprise 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.

[0234] Dosage forms for topical administration of the compounds of this 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.

[0235] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0236] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0237] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0238] Compared with the prior art, the present invention has the following main advantages:

[0239] (1) The compound has excellent selective inhibitory activity against PI3Kα mutations;

[0240] (2) The compound has excellent anti-tumor effect;

[0241] (3) The compound has excellent safety;

[0242] (4) The compound has excellent pharmacokinetic properties.

[0243] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0244] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0245] Example Synthesis Route

[0246] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is defined as follows. A compound marked with an "or1" symbol indicates that the compound is a single-configuration compound, but the absolute configuration is unknown; a compound marked with an "or2" symbol indicates that the compound is a single-configuration compound that is an enantiomer of the "or1" structure, but the absolute configuration is unknown; a compound marked with an "abs" symbol indicates that the absolute configuration of the compound is the structure shown; a compound marked with a "rac" symbol indicates that the compound is a racemate; a compound marked with an "S" or "R" symbol indicates that the chirality of the carbon at that position in the compound is the known configuration marked.

[0247] Synthesis of intermediates

[0248] Synthesis of intermediate int1:

[0249] The synthetic route and experimental process are as follows:

[0250] 1. Synthesis of compound int1-2:

[0251] Int1-1 (2 g, 1 eq), sodium carbonate (4.2 g, 2 eq), water (20 mL), and 1,4-dioxane (60 mL) were added to a 100 mL single-necked flask. The temperature was then cooled to 0°C and Fmoc-Cl (5.7 g, 1.1 eq) was added. The mixture was naturally warmed to room temperature and stirred for 4 h before being diluted with saturated brine (200 mL). Extraction was performed with ethyl acetate, and the combined organic phases were dried and concentrated to yield 6.7 g of product.

[0252] 2. Synthesis of compound int1-3:

[0253] Int1-2 (5 g 1 eq), toluene (100 ml), 2-amino-3-bromo-5-fluorobenzoic acid (4.7 g 1.3 eq), and thionyl chloride (2.58 g 1.4 eq) were added to a 100 mL three-necked flask. The mixture was stirred at 80 ° C for 1 h, then heated to 120 ° C and stirred for 3 h. After the reaction was completed, 2.2 g of the product was directly purified by column.

[0254] 1H 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).

[0255] 3. Synthesis of compound int1-4:

[0256] Int1-3 (2.2 g, 1 eq), dioxane (30 ml), tributyl(1-ethoxyethylene)tin (1.82 g, 1.2 eq), and Pd(PPh3)2Cl2 (0.59 g, 0.2 eq) were added to a reaction flask and reacted at 80°C under nitrogen for 3 h. After the reaction, the reaction system was cooled to room temperature, 100 ml of 2M hydrochloric acid was added and stirred for 30 min, followed by 100 ml of saturated potassium fluoride solution and stirring for 30 min. The pH was adjusted to near neutral with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate, dried, concentrated, and purified by column chromatography to obtain 1.7 g of the product.

[0257] 4. Synthesis of compound int1-5:

[0258] Int1-4 (1.7 g 1 eq), methanol (3 mL), and dichloromethane (30 mL) were added to a 500 mL single-necked flask. The temperature was cooled to 0°C, and NaBH4 (0.2 g 1.5 eq) was added. The mixture was stirred at 0°C for 1 h. After completion of the reaction, saturated ammonium chloride (10 mL) was added and stirred for 30 min. The mixture was then extracted with dichloromethane (20 mL x 3), dried, concentrated, and purified by column chromatography to yield 1.22 g of the product.

[0259] 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).

[0260] 5. Synthesis of compound int1:

[0261] Int1-5 (1.22 g, 1 eq) and dichloromethane (60 mL) were added to a 25 mL three-necked flask under nitrogen. The temperature was cooled to 0°C, and phosphorus tribromide (1 mL) was added dropwise. The mixture was stirred for 16 h. After completion of the reaction, the crude product (2.2 g) was obtained after concentration. The product was used directly in the next reaction.

[0262] 1 H NMR(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=7.3Hz ,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).

[0263] Synthesis of intermediate int2:

[0264] The synthetic route and experimental process are as follows:

[0265] Int2-1 (300 mg, 1.0 eq), DHP (234 mg, 2 eq), and dichloromethane (50 ml) were added to a 100 mL three-necked flask, followed by p-toluenesulfonic acid (64 mg, 0.2 eq). The mixture was reacted under nitrogen at room temperature for 1 h. After completion of the reaction, the product was washed with saturated sodium chloride solution, extracted with dichloromethane, concentrated, and purified to obtain 300 mg of the product.

[0266] Synthesis of intermediate int3:

[0267] The synthetic route and experimental process are as follows:

[0268] 1. Synthesis of compound int3-2:

[0269] Compound int3-1 (8.25 g, 43.2 mmol) was dissolved in 150 mL of N,N-dimethylformamide. 3-Chloro-4-cyanopyridine (5 g, 36 mmol) and cesium carbonate (23.5 g, 72 mmol) were added. The mixture was heated to 110°C and allowed to react for 2 h until the reaction was complete. Water was slowly added to quench the reaction, followed by extraction with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified to yield 12 g of the product.

[0270] 1H NMR (400MHz, Chloroform-d) δ8.48(d,J=4.8Hz,1H),8.11(s,1H),7.56(d,J=4.8Hz,1H),7.45(dd,J=7.6,2.8Hz,1H),7.24–7.09(m,2H).

[0271] 2. Synthesis of compound int3-3:

[0272] Int3-2 (12 g, 41 mmol) was dissolved in 120 g of polyphosphoric acid and the temperature was slowly raised to 220°C with stirring for 3 h. After the reaction was complete, the reaction solution was cooled to room temperature and dissolved in water. The base was adjusted with saturated sodium bicarbonate aqueous solution, and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to yield 9.69 g of the product.

[0273] 1 H NMR (400MHz, Chloroform-d) δ9.17 (s, 1H), 8.71 (d, J = 5.1Hz, 1H), 8.09 (d, J = 5.1Hz, 1H), 7.97 (dd, J = 7.6, 3.2Hz, 1H), 7.83 (dd, J = 7.2, 3.2Hz, 1H).

[0274] 3. Synthesis of compound int3-4:

[0275] Int3-3 (9 g, 30.6 mmol), potassium iodide (11.2 g, 67.32 mmol), and benzyl chloride (9.6 g, 61.2 mmol) were added to 360 mL of acetonitrile. The reaction mixture was slowly heated to 80°C and stirred overnight. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to yield 17 g of crude product, which was used directly in the next reaction.

[0276] 4. Synthesis of compound int3-5:

[0277] Compound int3-4 (17 g, 30.9 mmol) was dissolved in 200 mL of anhydrous ethanol, and sodium cyanoborohydride (15.5 g, 247.2 mmol) and acetic acid (1.8 g, 30.6 mmol) were added. The mixture was stirred at room temperature for 30 min. After the reaction of the raw materials was complete, the reaction solution was diluted with water and then extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 6 g of product.

[0278] 1H NMR(400MHz,Chloroform-d)δ7.81(dd,J=8.0,3.2Hz,1H),7.61(dd,J=7.2,3.2Hz,1H),7.32–7.27(m,2H),6 .95–6.86(m,2H),3.82(s,3H),3.69(s,2H),3.53(t,J=1.6Hz,2H),2.77(t,J=5.8Hz,2H),2.71–2.62(m,2H).

[0279] 5. Synthesis of compound int3-6:

[0280] Compound int3-5 (6 g, 14.4 mmol), tributyl(1-ethoxyethylene)tin (6.2 g, 17.2 mmol), and Pd(PPh3)2Cl2 (1 g, 1.44 mmol) were dissolved in dry dioxane (250 mL) and stirred at 80°C for 12 h. Potassium fluoride solution was then added at room temperature, stirred for 0.5 h, filtered, and the mother liquor was extracted three times with ethyl acetate. The organic phase was separated, dried, and dissolved in dichloromethane. 2 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 25°C for 10 min. After completion of the reaction, 4 g of the product was purified by column chromatography.

[0281] 1 H NMR(400MHz,Chloroform-d)δ8.03(dd,J=7.6,3.2Hz,1H),7.80(dd,J=8.0,3.2Hz,1H),7.31–7.27(m,2H),6.93–6.8 7(m,2H),3.82(s,3H),3.69(s,2H),3.53(d,J=1.6Hz,2H),2.78(t,J=5.8Hz,2H),2.71(s,3H),2.68(d,J=6.8Hz,2H).

[0282] 6. Synthesis of compound int3-7:

[0283] Compound int3-6 (1 g, 2.62 mmol) was dissolved in a mixed solvent consisting of 10 mL of dichloromethane and 10 mL of methanol. Under nitrogen, sodium borohydride (50 mg, 1.31 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 10 minutes. After the reaction was complete, the reaction mixture was diluted with water and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to yield 600 mg of the product.

[0284] 1H NMR(400MHz,Chloroform-d)δ7.67(dd,J=7.9,3.2Hz,1H),7.52(dd,J=8.8,3.2Hz,1H),7.36–7.29(m,2H),6.97–6.86(m,2H),5.2 8(q,J=6.1Hz,1H),3.83(s,3H),3.76–3.63(m,2H),3.40(s,2H),2.86–2.70(m,2H),2.66(d,J=5.8Hz,2H),1.47(d,J=6.4Hz,3H).

[0285] 7. Synthesis of compound int3-8:

[0286] Compound int3-7 (600 mg, 1.56 mmol) was dissolved in 50 mL of anhydrous dichloromethane. Under nitrogen protection, phosphorus tribromide (1.3 g, 4.68 mmol) was slowly added and stirred at room temperature for 12 h. After the reaction of the raw materials was complete, the mixture was concentrated under reduced pressure to obtain 600 mg of the product.

[0287] 8. Synthesis of compound int3-9:

[0288] The compound int3-8 (600 mg, 1.35 mmol) was dissolved in 20 mL of anhydrous N,N-dimethylformamide. At room temperature, tert-butyl 2-aminobenzoate (782 mg, 4.05 mmol) was slowly added. The temperature was slowly raised to 60 ° C. and the reaction was stirred for 12 hours. After the raw material reaction was complete, the reaction solution was diluted with water and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 400 mg of the product.

[0289] 1 H NMR(400MHz,Chloroform-d)δ8.27(d,J=6.0Hz,1H),7.88(dd,J=8.0,1.6Hz,1H),7.70(dd,J=8.0 ,3.2Hz,1H),7.38(dd,J=8.8,3.2Hz,1H),7.31(d,J=8.4Hz,2H),7.19–7.08(m,1H),6.94–6.87(m ,2H),6.56(t,J=7.6Hz,1H),6.21(d,J=8.4Hz,1H),5.05(t,J=6.4Hz,1H),3.82(s,3H),3.74–3.6 4(m,2H),3.55(d,J=6.9Hz,2H),2.78(dt,J=9.6,5.6Hz,2H),2.71(d,J=6.0Hz,2H),1.62(s,9H).

[0290] 9. Synthesis of compound int3:

[0291] The compound int3-9 (180 mg, 0.32 mmol) was dissolved in 20 mL of 1,2-dichloroethane. 1-Chloroethyl chloroformate (92 mg, 0.64 mmol) was slowly added at room temperature. The temperature was slowly raised to 83 ° C. and stirred for 3 h. After the raw materials reacted completely, the reaction solution was concentrated and methanol was added. The temperature was raised to 65 ° C. and stirred for 1 h. Then it was concentrated and slurried with methyl tert-butyl ether to obtain 140 mg of the product.

[0292] 1 H NMR (400MHz, Methanol-d4) δ7.87(dd,J=8.0,1.6Hz,1H),7.70(dd,J=8.0,3.2Hz,1H),7.55(dd,J=8.8,3.2Hz,1H),7.19(m,1H),6.59(ddd,J=8.0,7.2,1 .2Hz,1H),6.46(d,J=8.4Hz,1H),5.23(q,J=6.8Hz,1H),4.54–4.39(m,2H),3 .58(t,J=6.0Hz,2H),2.96–2.86(m,2H),1.71(d,J=6.8Hz,3H),1.66(s,9H).

[0293] Synthesis of intermediate int4:

[0294] The synthetic route and experimental process are as follows:

[0295] 1. Synthesis of int4-1:

[0296] Compound int3-6 (9 g, 23.6 mmol) was dissolved in 200 ml of tetrahydrofuran, followed by the addition of R-tert-butylsulfenamide (5.7 g, 47.2 mmol) and tetraethyl titanate (21.5 g, 94.4 mmol). The mixture was stirred overnight at 70°C. After completion of the reaction, water was added, the mixture was filtered, and the filter cake was washed with ethyl acetate. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, concentrated, and subjected to column chromatography to obtain 10 g of the product.

[0297] 2. Synthesis of int4-2:

[0298] Dissolve compound int4-1 (10 g, 20.6 mmol) in 400 ml of methanol, then add cerium chloride heptahydrate (3.8 g, 10.3 mmol). After addition, sodium borohydride (1.17 g, 30.9 mmol) was added portionwise to the reaction system. The mixture was allowed to react at room temperature for 10 minutes. After completion of the reaction, the mixture was concentrated and purified by column chromatography to yield 8.87 g of the product.

[0299] 3. Synthesis of int4-3:

[0300] Dissolve compound int4-2 (12 g, 24.6 mmol) in 120 ml of methanol / hydrogen chloride solution and allow to react at room temperature for 10 min. After the reaction, spin dry the mixture, adjust the base with saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, dry, concentrate, and perform column chromatography to obtain 10 g of the product.

[0301] 4. Synthesis of int4-4:

[0302] Compound int4-3 (5 g, 13.1 mmol) was dissolved in 100 ml of dimethyl sulfoxide, and N,N-diisopropylethylamine (8.5 g, 65.5 mmol) was added. After addition, tert-butyl 6-chloro-3-fluoropyridine-2-carboxylate (18.1 g, 78.6 mmol) was added to the reaction system. The mixture was reacted at 70°C under nitrogen for 4 h. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The mixture was dried, concentrated, and purified by column chromatography to obtain 3.4 g of the product.

[0303] 5. Synthesis of int4:

[0304] Compound int4-4 (3.4 g, 5.72 mmol) was dissolved in 300 ml of 1,2-dichloroethane, and 1-chloroethyl chloroformate (1.63 g, 11.44 mmol) was added. After addition, the mixture was reacted at 83°C for 0.5 h. After completion of the reaction, the mixture was directly spin-dried to dryness. After spin-drying, 300 ml of methanol was added to dissolve the mixture. Triethylamine (2.3 g, 22.88 mmol) was immediately added. After addition, the mixture was reacted at 65°C for 2 h. After completion of the reaction, the mixture was concentrated and purified by column chromatography to obtain 2.3 g of the product.

[0305] Synthesis of intermediate int5:

[0306] The synthetic route and experimental process are as follows:

[0307] 1. Synthesis of int5-1:

[0308] Compound int4-3 (930 mg, 2.43 mmol) was dissolved in 40 ml of dry toluene. Tert-butyl o-iodobenzoate (888.1 mg, 2.92 mmol), cesium carbonate (2.14 g, 6.56 mmol), palladium acetate (54.5 mg, 0.25 mmol), and Xantphos (281 mg, 0.5 mmol) were added sequentially. The mixture was reacted at 60°C under nitrogen overnight. Filtered, the filter cake was washed with ethyl acetate, and then filtered through a column, dried, concentrated, and purified by column chromatography to yield 710 mg of the product.

[0309] 2. Synthesis of int5:

[0310] Compound int5-1 (710 mg, 1.27 mmol) was dissolved in 50 ml of 1,2-dichloroethane, and 1-chloroethyl chloroformate (365 mg, 2.54 mmol) was added. After addition, the mixture was reacted at 83°C for 1 h. After the reaction was completed, the mixture was directly dried by spin drying. After drying, 50 ml of methanol was added for dissolution. Triethylamine (600 mg, 5.08 mmol) was immediately added. After addition, the mixture was reacted at 65°C for 3 h. After the reaction was completed, the mixture was dried by spin drying, concentrated, and purified by column chromatography to obtain 710 mg of the product.

[0311] Synthesis of intermediate int6:

[0312] The synthetic route and experimental process are as follows:

[0313] 1. Synthesis of compound int6-2:

[0314] Compounds int6-1 (3.8 g, 20 mmol) and int6-0 (6 g, 20 mmol) were dissolved in 1,2-dichloroethane (20 mL). The solution was then added to a sealed tube containing 18 g of polyphosphoric acid and stirred at 85°C for 12 h. The reaction was allowed to cool to room temperature and the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, adjusted to alkaline, extracted three times with ethyl acetate, and dried by spin drying. The product was purified by column chromatography to obtain 1.7 g.

[0315] 1 HNMR: (CDCl3, 400Hz), δ8.90~8.88(m,1H), 7.94~7.92(m,1H), 7.39~7.28(m,5H), 3.75(s,2H), 3.68(s,2H), 2.84~2.80(m,4H).

[0316] 2. Synthesis of compound int6-3:

[0317] Compound int6-2 (1.2 g, 3.1 mmol), tributyl(1-ethoxyethylene)tin (1.57 g, 4.3 mmol), and Pd(PPh3)2Cl2 (200 mg, 0.31 mmol) were dissolved in dry dioxane (50 mL) and stirred at 80°C for 12 h. Potassium fluoride solution was then added at room temperature, stirred for 0.5 h, filtered, and the mother liquor was extracted three times with ethyl acetate. The organic phase was separated and dried by rotary evaporation. 10 ml of dioxane and concentrated hydrochloric acid (10 mL) were added, stirred at 25°C for 1 h. After completion of the reaction, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, dried by rotary evaporation, and purified by column chromatography to obtain 0.88 g of the product.

[0318] 1HNMR: (CDCl3, 400Hz), δ8.99~8.97(m,1H),7.87~7.85(m,1H),7.38~7.28(m,5H),3.75(s,2H),3.63(s,2H),2.84~2.80(m,7H).

[0319] 3. Synthesis of compound int6-4:

[0320] Compound int6-3 (465 mg, 13.3 mmol) was dissolved in 1,2-dichloroethane (10 mL). 1-Chloroethyl chloroformate (0.2 g, 26.5 mmol) was added under nitrogen at room temperature and stirred at 83°C for 2 h. After the reaction, the mixture was concentrated and used directly in the next step.

[0321] 4. Synthesis of compound int6-5

[0322] Compound int6-4 (650 mg crude product) was dissolved in methanol (10 mL) and reacted at 65°C under nitrogen for 1 h. After the reaction, the mixture was spin-dried and slurried with methyl tert-butyl ether to obtain 360 mg of the product.

[0323] 1 HNMR: (DMSO-d6, 400Hz) δ9.75(s,2H),9.03~9.01(m,1H),8.23~8.21(m,1H),4.22(s,2H),3.38~3.35(m,2H),2.87~2.84(m,2H),2.71(s,2H),.

[0324] 5. Synthesis of compound int6-6:

[0325] Compound int6-5 (150 mg, 0.5 mmol) was dissolved in dioxane / H₂O (3 mL / 1 mL). Sodium carbonate (160 mg, 1.5 mmol) and Fmoc-Cl (142 mg, 0.55 mmol) were added under nitrogen at 0°C. The temperature was slowly raised to room temperature and stirred for 12 h. After the reaction, saturated brine was added, and the mixture was extracted three times with dichloromethane. The mixture was then spin-dried and slurried to obtain 120 mg of the product.

[0326] 1 HNMR: (CDCl3, 400Hz), δ9.00~8.97(m,1H),7.95~7.94(m,1H),7.78~7.58(m,4H),7.4 0~7.36(m,4H),4.62~4.54(m,2H),4.42~4.28(m,2H),3.71~3.70(m,3H),2.86(s,3H), 2.77(s,2H).

[0327] 6. Synthesis of compound int6-7:

[0328] Compound int6-6 (120 mg, 0.25 mmol) was dissolved in methanol / dichloromethane (3 mL / 3 mL). Sodium borohydride (9.4 mg, 0.25 mmol) was added under nitrogen at room temperature and stirred at 25°C for 10 min. After completion of the reaction, the mixture was quenched with water, dried, and separated by column chromatography to yield 80 mg of the product.

[0329] 7. Synthesis of compound int6-8:

[0330] Compound int6-7 (80 mg, 0.165 mmol) was dissolved in dry dichloromethane (10 mL), and phosphorus tribromide (134 mg, 0.494 mmol) was added at room temperature under nitrogen protection, and stirred at 25°C for 12 h. The solution was concentrated and used directly in the next reaction.

[0331] 8. Synthesis of compound int6-9:

[0332] The compound int6-8 (180 mg crude product) was dissolved in dry N,N-dimethylformamide (1 mL) and added to a solution of tert-butyl 2-aminobenzoate (191 mg, 0.989 mmol) in N,N-dimethylformamide (2 mL) at 25°C. The mixture was stirred at 60°C for 12 h. After the reaction was completed, saturated brine was added, and the mixture was extracted three times with ethyl acetate. The mixture was concentrated and separated by column chromatography to obtain 15 mg of the product.

[0333] 9. Synthesis of compound int6:

[0334] Compound int6-9 (15 mg, 0.223 mmol) was dissolved in dry dichloromethane (5 mL) and diethylamine (0.5 mL) and stirred at room temperature under nitrogen for 12 h. After the reaction was complete, 6 mg of the product was isolated by column chromatography.

[0335] 1 HNMR: (CDCl3, 400Hz) δ8.82~8.80(m,1H),8.33~8.30(m,1H),7.92~7.90(m,1H),7.65~7.63(m,1H),7.16~7.12(m, 1H),6.61~6.57(m,1H),6.21~6.19(m,1H),5.44~5.32(m,2H),3.38~3.36(m,2H),3.00~2.91(m,4H),1.65(s,9H).

[0336] Synthesis of intermediate int7:

[0337] The synthetic route and experimental process are as follows:

[0338] 1. Synthesis of compound int7-2:

[0339] Compound int7-1 (4.48 g, 24 mmol) was dissolved in 60 mL of N,N-dimethylformamide. 3-Chloro-4-cyanopyridine (2.78 g, 20 mmol) and cesium carbonate (13 g, 40 mmol) were added. The mixture was heated to 110°C and allowed to react for 3 h until the reaction was complete. Water was slowly added to quench the reaction, followed by extraction with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by column chromatography to yield 4.5 g of the product.

[0340] 1 H NMR (400MHz, Chloroform-d) δ8.47(d,J=4.8Hz,1H),8.12(s,1H),7.56~7.52(m,2H),7.23~7.20(m,1H),7.11~7.09(m,1H),2.41(s,3H),

[0341] 2. Synthesis of compound int7-3:

[0342] Int7-2 (4.5 g, 15.5 mmol) was dissolved in 40 g of polyphosphoric acid and the temperature was slowly raised to 220°C with stirring for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and dissolved in water. The base was adjusted with saturated sodium bicarbonate aqueous solution, and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by pulping to obtain 3.5 g of the product.

[0343] 1 H NMR (400MHz, Chloroform-d) δ9.17(s,1H),8.71(d,J=5.1Hz,1H),8.12(s,1H),8.03(d,J=5.2Hz,1H),7.99(s,1H).

[0344] 3. Synthesis of compound int7-4:

[0345] Int7-3 (2.5 g, 8.6 mmol), potassium iodide (3.15 g, 19 mmol), and benzyl chloride (2.7 g, 17.2 mmol) were added to 40 mL of acetonitrile. The reaction mixture was slowly heated to 80°C and stirred for 2 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to yield 8.2 g of crude product, which was used directly in the next step.

[0346] 4. Synthesis of compound int7-5:

[0347] Compound int7-4 (8.2 g, 20 mmol) was dissolved in 200 mL of anhydrous ethanol, and sodium cyanoborohydride (10.8 g, 160 mmol) and acetic acid (1.2 g, 20 mmol) were added. The mixture was stirred at room temperature for 30 min. After the reaction of the raw materials was complete, the reaction solution was diluted with water and then extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 3.8 g of product.

[0348] 5. Synthesis of compound int7-6:

[0349] Compound int7-5 (3 g, 7.24 mmol), tributyl(1-ethoxyethylene)tin (3.14 g, 8.7 mmol), and Pd(PPh3)2Cl2 (510 mg, 0.724 mmol) were dissolved in dry dioxane (50 mL) and stirred at 80°C for 12 h. Potassium fluoride solution was then added at room temperature, stirred for 0.5 h, filtered, and the mother liquor was extracted three times with ethyl acetate. The organic phase was separated, dried, and dissolved in dichloromethane. 2 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 25°C for 10 min. After completion of the reaction, 2.5 g of the product was obtained by column chromatography.

[0350] 1 H NMR(400MHz,Chloroform-d)δ8.20(s,1H),7.91(s,1H),7.32(d,J=8.4Hz,2H),6.93(d,J=8.4Hz ,2H), 3.84(s,3H),3.71(s,2H),3.54(s,2H),2.79~2.77(m,2H),2.71~2.68(m,5H),2.48(s,3H).

[0351] 6. Synthesis of compound int7-7:

[0352] Compound int7-6 (2.5 g, 6.63 mmol) was dissolved in a mixed solvent consisting of 30 mL of dichloromethane and 30 mL of methanol. Under nitrogen, sodium borohydride (251 mg, 6.63 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 10 minutes. After the reaction of the starting materials was complete, the reaction mixture was diluted with water and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 1.5 g of the product.

[0353] 1H NMR (400MHz, Chloroform-d) δ7.90 (s, 1H), 7.61 (s, 1H), 7.34 (d, J = 8.4Hz, 2H), 6.94 (d, J = 8.4Hz, 2H), 5.35 ~ 5. 32(m,1H),3.85(s,3H),3.71~3.68(m,2H),3.43(s,2H),2.78~2.68(m,4H),2.44(s,3H),1.27(d,J=6.4Hz,2H).

[0354] 7. Synthesis of compound int7-8:

[0355] Compound int7-7 (1.5 g, 3.95 mmol) was dissolved in 50 mL of anhydrous dichloromethane. Under nitrogen protection, phosphorus tribromide (3.21 g, 11.9 mmol) was slowly added and stirred at room temperature for 12 h. After the raw materials reacted completely, the mixture was concentrated under reduced pressure to obtain 3.5 g of product.

[0356] 8. Synthesis of compound int7-9:

[0357] Compound int7-8 (3.5 g, 3.95 mmol) was dissolved in 100 mL of anhydrous N,N-dimethylformamide. At room temperature, tert-butyl 2-aminobenzoate (4.57 g, 23.7 mmol) was slowly added. The temperature was slowly raised to 60°C and stirred for 12 hours. After the reaction of the raw materials was complete, the reaction solution was diluted with water and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 1.1 g of the product.

[0358] 9. Synthesis of compound int7:

[0359] Compound int7-9 (90 mg, 1.65 mmol) was dissolved in 5 mL of 1,2-dichloroethane. 1-Chloroethyl chloroformate (47.1 mg, 3.3 mmol) was slowly added at room temperature. The temperature was slowly raised to 83 ° C. and stirred for 3 h. After the raw materials reacted completely, the reaction solution was concentrated and methanol was added. The temperature was raised to 65 ° C. and stirred for 1 h. Then it was concentrated and slurried with methyl tert-butyl ether to obtain 51 mg of product.

[0360] Synthesis of intermediate int8:

[0361] The synthetic route and experimental process are as follows:

[0362] 1. Synthesis of int-8-1:

[0363] Dissolve int7-8 (260 mg, 0.59 mmol) in N,N-dimethylformamide (5 ml), add 3-amino-6-chloropyridine-2-carboxylic acid (507.0 mg, 2.95 mmol), and react at 80°C for 16 h. The reaction is complete. The reaction mixture is diluted with ethyl acetate, made alkaline with sodium bicarbonate solution, and washed three times with saturated ammonium chloride. The organic phase is dried, concentrated, and purified by column chromatography to yield 90 mg of the product.

[0364] 2. Synthesis of int8:

[0365] Dissolve int8-1 (90 mg, 0.17 mmol) in 1,2-dichloroethane (4 ml), add 1-chloroethyl chloroformate (72.5 mg, 0.51 mmol), and react at 83°C for 3 h. After the reaction is complete, the reaction solution is dried by rotary evaporation, methanol is added, and the reaction is continued at 65°C for 1 h. The reaction solution is concentrated to yield 70 mg of the product.

[0366] Synthesis of intermediate int9:

[0367] The synthetic route and experimental process are as follows:

[0368] 1. Synthesis of int9-1:

[0369] Compound int7-6 (10 g) was dissolved in 210 ml of tetrahydrofuran, followed by the addition of R-tert-butylsulfenamide (6.0 g) and tetraethyl titanate (22.3 g). The mixture was stirred at 70°C overnight. After completion of the reaction, water was added, the mixture was filtered, and the filter cake was washed with ethyl acetate. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, concentrated, and subjected to column chromatography to obtain 11.2 g of the product.

[0370] 2. Synthesis of int9-2:

[0371] Compound int9-1 (11.2 g) was dissolved in 400 ml of methanol, followed by the addition of cerium chloride heptahydrate (3.9 g). After addition, sodium borohydride (1.3 g) was added portionwise to the reaction system and allowed to react at room temperature for 10 min. After completion of the reaction, the mixture was concentrated and purified by column chromatography to yield 9.1 g of the product.

[0372] 3. Synthesis of int9-3:

[0373] Compound int9-2 (9.1 g) was dissolved in 120 ml of methanol / hydrogen chloride solution and reacted at room temperature for 10 min. After the reaction, the mixture was directly dried, alkali-adjusted with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried, concentrated, and subjected to column chromatography to obtain 7.2 g of the product.

[0374] 4. Synthesis of int9-4:

[0375] Compound int9-3 (7.0 g) was dissolved in 100 ml of dimethyl sulfoxide, and N,N-diisopropylethylamine (9.3 g) was added. After addition, tert-butyl 6-chloro-3-fluoropyridine-2-carboxylate (20.1 g) was added to the reaction system. The reaction was carried out at 70°C under nitrogen for 4 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The mixture was dried, concentrated, and subjected to column chromatography to obtain 4.3 g of the product.

[0376] 5. Synthesis of int9:

[0377] Compound int9-4 (4.3 g) was dissolved in 300 ml of 1,2-dichloroethane, and 1-chloroethyl chloroformate (2.33 g) was added. After addition, the mixture was reacted at 85°C for 0.5 h. After the reaction was complete, the mixture was directly spin-dried to dryness. After spin-drying, 300 ml of methanol was added to dissolve the mixture. Triethylamine (3.5 g) was immediately added. After addition, the mixture was reacted at 65°C for 2 h. After completion of the reaction, the mixture was concentrated and purified by column chromatography to obtain 3.1 g of the product.

[0378] Synthesis of intermediate int10:

[0379] The synthetic route and experimental process are as follows:

[0380] 1. Synthesis of int10-1:

[0381] Compound int9-3 (3.78 g) was dissolved in 150 ml of dry toluene. Tert-butyl o-iodobenzoate (3.34 g), cesium carbonate (8.14 g), palladium acetate (216.5 mg), and Xantphos (964 mg) were added sequentially. The mixture was reacted at 60°C under nitrogen overnight. Filtered, the filter cake was washed with ethyl acetate, and then filtered through a column, dried, concentrated, and purified by column chromatography to yield 2.84 g of the product.

[0382] 2. Synthesis of int10:

[0383] Compound int10-1 (2.84 g) was dissolved in 150 ml of 1,2-dichloroethane, and 1-chloroethyl chloroformate (1.46 g) was added. After addition, the mixture was reacted at 85°C for 1 h. After the reaction was completed, the mixture was directly spin-dried to dryness. After spin-dried to dryness, 150 ml of methanol was added for dissolution. Triethylamine (2.43 g) was immediately added. After addition, the mixture was reacted at 65°C for 3 h. After the reaction was completed, the mixture was spin-dried to dryness, concentrated, and subjected to column chromatography to obtain 1.78 g of the product.

[0384] Synthesis of intermediate int11:

[0385] The synthetic route and experimental process are as follows:

[0386] 1. Synthesis of int11-2

[0387] Int11-1 (800 mg) was dissolved in 1,4-dioxane (25 mL). Benzyl mercaptan (500 mg), N,N-diisopropylethylamine (2.1 mL), Xantphos (465 mg), and Pd2(dba)3 (368 mg) were added sequentially at room temperature. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 18 hours. The starting materials reacted completely. A small amount of ethyl acetate was added to the reaction mixture, which was then concentrated under reduced pressure and purified by column chromatography to yield 603 mg of the product.

[0388] 2. Synthesis of int11

[0389] Int11-2 (603 mg) was dissolved in a mixed solvent of acetonitrile (9 mL) and water (1 mL). Trifluoroacetic acid (7.79 g) and N-chlorosuccinimide (667 mg) were added under an ice-water bath and the mixture was stirred at room temperature for 18 h. N-chlorosuccinimide (667 mg) was added the next day and the mixture was stirred at room temperature for 4 h. The reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to alkaline. The aqueous phase was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 588 mg of crude product, which was used directly in the next reaction.

[0390] Synthesis of intermediate int12:

[0391] The synthetic route and experimental process are as follows:

[0392] 1. Synthesis of int12-2

[0393] Int6-0 (10 g, 53.47 mmol) and int12-1 (10 g, 53.47 mmol), polyphosphoric acid (25 mL), and 1,2-dichloroethane (50 mL) were added to a 250 mL single-necked flask and stirred at 85°C for 16 h. The reaction mixture was then cooled to room temperature. The pH was adjusted to 8 with saturated sodium carbonate solution and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 3.5 g of the product.

[0394] 2. Synthesis of int12-3

[0395] Compound int12-2 (7 g, 18.3 mmol), tributyl(1-ethoxyethylene)tin (7.9 g, 21.9 mmol), and Pd(PPh3)2Cl2 (1.26 g, 1.83 mmol) were dissolved in dry dioxane (70 ml) and stirred at 80°C for 12 h. Then, 70 ml of potassium fluoride solution was added at room temperature, stirred for 0.5 h, filtered, and the mother liquor was extracted with ethyl acetate (50 ml*3). The organic phase was separated, dried, and dissolved in ethyl acetate (70 ml). 6 M hydrochloric acid (130 ml) was added and stirred at 25°C for 10 min. A large amount of solid precipitated. The filter cake was washed with ethyl acetate (100 ml*2), the pH was adjusted to neutral with saturated sodium bicarbonate, extracted with dichloromethane (70 ml*2), dried, concentrated, and purified by column chromatography to obtain 3.9 g of the product.

[0396] 3. Synthesis of int12-4:

[0397] Compound int12-3 (3.8 g, 10.95 mmol) was dissolved in 38 mL of tetrahydrofuran. Under nitrogen, R-tert-butylsulfenamide (2.65 g, 21.9 mmol) and tetraethyl titanate (9.98 g, 43.8 mmol) were added. The mixture was reacted at 70°C under nitrogen for 16 h. After the reaction was complete, 38 mL of water was added to the reaction solution, followed by extraction with ethyl acetate (60 mL x 4). The combined organic phases were washed with saturated sodium chloride (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 4.64 g of a crude product.

[0398] 4. Synthesis of int12-5:

[0399] Compound int12-4 (4.64 g, 10.3 mmol) was dissolved in 70 mL of methanol. Under nitrogen protection, cerium chloride heptahydrate (1.92 g, 5.16 mmol) was added. The temperature was raised to 50 ° C and stirred for 30 min under nitrogen protection. The temperature was lowered to 15 ° C and sodium borohydride (0.58 g, 15.5 mmol) was added in batches. After the addition, the temperature was kept at 15 ° C for 30 min. After the raw materials reacted completely, dichloromethane (140 ml) and water (70 ml) were added to the reaction solution. After the layers were separated, the aqueous phase was extracted with dichloromethane (60 ml), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 3 g of the product.

[0400] 5. Synthesis of int12:

[0401] Compound int12-5 (3 g) was dissolved in 15 ml of ethanol and, under nitrogen, 2 M HCl (30 ml) was added and reacted at 30°C for 30 min. After the reaction was complete, the reaction solution was concentrated, 500 ml of dichloromethane was added, and the mixture was adjusted to neutrality with saturated sodium bicarbonate. The aqueous phase was extracted once with dichloromethane (20 ml). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2.1 g of the product.

[0402] Synthesis of intermediate int13:

[0403] The synthetic route and experimental process are as follows:

[0404] 1. Synthesis of int13-1:

[0405] Compound int6-3 (4.2 g, 11.93 mmol) was dissolved in 50 mL of tetrahydrofuran, and R-tert-butylsulfenamide (2.88 g, 23.80 mmol) and tetraethyl titanate (10.8 g, 47.37 mmol) were added. The mixture was allowed to react at 70°C for 4 h. After the reaction was complete, 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 4). The organic phases were combined, washed with saturated sodium chloride (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 4 g of the product.

[0406] 2. Synthesis of int13-2:

[0407] Compound int13-1 (4 g, 8.79 mmol) was dissolved in 60 mL of methanol. Under nitrogen, cerium chloride heptahydrate (1.64 g, 4.4 mmol) was added. The mixture was heated to 50°C and stirred for 30 min. The temperature was then lowered to 15°C and sodium borohydride (0.50 g, 13.2 mmol) was added portionwise. After addition, the mixture was maintained at 15°C for 30 min. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain 2.8 g of the product.

[0408] 3. Synthesis of int13:

[0409] Compound int13-2 (2.8 g, 6.13 mmol) was added to 2M HCl (30 ml) and reacted at room temperature for 10 min. After the reaction was complete, the mixture was concentrated and ethyl acetate (50 ml) was added to the reaction solution. The pH was adjusted to alkaline with saturated sodium bicarbonate. The layers were separated and the aqueous phase was extracted once with ethyl acetate (20 ml). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 2 g of the product.

[0410] Synthesis of intermediate int14:

[0411] The synthetic route and experimental process are as follows:

[0412] 1. Synthesis of int14-1:

[0413] Compound int12-3 (3.47 g, 10 mmol) was dissolved in 50 mL of tetrahydrofuran, and R-tert-butylsulfenamide (2.42 g, 20 mmol) and tetraethyl titanate (9.12 g, 40 mmol) were added. The mixture was reacted at 70°C for 4 h. After the reaction was complete, 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml x 4). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 4.1 g of the product.

[0414] 2. Synthesis of int14-2:

[0415] Compound int14-1 (4.1 g, 9.1 mmol) was dissolved in 80 ml of methanol. Under nitrogen, cerium chloride heptahydrate (1.65 g, 4.4 mmol) was added. The mixture was heated to 50°C and stirred for 30 minutes. The temperature was then lowered to 15°C and sodium borohydride (0.55 g) was added portionwise. After addition, the mixture was incubated at 15°C for 30 minutes. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain 2.73 g of the product.

[0416] 3. Synthesis of int14:

[0417] Compound int14-2 (2.73 g, 6.0 mmol) was added to 2M HCl (30 ml) and reacted at room temperature for 10 min. After the reaction was complete, the mixture was concentrated and ethyl acetate (50 ml) was added to the reaction solution. The pH was adjusted to alkaline with saturated sodium bicarbonate. The layers were separated and the aqueous phase was extracted once with ethyl acetate (20 ml). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 2.08 g of the product.

[0418] Synthesis of intermediate int15:

[0419] The synthetic route and experimental process are as follows:

[0420] 1. Synthesis of int15-1

[0421] Dissolve int12-1 (5.0 g, 26.88 mmol) and triethyl 1,1,2-ethanetricarboxylate (6.61 g, 26.88 mmol) in toluene (100 ml), heat to 110°C, and stir for 24 h. The reaction is complete. The reaction mixture is cooled to room temperature, and the solid is washed with cold ethanol to obtain 3.6 g of crude product, Ms[M+H] + :341.0.

[0422] 2. Synthesis of int15-2

[0423] Dissolve int15-1 (3.5 g, 10.29 mmol) in phosphorus oxychloride (50 mL) and heat to 120°C for overnight reaction. Slowly pour the reaction solution into water to quench the reaction, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography to obtain 1.81 g of the product, Ms[M+H] + :359.0.

[0424] 3. Synthesis of int15-3

[0425] Dissolve int15-2 (1.7 g, 4.74 mmol) in tetrahydrofuran (35 mL), add 4-methoxybenzylamine (0.58 g, 5.69 mmol), cool to 0°C, add potassium tert-butoxide (0.80 g, 7.12 mmol) in portions, and after addition, warm to room temperature and stir for 3 h. The raw materials react completely. Water is added to the reaction system at low temperature, and the reaction solution is extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.3 g of the product, Ms[M+H] + :414.0.

[0426] 4. Synthesis of int15-4

[0427] Compound int15-3 (1.3 g, 3.14 mmol) was dissolved in tetrahydrofuran (25 mL), and borane tetrahydrofuran complex (3.77 ml, 3.77 mmol) was added dropwise. The temperature was raised to 60°C and the reaction was allowed to proceed for 1 h. The reaction was complete. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, 0.74 g of the product was obtained, with Ms[M+H] + :400.1.

[0428] 5. Synthesis of int15-5

[0429] Compound int15-4 (0.74 g, 1.85 mmol) and tributyl(1-ethoxyethylene)tin (1.08 g, 2.23 mmol) and Pd(PPh3)2Cl2 (0.14 g, 0.19 mmol) were dissolved in dry dioxane (70 ml) and stirred at 80°C for 12 h. Then, 30 ml of potassium fluoride solution was added at room temperature, stirred for 0.5 h, filtered, and the mother liquor was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was dissolved in ethyl acetate (50 ml) and 6 M hydrochloric acid (80 ml) was added. The product was stirred at 25°C for 10 min, filtered, and the filter cake was washed with ethyl acetate. The filtrate was adjusted to neutral pH with saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 0.55 g of the product, Ms[M+H] + :364.2.

[0430] 6. Synthesis of int15-6:

[0431] Compound int15-5 (0.55 g, 1.51 mmol) was dissolved in 20 mL of tetrahydrofuran. Under nitrogen protection, R-tert-butylsulfenamide (0.37 g, 3.02 mmol) and tetraethyl titanate (1.38 g 6.04 mmol) were added. The mixture was reacted at 70°C under nitrogen protection for 16 h. After the reaction of the raw materials was complete, 20 mL of water was added to the reaction solution, and then extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.47 g of crude product, Ms[M+H] + :467.2.

[0432] 7. Synthesis of int15-7:

[0433] Compound int15-64 (0.47 g, 1.18 mmol) was dissolved in 20 mL of methanol. Under nitrogen protection, cerium chloride heptahydrate (1.92 g, 0.59 mmol) was added. The temperature was raised to 50 ° C and stirred for 30 min under nitrogen protection. The temperature was lowered to 15 ° C and sodium borohydride (0.06 g, 1.77 mmol) was added in batches. After the addition, the temperature was kept at 15 ° C for 30 min. After the raw material reaction was complete, dichloromethane and water were added to the reaction solution, and the liquid was extracted. The aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.28 g of the product, Ms [M + H] + :469.2.

[0434] 8. Synthesis of int15-8:

[0435] Compound int15-7 (0.28 g, 0.60 mmol) was dissolved in 5 ml of dichloromethane. Under nitrogen protection, 2 M hydrogen chloride / ethanol solution (2 mL) was added and the mixture was allowed to react at room temperature for 30 min. After the reaction of the raw materials was complete, the reaction solution was concentrated, dichloromethane was added, and the mixture was adjusted to neutral with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.2 g of the product, Ms[M+H] + :365.2.

[0436] 9. Synthesis of int15-9:

[0437] Compound int15-8 (0.2 g, 0.55 mmol) and tert-butyl 2-bromobenzoate (0.17 g, 0.66 mmol), palladium acetate (12 mg, 0.055 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.11 mmol) and cesium carbonate (0.48 g, 1.48 mmol) were dissolved in dry toluene (10 mL) and stirred at 100°C for 2 h. After the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate, and the organic phase was dried and purified by column chromatography to obtain 0.26 g of the product, Ms[M+H] + :541.3.

[0438] 10. Synthesis of int15:

[0439] Compound int15-9 (0.26 g, 0.48 mmol) was dissolved in 10 ml of 1,2-dichloroethane, and 1-chloroethyl chloroformate (0.14 g, 0.96 mmol) was added. After the addition was complete, the mixture was reacted at 80°C for 1 h. After the reaction was complete, the mixture was concentrated, 20 ml of methanol was added for dissolution, and triethylamine (0.19 g, 1.92 mmol) was added. After the addition was complete, the mixture was reacted at 65°C for 3 h. After the reaction was complete, the mixture was concentrated and purified by column chromatography to obtain 0.15 g of the product, Ms[M+H] + :421.2.

[0440] Synthesis of intermediate int16:

[0441] The synthetic route and experimental process are as follows:

[0442] 1. Synthesis of compound int16-2

[0443] Int16-1 (5.0 g, 34.2 mmol), methyl 2-(benzylamino)acetate (6.74 g, 37.7 mmol) and N,N-diisopropylethylamine (17.9 mL, 102.6 mmol) were dissolved in 60 mL of anhydrous N,N-dimethylformamide. Under an ice bath, O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (19.5 g, 51.3 mmol) was added in batches. The mixture was heated to room temperature for half an hour. After the reaction of the raw materials was complete, water was added under an ice bath. The aqueous phase was extracted with ethyl acetate. The organic phases were combined and washed several times with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 11.5 g of the product, [M+H] + :308.

[0444] 2. Synthesis of compound int16-3

[0445] Int16-2 (5.0 g, 16.29 mmol) was dissolved in 60 mL of anhydrous tetrahydrofuran. Lithium bis(trimethylsilyl)amide (33 mL, 33 mmol) was slowly added dropwise under a nitrogen atmosphere and ice bath. The temperature was naturally raised to room temperature and the reaction was carried out for 4 hours. After the reaction of the raw materials was complete, saturated aqueous ammonium chloride solution was added under ice bath. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by column chromatography to obtain 2.18 g, [M+H] + :276.

[0446] 3. Synthesis of compound int16-4

[0447] Int16-3 (1.0 g, 3.64 mmol), 2-amino-3-bromo-5-methylpyridine (680 mg, 3.64 mmol), and 4-methylbenzenesulfonic acid pyridine (1.10 g, 4.37 mmol) were added to a 50 ml single-mouth glass jar and stirred at 120 ° C for 16 hours. The reaction mixture was cooled to room temperature. The pH was adjusted to alkaline with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography to obtain 878 mg of the product, [M+H] + :412 / 414.

[0448] 4. Synthesis of compound int16-5

[0449] Compound int16-4 (878 mg, 2.14 mmol) and tributyl (1-ethoxyethylene) tin (1.16 g, 3.20 mmol), Pd (PPh 3) 2 Cl 2 (150 mg, 0.21 mmol) were dissolved in dry dioxane (15 mL) and stirred at 85 ° C for 2 h. Then, 15 mL of potassium fluoride solution was added at room temperature, stirred for 0.5 h, filtered, and the reaction solution was extracted with ethyl acetate. The organic phase was separated, dried, and then redissolved with 5 mL of ethyl acetate. 1 ml of 6M hydrochloric acid was added and stirred at 25 ° C for 10 min. After the reaction was completed, the aqueous phase was extracted with ethyl acetate. The aqueous phase was then adjusted to neutral with saturated sodium bicarbonate and extracted with ethyl acetate. After drying and concentration, 500 mg of the product was obtained by column chromatography. [M+H] + :376.

[0450] 3. Synthesis of compound int16-6:

[0451] Compound int16-5 (500 mg, 1.33 mmol) was dissolved in 20 mL of tetrahydrofuran, and R-tert-butylsulfenamide (323 mg, 2.67 mmol) and tetraethyl titanate (1.21 g, 5.32 mmol) were added. The reaction solution was reacted at 70°C for 18 h. After the reaction of the raw materials was complete, 5 mL of water was added to the reaction solution, and then filtered. The filter cake was washed several times with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed to obtain 460 mg of the product, [M+H] + :479.

[0452] 4. Synthesis of compound int16-7:

[0453] Compound int16-6 (460 mg, 0.96 mmol) was dissolved in 10 mL of methanol. Under nitrogen protection, cerium chloride heptahydrate (179 mg, 0.48 mmol) was added. Under nitrogen protection, sodium borohydride (54 mg 1.44 mmol) was added in batches under ice bath and then reacted for 30 min. After the reaction of the raw materials was complete, the mixture was directly concentrated under reduced pressure and purified by column chromatography to obtain 286 mg of the product, [M+H] + :481.

[0454] 5. Synthesis of compound int16:

[0455] Compound int16-7 (286 mg, 0.59 mmol) was dissolved in dichloromethane, and a 2M hydrogen chloride / ethanol solution (2 mL) was added, followed by reaction at room temperature for 10 min. After the reaction was complete, the ethanol was removed by vortexing, and the reaction solution was redissolved in ethyl acetate and adjusted to alkalinity with saturated sodium bicarbonate. The aqueous phase was separated, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 220 mg of the product, [M+H] + :377.

[0456] Synthesis of intermediate int17:

[0457] The synthetic route and experimental process are as follows:

[0458] 1. Synthesis of int17-2

[0459] Dissolve int17-1 (16.34 g, 83.80 mmol), benzylglycine tert-butyl ester (10 g, 55.87 mmol), and triethylamine (8.46 g, 83.80 mmol) in acetonitrile (200 mL) and react at 80°C overnight. Cool the reaction mixture to room temperature, concentrate, and purify by column chromatography to obtain 11.4 g of the product. [M+H] + :294.

[0460] 2. Synthesis of int17-3

[0461] Dissolve int17-2 (11.4 g, 38.91 mmol) in ultra-dry tetrahydrofuran (300 mL), cool to -30°C, and slowly add lithium bistrimethylsilylamide (97.28 mL, 97.28 mmol) dropwise. The reaction mixture is slowly heated to 5°C and stirred until the starting material disappears. The reaction is quenched by adding aqueous ammonium chloride in an ice bath. The aqueous phase is extracted with ethyl acetate, and the organic phase is dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography yields 950 mg of the product. [M+H] + :262.

[0462] 1 H NMR(400MHz,DMSO)δppm 7.39-7.30(m,4H),7.30-7.24(m,1H),3.90(d,J=6.0Hz,1H),3.67(s,2H),3.63(s,3H),3.3 1-3.24(m,2H),2.63-2.55(m,1H),2.50-2.43(m,1H),1.97-1.81(m,2H),1.73-1.51(m,2H).

[0463] 3. Synthesis of int17-4

[0464] Int17-3 (950 mg, 3.64 mmol), 2-amino-3-bromo-5-methylpyridine (680 mg, 3.64 mmol) and 4-methylbenzenesulfonic acid pyridine (1.10 g, 4.37 mmol) were stirred at 120 ° C for 16 hours, and the reaction solution was cooled to room temperature. After adjusting the pH to alkaline with saturated sodium bicarbonate solution, the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography to obtain 380 mg of the product, [M+H] + :398 / 400.

[0465] 1 H NMR(400MHz,DMSO-d6)δppm 8.27-8.23(m,1H),8.01-7.96(m,1H),7.43-7.36(m,2H),7.33-7.26(m,3H),4.52(s,2H), 4.41(s,2H),3.21(t,J=5.6Hz,2H),2.30(s,3H),2.14(t,J=6.0Hz,2H),1.88-1.72(m,2H).

[0466] 4. Synthesis of int17-5

[0467] Compound int17-4 (380 mg, 0.96 mmol), tributyl (1-ethoxyethylene) tin (415 mg, 1.15 mmol) and Pd (PPh 3 ) 2 Cl 2 (150 mg, 0.09 mmol) were dissolved in dry dioxane (15 mL) and stirred at 90 ° C for 16 h. Then, 15 mL of potassium fluoride solution was added at room temperature, stirred for 0.5 h, filtered, and the reaction solution was extracted with ethyl acetate. The organic phase was separated, concentrated, redissolved with 5 mL of ethyl acetate, and 6 M hydrochloric acid (1 ml) was added. Stirred for 10 min at 25 ° C. After the reaction was completed, the aqueous phase was extracted with ethyl acetate. The aqueous phase was then adjusted to neutral with saturated sodium bicarbonate, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography to obtain 250 mg of the product, [M+H] + :362.

[0468] 5. Synthesis of int17-6

[0469] Compound int17-5 (250 mg, 0.69 mmol) was dissolved in 20 mL of tetrahydrofuran, and R-tert-butylsulfenamide (167 mg, 1.38 mmol) and tetraethyl titanate (629 mg, 2.76 mmol) were added. The reaction solution was reacted at 75°C for 18 hours. After the reaction of the raw materials was complete, 5 mL of water was added to the reaction solution, and then filtered. The filter cake was washed several times with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, 200 mg of the product was obtained, [M+H] + :465.

[0470] 6. Synthesis of int17-7

[0471] Compound int17-6 (200 mg, 0.43 mmol) was dissolved in 10 mL of methanol. Under nitrogen protection, cerium chloride heptahydrate (82 mg, 0.22 mmol) was added. Under nitrogen protection, sodium borohydride (25 mg, 0.65 mmol) was added in batches under ice bath and reacted for 30 min. After the reaction of the raw materials was complete, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain 120 mg of the product, [M+H] + :467.

[0472] 7. Synthesis of int17

[0473] Compound int17-7 (120 mg, 0.26 mmol) was dissolved in dichloromethane, and 2M HCl / EtOH (2 mL) was added. The mixture was then allowed to react at room temperature for 10 min. After the reaction was complete, the ethanol was removed by vortexing. The reaction solution was redissolved in ethyl acetate and adjusted to alkalinity with saturated sodium bicarbonate. The aqueous phase was separated, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography afforded 80 mg of the product, [M+H] + :363.

[0474] Example 1

[0475] Compounds of the present invention

[0476] The synthetic route and experimental process are as follows:

[0477] 1. Synthesis of Compound C1-1:

[0478] Int1 (2.2 g), dry N,N-dimethylformamide (60 mL), and tert-butyl anthranilate (2.9 g, 6 eq) were added to a 100 mL three-necked flask and reacted at 80°C under nitrogen for 8 h. After completion of the reaction, saturated ammonium chloride was added, and the mixture was extracted with ethyl acetate. The mixture was then dried and concentrated to yield 1.7 g of a crude product.

[0479] 2. Synthesis of Compound C1-2

[0480] To a 100 mL three-necked flask, add C1-1 (1.7 g, 1.0 eq), diethylamine (5 ml), and dichloromethane (50 ml). The mixture was reacted at room temperature under nitrogen for 8 h. After completion of the reaction, the product was washed with saturated aqueous ammonium chloride, extracted with dichloromethane, concentrated, and purified by column chromatography to obtain 258 mg of the product.

[0481] 1 H 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).

[0482] 3. Synthesis of Compound C1-3

[0483] To a 20 mL sealed vial was added 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), and toluene (5 ml). The mixture was reacted at 100°C for 0.5 h. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography to yield 60 mg of the product.

[0484] 4. Synthesis of Compound C1-4

[0485] 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 complete, the mixture was concentrated and purified by TLC plate to obtain 72 mg of the product.

[0486] 5. Synthesis of Compounds C1 and C2

[0487] Compound C1-4 was separated by chiral preparative chromatography using the following chiral separation conditions: instrument: Agilent 1260 Infinity II, column: phenomenex 5μm Amylose-1 (250×21.2mm), mobile phase: n-hexane: isopropanol = 7:3, column temperature: 25℃. Separation:

[0488] C1 (peak time 8.2 min, 9.54 mg) 1 H 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),

[0489] C2 (peak time 16.2 min, 2 mg) 1H 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).

[0490] Example 2

[0491] Compounds of the present invention

[0492] The synthetic route and experimental process are as follows:

[0493] 1. Synthesis of compound C3-1:

[0494] Compound C1-2 (100 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane. Potassium carbonate (95 mg, 0.69 mmol) and methyl chloroformate (28 mg, 0.3 mmol) were added under ice-water cooling and stirred at room temperature for 2 h. The reaction was completed. Saturated brine was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed three times with saturated brine, dried, and spin-dried. Purification by column chromatography gave 46 mg of the product.

[0495] 2. Synthesis of compound C3-2:

[0496] Compound C3-1 (46 mg, 0.09 mmol) was dissolved in dichloromethane (4 mL) / trifluoroacetic acid (2 mL) and stirred at 23°C under nitrogen for 12 h. After the reaction was complete, the mixture was dried to give 35 mg of the product.

[0497] 3. Synthesis of compounds C3 and C4:

[0498] Compound C3-2 (35 mg, 0.08 mmol) was isolated using the following resolution method:

[0499] 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:

[0500] C3 (6.5 min, 15 mg) [M+H] + :441.2

[0501] C4 (8.8 min, 10 mg) [M+H] + :441.2

[0502] Example 3

[0503] Compounds of the present invention

[0504] The synthetic route and experimental process are as follows:

[0505] 1. Synthesis of compound C5-1:

[0506] Compound C1-2 (100 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane. Potassium carbonate (96 mg, 0.69 mmol) was added and stirred for 10 minutes. Isobutyl acyl chloride (30 mg, 0.27 mmol) was then added and the mixture was stirred at room temperature for 3 hours. The reaction was complete. Filter, spin dry, and purify by column chromatography to obtain 40 mg of the product. [M+H] + :509.0

[0507] 2. Synthesis of compound C5-2:

[0508] Compound C5-1 (40 mg, 0.08 mmol) was dissolved in dichloromethane (3 mL) / trifluoroacetic acid (1.5 mL) and stirred at 25°C for 16 h. After the reaction was complete, the product was dried to give 25 mg.

[0509] 3. Synthesis of compounds C5 and C6:

[0510] Compound C5-2 (25 mg, 0.06 mmol) was isolated using the following resolution method:

[0511] Instrument: Agilent 1260 Infinity II, chromatographic column: phenomenex 5μm Amylose-1 (250×21.2mm), mobile phase: n-hexane:ethanol = 4:6, column temperature: 25°C. Separation:

[0512] C5 (5.8 min, 8.7 mg) [M+H] + :453.3 1H NMR (400MHz, DMSO-d6) δ12.73(s,1H),8.47(d,J=6.3Hz,1H),7.80(dd,J=7.9,1.7Hz, 1H),7.70(dd,J=8.3,3.1Hz,1H),7.61–7.51(m,1H),7.17(t,J=7.9Hz,1H),6.53(t,J= 7.5Hz,1H),6.38(d,J=8.5Hz,1H),5.47(s,1H),4.95–4.67(m,2H),4.16(s,2H),3.97 (s,1H),3.81(s,1H),3.06–2.88(m,1H),1.58(d,J=6.6Hz,3H),1.06(d,J=6.7Hz,6H).

[0513] C6 (9.8 min, 6.6 mg) [M+H] + :453.3 1 H NMR(400MHz,DMSO-d6)δ12.74(s,1H),8.54–8.41(m,1H),7.80(dd,J=7.9,1.7Hz,1H),7.7 0(dd,J=8.4,3.0Hz,1H),7.55(dd,J=9.3,3.3Hz,1H),7.17(t,J=7.9Hz,1H),6.53(t,J=7.5 Hz,1H),6.38(d,J=8.5Hz,1H),5.47(s,1H),4.89(s,1H),4.82–4.67(m,1H),4.17(s,2H), 3.97(s,1H),3.81(s,1H),3.05–2.87(m,1H),1.58(d,J=6.6Hz,3H),1.06(d,J=6.6Hz,6H).

[0514] Example 4

[0515] Compounds of the present invention

[0516] The synthetic route and experimental process are as follows:

[0517] 1. Synthesis of C9-1:

[0518] To a 10 mL single-necked flask, add C1-2 (200 mg, 0.46 mmol), tetrahydropyrone (60 mg, 0.59 mmol), sodium triacetoxyborohydride (155 mg, 0.73 mmol), and 20 mL of dichloromethane. After all the raw materials are added, stir at room temperature overnight under nitrogen. Treatment and purification by column chromatography yield 170 mg of the product.

[0519] 2. Synthesis of C9-2:

[0520] Compound C9-1 (170 mg) was dissolved in 4 mL of anhydrous dichloromethane and 2 mL of trifluoroacetic acid, and stirred at room temperature overnight under nitrogen. The reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted, dried, concentrated, and purified by column chromatography to obtain 100 mg of the product.

[0521] 3. Synthesis of C9 and C10:

[0522] First, compound C9-2 (100 mg) was separated using the following separation method:

[0523] Instrument: Agilent 1260 Infinity II, chromatographic column: CHIRALPAK IA 5μm (250×20mm), mobile phase: n-hexane:ethanol = 95:5, column temperature: 25°C. Separation:

[0524] C9 (14.1 min, 9.33 mg) [M+H] + :467.3; 1 H NMR (400MHz, DMSO-d6) δ8.52(m,1H),7.81(d,J=7.8Hz,1H),7.74(dd,J=8.2,2.9Hz,1H),7.62(dd,J=9.4,3.1Hz ,1H),7.18(dd,J=8.6,6.9Hz,1H),6.54(t,J=7.5Hz,1H),6.37(d,J=8.5Hz,1H),5.45(m,1H),4.47(m,2H),4.23 -3.31(m,9H),2.03(d,J=12.2Hz,2H),1.81–1.64(m,2H),1.59(d,J=6.6Hz,2H).

[0525] C10 (16.2 min, 10.53 mg) [M+H] + :467.3; 1H NMR (400MHz, DMSO-d6) δ8.52(m,1H),7.81(d,J=7.8Hz,1H),7.74(dd,J=8.2,2.9Hz,1H),7.62(dd,J=9.4 ,3.1Hz,1H),7.18(dd,J=8.6,6.9Hz,1H),6.54(t,J=7.5Hz,1H),6.37(d,J=8.5Hz,1H),5.45(m,1H),4.47 (m,2H),4.23 -3.31(m,9H),2.03(d,J=12.2Hz,2H),1.81–1.64(m,2H),1.59(d,J=6.6Hz,2H).

[0526] Example 5

[0527] Compounds of the present invention

[0528] The synthetic route and experimental process are as follows:

[0529] 1. Synthesis of compound C11-1:

[0530] Compound int3 (110 mg, 0.25 mmol) was dissolved in 5 mL of N,N-dimethylformamide. Potassium carbonate (103 mg, 0.75 mmol) was added at room temperature, and then methyl chloroformate (28.5 mg, 0.3 mmol) was slowly added dropwise. After the addition, the mixture was stirred at room temperature for 3 h. After the reaction of the raw materials was complete, water was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, concentrated, dried, and purified by column chromatography to obtain 80 mg of the product.

[0531] 2. Synthesis of compound C11-2:

[0532] Compound C11-1 (80 mg, 0.16 mmol) was dissolved in a mixed solvent of dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred at 25°C for 12 h. After the reaction was completed, the mixture was spin-dried and separated on a preparative plate to obtain 40 mg of the product.

[0533] 3. Synthesis of compounds C11 and C12:

[0534] Compound C11-2 (40 mg) was isolated using the following resolution method:

[0535] Instrument: Agilent 1260 Infinity II, chromatographic column: phenomenex 5μm cellulose-4 (250×21.2mm), mobile phase: n-hexane:ethanol = 9:1, column temperature: 25°C. Separation:

[0536] C11 (5.5 min, 14 mg) [M+H] + :441.2

[0537] 1 H NMR (400MHz, DMSO-d6) δ12.81 (s, 1H), 8.45 (d, J = 7.2Hz, 1H), 7.81 (dd, J = 7.8, 1.6Hz,1H),7.59(m,2H),7.24(m,1H),6.60–6.51(m,2H),5.21(t,J=6.8Hz,1H) ,4.68–4.52(m,2H),3.70(s,5H),2.54(d,J=5.6Hz,2H),1.64(d,J=6.8Hz,3H).

[0538] C12 (8.2 min, 13 mg) [M+H] + :441.2

[0539] 1 H NMR (400MHz, DMSO-d6) δ12.81(s,1H),8.45(d,J=7.2Hz,1H),7.81(dd,J=7.8,1.6Hz,1H),7.59(m,2H),7.24(m,1H),6 .60–6.51(m,2H),5.21(t,J=6.8Hz,1H),4.68–4.52(m,2H),3.70(s,5H),2.54(d,J=5.6Hz,2H),1.64(d,J=6.8Hz,3H).

[0540] Example 6

[0541] Compounds of the present invention

[0542] The synthetic route and experimental process are as follows:

[0543] 1. Synthesis of compound C13-1:

[0544] Compound int6 (17 mg, 0.039 mmol) and potassium carbonate (16 mg, 0.117 mmol) were dissolved in dry dichloromethane (10 mL). Methyl chloroformate (8.8 mg, 0.092 mmol) was added at room temperature under nitrogen protection and stirred at 25°C for 12 h. The mixture was then concentrated, dried, and purified by column chromatography to obtain 9 mg of the product.

[0545] 2. Synthesis of compound C13-2:

[0546] Compound C13-1 (13 mg, 0.026 mmol) was dissolved in dichloromethane (2 mL) / trifluoroacetic acid (2 mL) and stirred at 23°C under nitrogen for 12 h. After the reaction was complete, the product (14 mg) was obtained by spin drying.

[0547] 3. Synthesis of Compounds C13 and C14

[0548] Compound C13-2 (50 mg, 0.113 mmol) was isolated using the following resolution method:

[0549] Instrument: Agilent 1260 Infinity II, chromatographic column: phenomenex 5μm cellulose-4 (250×21.2mm), mobile phase: n-hexane:ethanol = 2:8, column temperature: 25°C. Separation:

[0550] C13 (11.2 min, 20.73 mg) [M+H] + :441.2, 1 H NMR (DMSO-d6, 400MHz) δppm 12.78(br,1H),8.80(dd,J=4.8,2.8Hz,1H),8.50(s,1H),7.86(dd,J=8.4,2.8Hz,1H),7.82(dd,J=8.0,2.0Hz,1H),7.24-7.19(m,1H),6 .57(t,J=8.0Hz,1H),6.38(d,J=8.8Hz,1H),5.32(s,1H),4.59(s,2H),3.74-3.62(m,5H),2.69(t,J=5.6Hz,2H),1.63(d,J=6.8Hz,3H).

[0551] C14 (13.1 min, 21.16 mg) [M+H] + :441.2, 1 HNMR: (DMSO-d6, 400Hz) δ12.81(s,1H),8.80~8.78(m,1H),8.50(s,1H),7.87~7.80(m,2H),7.23~7.19(m,1H),6.58~6.5 5(m,1H),6.39~6.37(m,1H),5.33~5.30(m,1H),4.58(s,2H),3.71~3.68(m,5H),2.70~2.67(m,2H),1.63(d,J=7.8Hz,3H)

[0552] Example 7

[0553] Compounds of the present invention

[0554] The synthetic route and experimental process are as follows:

[0555] 1. Synthesis of compound C19-1:

[0556] Compound C1-2 (100 mg, 0.23 mmol) was dissolved in 5 mL of tetrahydrofuran, and carbonyldiimidazole (370 mg, 2.3 mmol) was added. After addition, the temperature was raised and the reaction was continued at 60°C for 24 h. Cyclopentylamine (387 mg, 4.6 mmol) was then added, and the reaction was continued at 60°C for 16 h. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified to yield 50 mg of the product.

[0557] 2. Synthesis of compound C19-2:

[0558] Compound C19-1 (50 mg, 0.09 mmol) was dissolved in a mixed solvent of dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred at 25°C for 12 h. After the reaction was completed, the mixture was spin-dried and separated on a preparative plate to obtain 40 mg of the product.

[0559] 3. Synthesis of compounds C19 and C20:

[0560] Compound C19-2 (40 mg) was separated using the following separation method:

[0561] Instrument: Agilent 1260 Infinity II, chromatographic column: phenomenex 5μm cellulose-4 (250×21.2mm), mobile phase: n-hexane:ethanol = 4:6, column temperature: 25°C. Separation:

[0562] C19 (4.4 min, 15 mg) [M+H] + :494.4 1H NMR(400MHz,DMSO-d6)δppm 12.79(br,1H),8.46(s,1H),7.81(dd,J=8.0,2.0Hz,1H),7.70(dd,J=8.0,3.2Hz,1H),7.53(dd,J=9.6,3.2Hz,1H),7.22-7.14(m,1 H),6.63-6.49(m,2H),6.34(d,J=8.4Hz,1H),5.53-5.41(m,1H),4.77-4.60(m,2H),4.10(t,J=5.6Hz,2H),4.03-3.90(m,1H),3.83 -3.65(m,2H),1.88-1.76(m,2H),1.72-1.62(m,2H),1.58(d,J=7.6Hz,3H),1.54-1.39(m,4H).

[0563] C20 (7.4 min, 15 mg) [M+H] + :494.4 1 H NMR(400MHz,DMSO-d6)δppm 12.76(br,1H),8.46(s,1H),7.81(dd,J=8.0,2.0Hz,1H),7.70(dd,J=8.0,3.2Hz,1H),7.53(dd,J=9.6,3.2Hz,1H),7.21-7.11(m,1 H),6.63-6.48(m,2H),6.34(d,J=8.0Hz,1H),5.53-5.40(m,1H),4.77-4.60(m,2H),4.10(t,J=5.6Hz,2H),4.03-3.91(m,1H),3.83 -3.66(m,2H),1.88-1.76(m,2H),1.72-1.62(m,2H),1.58(d,J=7.2Hz,3H),1.54-1.38(m,4H).

[0564] Example 8

[0565] Compounds of the present invention

[0566] The synthetic route and experimental process are as follows:

[0567] 1. Synthesis of compound C44-1:

[0568] Compound int7 (51 mg, 0.11 mmol) was dissolved in 5 mL of dichloromethane. Triethylamine (56 mg, 0.55 mmol) was added at zero degrees, and then isopropylsulfonyl chloride (37 mg, 0.26 mmol) was slowly added dropwise. After the addition, the temperature was naturally raised and stirred to react for 12 hours. After the raw material reacted completely, water was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, concentrated, and purified by column chromatography to obtain 20 mg of the product.

[0569] 2. Synthesis of compounds C44 and C45:

[0570] Compound C44-1 (20 mg) was separated using the following separation method: instrument: Agilent 1260 Infinity II, column: phenomenex 5μm cellulose-4 (250×21.2mm), mobile phase: n-hexane:ethanol = 9:1, column temperature: 25°C. After concentration, dichloromethane (4mL) / trifluoroacetic acid (2mL) were added. Under nitrogen protection, the mixture was stirred at 23°C for 12h. After completion of the reaction, the mixture was concentrated and purified by thin-layer preparative chromatography to obtain the product:

[0571] C45 (17.4 min, 2.18 mg) [M+H] + :485.3 1 HNMR: (DMSO-d6, 400Hz), δ8.59(s,1H),7.81~7.79(m,1H),7.73(s,1H),7.54(s,1H),7.18~7.16(m,1H),6.54~6.47(m,2H),5.21~ .5.13(m,1H),4.50~4.46(m,2H),3.59~3.54(m,3H),2.59~2.57(m,2H),2.35(s,3H),1.60(d,J=6.4Hz,3H),1.28(d,J=6.5Hz,6H).

[0572] C44 (20.3 min, 2.74 mg) [M+H] + :485.3 1HNMR: (DMSO-d6, 400Hz), δ8.59(s,1H),7.81~7.79(m,1H),7.73(s,1H),7.54(s,1H),7.18~7.16(m,1H),6.54~6.47(m,2H),5.21~ .5.13(m,1H),4.50~4.46(m,2H),3.59~3.54(m,3H),2.59~2.57(m,2H),2.35(s,3H),1.60(d,J=6.4Hz,3H),1.28(d,J=6.5Hz,6H).

[0573] Example 9

[0574] Compounds of the present invention

[0575] The synthetic route and experimental process are as follows:

[0576] 1. Synthesis of compound C54-1:

[0577] Dissolve int7 (80 mg, 0.18 mmol) in dichloromethane (10 ml), add triethylamine (60 mg, 0.54 mmol), and add morpholinesulfonyl chloride (103 mg, 0.54 mmol) dropwise in an ice bath. Allow to react at 30°C for 12 h. The reaction is complete. Concentrate the reaction solution, dilute with ethyl acetate, wash twice with saturated brine, dry, concentrate, and separate using the following separation method: instrument: Agilent 1260 Infinity II, column: Phenomenex 5 μm cellulose-4 (250×21.2 mm), mobile phase: n-hexane:ethanol = 8:2, column temperature: 25°C. Products C54-2 (21.0 min, 25 mg) and C55-1 (26.7 min, 25 mg) were obtained.

[0578] 2. Synthesis of compounds C54 and C55:

[0579] Dissolve C54-2 and C55-1 in dichloromethane (5 ml) separately, add trifluoroacetic acid (5 ml), and react at 30°C for 24 hours. After the reaction is complete, concentrate and purify by column chromatography to obtain the product.

[0580] C54 (16.5 min, 10 mg) 1H NMR(400MHz, DMSO-d6),12.79(m,1H)8.47(d,J=7.2Hz,1H),7.80(dd,J=8.0,1.6Hz,1H ),7.73(d,J=2.4Hz,1H),7.55(d,J=2.4Hz,1H),7.22(m,1H),6.57–6.49(m,2H),5.17( t,J=6.8Hz,1H),4.44(d,J=8.0Hz,2H),3.64(t,J=4.8Hz,4H),3.53(q,J=6.0Hz,2H),3 .19(dd,J=5.6,3.6Hz,4H),2.59(t,J=5.6Hz,2H),2.35(s,3H),1.60(d,J=6.4Hz,3H).

[0581] C55 (18.1 min, 10 mg) 1 H NMR (400MHz, DMSO-d6) δ12.79(m,1H),8.47(d,J=7.2Hz,1H),7.80(dd,J=8.0,1.6Hz,1 H),7.73(d,J=2.4Hz,1H),7.55(d,J=2.4Hz,1H),7.22(m,1H),6.57–6.49(m,2H),5.17 (t,J=6.8Hz,1H),4.44(d,J=8.0Hz,2H),3.64(t,J=4.8Hz,4H),3.53(q,J=6.0Hz,2H), 3.19(dd,J=5.6,3.6Hz,4H),2.59(t,J=5.6Hz,2H),2.35(s,3H),1.60(d,J=6.4Hz,3H).

[0582] Example 10

[0583] Compounds of the present invention

[0584] The synthetic route and experimental process are as follows:

[0585] 1. Synthesis of compound C62-2:

[0586] Compound C62-1 (25 g, 113.6 mmol) was dissolved in 400 mL of methanol. Thionyl chloride (54 g, 454.5 mmol) was added dropwise under an ice bath. The temperature was raised to 70°C and the reaction was allowed to proceed for 4 h until the reaction was complete. The mixture was then directly dried with saturated sodium bicarbonate aqueous solution for base adjustment. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 26 g of the product.

[0587] 1H NMR (400MHz, Chloroform-d) δ8.41 (d, J = 2.0Hz, 1H), 7.89 (dd, J = 56.8, 5.2Hz, 1H), 4.00 (d, J = 1.2Hz, 3H).

[0588] 2. Synthesis of compound C62-3:

[0589] C62-2 (26 g, 111.1 mmol) was dissolved in 350 ml of dry dioxane. Potassium carbonate (22.9 g, 166.7 mmol), Pd(dppf)Cl2 (8.1 g, 11.1 mmol), and a 3.5 M solution of trimethylboroxine in tetrahydrofuran (80 ml, 277.8 mmol) were then added. The mixture was stirred overnight at 105°C under nitrogen. After the reaction of the starting materials was complete, the reaction mixture was cooled to room temperature, water was added, and extraction with ethyl acetate was performed three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to yield 13.7 g of product.

[0590] 1 H NMR (400MHz, Chloroform-d) δ8.49 (d, J = 2.4Hz, 1H), 7.62 (d, J = 5.6Hz, 1H), 3.98 (s, 3H), 2.60 (d, J = 1.2Hz, 3H).

[0591] 3. Synthesis of compound C62-4:

[0592] C62-3 (13.7 g, 80.6 mmol) was added to 120 mL of aqueous ammonia and stirred in an iron stew pot at 80°C for 5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure and slurried with dichloromethane and petroleum ether to obtain 12 g of the product.

[0593] 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=1.6Hz,1H),7.94(d,J=43.2Hz,2H),7.44(d,J=5.6Hz,1H),2.49(s,3H).

[0594] 4. Synthesis of compound C62-5:

[0595] Compound C62-4 (4 g, 25.8 mmol) was dissolved in 80 mL of dichloromethane, triethylamine (7.82 g, 77.4 mmol) was added, and then trifluoroacetic anhydride (10.8 g, 51.6 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. After the raw materials reacted completely, the reaction solution was diluted with water, and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 3 g of product.

[0596] 1 H NMR (400MHz, Chloroform-d) δ8.58 (s, 1H), 7.39 (d, J = 4.8Hz, 1H), 2.62 (d, J = 1.2Hz, 3H).

[0597] 5. Synthesis of compound C62-6:

[0598] Compound C62-5 (3 g, 21.9 mmol) was dissolved in 60 mL of N,N-dimethylformamide. 2-Bromo-4-fluorophenol (6.3 g, 32.9 mmol) and cesium carbonate (14.4 g, 43.8 mmol) were added. The mixture was heated to 130°C and allowed to react for 1 h until the reaction was complete. Water was slowly added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified to yield 5.7 g of the product.

[0599] 1 H NMR (400MHz, Chloroform-d) δ8.02(s,1H),7.51–7.45(m,1H),7.42(s,1H),7.20–7.09(m,2H),2.59(s,3H).

[0600] 6. Synthesis of compound C62-7:

[0601] Dissolve C62-6 (5.7 g, 41 mmol) in 57 g of polyphosphoric acid, slowly heat to 220°C, and stir for 3 hours. After the reaction is complete, cool the reaction mixture to room temperature, dissolve it in water, adjust the base with saturated sodium bicarbonate aqueous solution, and extract it three times with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to yield 4 g of product.

[0602] 1 H NMR (400MHz, Chloroform-d) δ9.08 (s, 1H), 8.02–7.92 (m, 2H), 7.84 (dd, J = 7.2, 3.2Hz, 1H), 2.74 (s, 3H).

[0603] 7. Synthesis of compound C62-8:

[0604] C62-7 (4 g, 13 mmol), potassium iodide (9.5 g, 57.2 mmol), and benzyl chloride (8.15 g, 52 mmol) were added to 150 mL of acetonitrile. The reaction mixture was slowly heated to 80°C and stirred overnight. After the starting materials reacted completely, the reaction mixture was concentrated under reduced pressure to obtain 9 g of crude product, which was used directly in the next reaction.

[0605] 8. Synthesis of compound C62-9:

[0606] Compound C62-8 (9 g, 15.9 mmol) was dissolved in 100 mL of anhydrous ethanol, and sodium cyanoborohydride (8 g, 127.4 mmol) and acetic acid (0.9 g, 15.9 mmol) were added. The mixture was stirred at room temperature for 30 min. After the reaction of the raw materials was complete, the reaction solution was diluted with water and then extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 2.5 g of the product.

[0607] 1 H NMR(400MHz,Chloroform-d)δ7.85(dd,J=8.0,3.2Hz,1H),7.64(dd,J=7.2,3.2Hz,1H),7.32(dd,J=8.8,3.2Hz,2H),6.93–6.91(m,2H),3 .84(s,3H),3.79(dd,J=3.6,1.2Hz,2H),3.60(m,2H),3.18(h,J=6.4Hz,1H),2.85–2.74(m,1H),2.55–2.44(m,1H),1.22(d,J=6.4Hz,3H).

[0608] 9. Synthesis of compound C62-10:

[0609] Compound C62-9 (2 g, 4.63 mmol), tributyl(1-ethoxyethylene)tin (2 g, 5.56 mmol), and Pd(PPh3)2Cl2 (0.33 g, 0.46 mmol) were dissolved in dry dioxane (80 mL) and stirred at 80°C for 12 h. Potassium fluoride solution was then added at room temperature, stirred for 0.5 h, filtered, and the mother liquor was extracted three times with ethyl acetate. The organic phase was separated, dried, and dissolved in dichloromethane. 2 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 25°C for 10 min. After completion of the reaction, the product (1.4 g) was purified by column chromatography.

[0610] 1 H NMR(400MHz,Chloroform-d)δ8.06(dd,J=7.6,3.2Hz,1H),7.83(dd,J=8.2,3.4Hz,1H),7.31(s,2H),6.94–6.89(m,2H),3.84(s, 3H),3.80(m,2H),3.64–3.55(m,2H),3.21(q,J=6.0Hz,1H),2.86–2.77(m,1H),2.71(s,3H),2.53(m,1H),1.22(d,J=6.4Hz,3H).

[0611] 10. Synthesis of compound C62-11:

[0612] Compound C62-10 (0.7 g, 1.77 mmol) was dissolved in a mixed solvent consisting of 10 mL of dichloromethane and 10 mL of methanol. Under nitrogen, sodium borohydride (40 mg, 0.88 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 10 minutes. After the reaction of the starting materials was complete, the reaction mixture was diluted with water and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to yield 600 mg of the product.

[0613] 11. Synthesis of compound C62-12:

[0614] Compound C62-11 (600 mg, 1.5 mmol) was dissolved in 30 mL of 1,2-dichloroethane. Under nitrogen protection, phosphorus tribromide (1.25 g, 4.5 mmol) was slowly added and stirred at 50°C for 4 h. After the reaction of the raw materials was complete, the dichloromethane was concentrated under reduced pressure and slurried with petroleum ether to obtain 600 mg of the product.

[0615] 12. Synthesis of compound C62-13:

[0616] Compound C62-12 (600 mg, 1.3 mmol) was dissolved in 20 mL of anhydrous N,N-dimethylformamide. At room temperature, tert-butyl 2-aminobenzoate (1.6 g, 7.8 mmol) was slowly added. The temperature was slowly raised to 60°C and stirred for 12 hours. After the raw material reaction was complete, the reaction solution was diluted with water and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 350 mg of the product.

[0617] 13. Synthesis of compound C62-14:

[0618] Compound C62-13 (350 mg, 0.61 mmol) was dissolved in 40 mL of 1,2-dichloroethane. 1-Chloroethyl chloroformate (174 mg, 1.22 mmol) was slowly added at room temperature. The temperature was slowly raised to 83°C and stirred for 3 h. After the reaction of the raw materials was complete, the reaction solution was concentrated to dryness and methanol was added. The temperature was raised to 65°C and stirred for 1 h. Then, the base was adjusted with triethylamine, and the mixture was dried and purified to obtain 200 mg of the product.

[0619] 14. Synthesis of compound C62-15:

[0620] Compound C62-14 (100 mg, 0.22 mmol) was dissolved in 5 mL of dichloromethane. DBU (100 mg, 0.66 mmol) was added at room temperature, and then a dichloromethane solution of isopropylsulfonyl chloride (78.3 mg, 0.55 mmol) was slowly added dropwise. After the addition, the mixture was stirred at 30°C for 2 h. After the reaction of the raw materials was complete, water was added to quench the mixture, and the mixture was extracted three times with dichloromethane. The organic phases were combined, concentrated, dried, and purified by column chromatography to obtain 80 mg of the product.

[0621] 15. Synthesis of compound C62-16:

[0622] Compound C62-15 (80 mg, 0.16 mmol) was dissolved in a mixed solvent of dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred at 25°C for 12 h. After the reaction was completed, the mixture was spin-dried and separated using a thin layer preparative plate to obtain 70 mg of the product.

[0623] 16. Synthesis of compounds C62, C63, C64, and C65:

[0624] C62-16 (70 mg) was separated by the following separation method, instrument: Agilent 1260 Infinity II, chromatographic column: phenomenex 5 μm cellulose-4 (250×21.2 mm), mobile phase: n-hexane:ethanol = 9:1, column temperature: 25°C.

[0625] C62 (19.2 min, 12.32 mg) [M+H] + :503.2

[0626] 1 H NMR (400MHz, DMSO-d6) δ12.86(m,1H),8.53(m,1H),7.81(dd,J=8.2,1.6Hz,1H),7.58(m,2H),7.23(t,J=7.6Hz,1H),6.57(dd,J=8.4,5. 6Hz,2H),5.23(t,J=6.8Hz,1H),4.65–4.28(m,3H),3.51(p,J=6.8Hz,1H),2.72–2.56(m,2H),1.66(d,J=6.8Hz,3H),1.29–1.19(m,9H).

[0627] C63 (29.5 min, 4.42 mg) [M+H] + :503.2

[0628] 1H NMR (400MHz, DMSO-d6) δ12.86(m,1H),8.53(m,1H),7.81(dd,J=8.2,1.6Hz,1H),7.58(m,2H),7.23(t,J=7.6Hz,1H),6.57(dd,J=8.4,5. 6Hz,2H),5.23(t,J=6.8Hz,1H),4.65–4.28(m,3H),3.51(p,J=6.8Hz,1H),2.72–2.56(m,2H),1.66(d,J=6.8Hz,3H),1.29–1.19(m,9H).

[0629] C64 (34.7 min, 1.72 mg) [M+H] + :503.2

[0630] 1 H NMR (400MHz, DMSO-d6) δ12.86(m,1H),8.53(m,1H),7.81(dd,J=8.2,1.6Hz,1H),7.58(m,2H),7.23(t,J=7.6Hz,1H),6.57(dd,J=8.4,5. 6Hz,2H),5.23(t,J=6.8Hz,1H),4.65–4.28(m,3H),3.51(p,J=6.8Hz,1H),2.72–2.56(m,2H),1.66(d,J=6.8Hz,3H),1.29–1.19(m,9H).

[0631] C65 (46.7 min, 8.72 mg) [M+H] + :503.2

[0632] 1 H NMR (400MHz, DMSO-d6) δ12.86(m,1H),8.53(m,1H),7.81(dd,J=8.2,1.6Hz,1H),7.58(m,2H),7.23(t,J=7.6Hz,1H),6.57(dd,J=8.4,5. 6Hz,2H),5.23(t,J=6.8Hz,1H),4.65–4.28(m,3H),3.51(p,J=6.8Hz,1H),2.72–2.56(m,2H),1.66(d,J=6.8Hz,3H),1.29–1.19(m,9H).

[0633] Example 11

[0634] Compounds of the present invention

[0635] The synthetic route and experimental process are as follows:

[0636] 1. Synthesis of compound C66-2:

[0637] Compound C66-1 (4.48 g, 24 mmol) was dissolved in 60 mL of N,N-dimethylformamide. 3-Chloro-4-cyanopyridine (2.78 g, 20 mmol) and cesium carbonate (13 g, 40 mmol) were added. The mixture was heated to 110°C and allowed to react for 3 h until the reaction was complete. Water was slowly added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by column chromatography to yield 4.5 g of the product.

[0638] 1 H NMR (400MHz, Chloroform-d) δ8.53(d,J=4.8Hz,1H),8.16(s,1H),7.74(d,J=5.6Hz,1H),7.60(d,J=4.8Hz,1H), 7.42~7.40(m,1H), 7.16(d,J=8.8Hz,1H),

[0639] 2. Synthesis of compound C66-3:

[0640] C66-2 (4.5 g, 15.5 mmol) was dissolved in 40 g of polyphosphoric acid and the temperature was slowly raised to 220°C with stirring for 3 h. After the reaction was complete, the reaction solution was cooled to room temperature and dissolved in water. The base was adjusted with saturated sodium bicarbonate aqueous solution, and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by pulping to obtain 3.5 g of the product.

[0641] 1 H NMR (400MHz, Chloroform-d) δ9.19 (s, 1H), 8.74 (s, 1H), 8.28 (d, J = 2.4Hz, 1H), 8.12 (s, 1H), 8.05 (d, J = 2.8Hz, 1H).

[0642] 3. Synthesis of compound C66-4:

[0643] C66-3 (2.5 g, 8.6 mmol), potassium iodide (3.15 g, 19 mmol), and benzyl chloride (2.7 g, 17.2 mmol) were added to 40 mL of acetonitrile. The reaction mixture was slowly heated to 80°C and stirred for 2 h. After the starting materials reacted completely, the reaction mixture was concentrated under reduced pressure to yield 8.2 g of crude product, which was used directly in the next reaction.

[0644] 4. Synthesis of compound C66-5:

[0645] Compound C66-4 (8.2 g, 20 mmol) was dissolved in 200 mL of anhydrous ethanol, and sodium cyanoborohydride (10.8 g, 160 mmol) and acetic acid (1.2 g, 20 mmol) were added. The mixture was stirred at room temperature for 30 min. After the reaction of the raw materials was complete, the reaction solution was diluted with water and then extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 3.8 g of the product.

[0646] 5. Synthesis of compound C66-6:

[0647] Compound C66-5 (3 g, 7.24 mmol), tributyl(1-ethoxyethylene)tin (3.14 g, 8.7 mmol), and Pd(PPh3)2Cl2 (510 mg, 0.724 mmol) were dissolved in dry dioxane (50 mL) and stirred at 80°C for 12 h. Potassium fluoride solution was then added at room temperature, stirred for 0.5 h, filtered, and the mother liquor was extracted three times with ethyl acetate. The organic phase was separated, dried, and dissolved in dichloromethane. 2 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 25°C for 10 min. After completion of the reaction, the product was purified by column chromatography to obtain 2.5 g.

[0648] 1 H NMR(400MHz,Chloroform-d)δ8.35(s,1H),8.03(s,1H),7.31(d,J=8.4Hz,2H),6.93(d,J=8.4Hz ,2H), 3.84(s,3H),3.71(s,2H),3.54(s,2H),2.79~2.77(m,2H),2.71~2.68(m,5H),2.48(s,3H).

[0649] 6. Synthesis of compound C66-7:

[0650] Compound C66-6 (1.13 g, 3 mmol) was dissolved in 50 mL of tetrahydrofuran. Under nitrogen, (R)-(+)-tert-butylsulfenamide (726 mg, 6 mmol) and Ti(OEt)4 (2.73 g, 1.2 mmol) were added sequentially. The reaction solution was stirred at 70°C for 12 h. After the reaction of the starting materials was complete, the reaction solution was diluted with water, filtered through a pad of celite, and then washed with ethyl acetate. The filtrate was separated, and the mother liquor was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 1.1 g of the product.

[0651] 7. Synthesis of compound C66-8:

[0652] Compound C66-7 (0.4 g, 0.8 mmol) was dissolved in 20 mL of methanol. Under nitrogen protection, CeCl3.7H2O (148 mg, 0.4 mmol) and sodium borohydride (45.6 mg, 1.2 mmol) were slowly added in sequence and stirred at room temperature for 20 min. After the reaction of the raw materials was complete, aqueous ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 0.38 g of the product.

[0653] 8. Synthesis of compound C66-9:

[0654] Compound C66-8 (320 mg, 0.64 mmol) was dissolved in 25 mL of methanol. 4N HCl / MeOH (5 mL) was slowly added at room temperature and stirred for 1 h. After the reaction of the raw materials was complete, the reaction solution was concentrated to dryness and water (8 mL) was added. The pH value of the aqueous phase was adjusted to 12 with 10% ammonia water, and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 250 mg of the product.

[0655] 9. Synthesis of compound C66-10:

[0656] Compound C66-9 (80 mg, 0.2 mmol) was dissolved in dimethyl sulfoxide (5 mL). At 25 ° C, tert-butyl 6-chloro-3-fluoropyridine-2-carboxylate (56 mg, 0.24 mmol) and N, N-diisopropylethylamine (129 mg, 1 mmol) were added. The reaction was stirred at 100 ° C for 10 h. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate three times. The mixture was spin-dried and purified by column chromatography to obtain 40 mg of the product.

[0657] 1 H NMR(400MHz,Chloroform-d)δ8.31(br,1H),8.08(s,1H),7.51(s,1H),7.31(d,J=8.4Hz,2H),7.09(d,J=8.8Hz,2H),6.93(d,J=8.4Hz,2H),6.63(d,J=8.8Hz, 1H),5.01~4.96(m,1H),3.73~3.67(m,2H),3.54~3.50(m,2H),2.82~2.72(m,4H),1.69~1.65(m,12H).

[0658] 10. Synthesis of compound C66-11:

[0659] Compound C66-10 (240 mg, 0.4 mmol) was dissolved in 1,2-dichloroethane (24 mL). 1-Chloroethyl chloroformate (112 mg, 0.8 mmol) was added and stirred at 83°C for 2 h under nitrogen at room temperature. After the reaction, the mixture was dried and used directly in the next step. The crude product from the previous step was dissolved in methanol (24 mL) and reacted at 65°C under nitrogen for 1 h. After the reaction, triethylamine was added to adjust the pH of the reaction solution to alkaline, and the mixture was dried and used directly in the next step.

[0660] 11. Synthesis of compound C66-12:

[0661] Compound C66-11 (19.2 mg, 0.04 mmol) was dissolved in 5 mL of 1,2-dichloroethane. Triethylamine (60 mg, 0.6 mmol) was added at room temperature, and then 4-morpholinesulfonyl chloride (74.4 mg, 0.4 mmol) was slowly added dropwise. After the addition, the mixture was stirred at 30°C for 12 h. After the reaction of the raw materials was complete, sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined. The organic phases were then washed once with 10% citric acid aqueous solution and saturated brine, dried, concentrated, and purified on a preparative plate to obtain 8 mg of the product.

[0662] 12. Synthesis of compound C66:

[0663] Compound C66-12 (40 mg, 0.06 mmol) was dissolved in dichloromethane (6 mL) / trifluoroacetic acid (3 mL) and stirred at 30°C under nitrogen for 12 h. After the reaction was complete, the mixture was spin-dried and purified on a preparative thin layer plate to obtain 5.64 mg of the product. [M+H] + :583.2

[0664] 1 HNMR (DMSO-d6, 400Hz), δ9.74(br,1H),7.86~7.81(m,2H),7.45~7.25(m,2H),5.21~5.19(m,1H), 4.55~4.39(m,2H),3.53~3.50(m,6H),3.14~3.10(m,4H),2.57~2.50(m,2H),1.64(d,J=2.4Hz,3H)

[0665] Example 12

[0666] Compounds of the present invention

[0667] The synthetic route and experimental process are as follows:

[0668] 1. Synthesis of compound C111-1:

[0669] Compound int7-6 (0.5 g, 1.33 mmol) was dissolved in a mixture of 10 mL of dichloromethane and 10 mL of methanol. Under nitrogen, sodium borohydride (50 mg, 1.33 mmol) was slowly added. The reaction mixture was stirred at room temperature for 10 minutes. After the reaction was complete, the reaction mixture was treated and purified to obtain 0.3 g of the product.

[0670] 2. Synthesis of compound C111-2:

[0671] Compound C111-1 (0.3 g, 0.79 mmol) was dissolved in 20 mL of anhydrous dichloromethane. Under nitrogen protection, phosphorus tribromide (0.64 g, 2.38 mmol) was slowly added and stirred at room temperature for 12 h. The reaction of the raw materials was completed, and 0.7 g of product was obtained.

[0672] 3. Synthesis of compound C111-3:

[0673] Compound C111-2 (0.7 g, 0.79 mmol) was dissolved in 20 mL of anhydrous N,N-dimethylformamide. 2-aminobenzoic acid tert-butyl ester (0.89 g, 4.74 mmol) was slowly added at room temperature. The temperature was slowly raised to 60°C and the reaction was stirred for 36 hours. After the reaction of the raw materials was completed, 120 mg of the product was obtained after purification.

[0674] 4. Synthesis of compound C111-4:

[0675] Compound C111-3 (90 mg, 1.65 mmol) was dissolved in 5 mL of 1,2-dichloroethane. 1-Chloroethyl chloroformate (47.1 mg, 3.3 mmol) was slowly added at room temperature. The temperature was slowly raised to 83°C and stirred for 3 h. After the reaction of the raw materials was completed, 51 mg of the product was obtained after purification.

[0676] 5. Synthesis of compound C111-5:

[0677] Compound C111-4 (51 mg, 0.11 mmol) was dissolved in 5 mL of dichloromethane. Triethylamine (56 mg, 0.55 mmol) was added at 0°C, and then phenylsulfonyl chloride (37 mg, 0.26 mmol) was slowly added dropwise. After the addition, the temperature was naturally raised and stirred for 12 hours. After the reaction was completed, 28 mg of the product was obtained after purification.

[0678] 6. Synthesis of compounds C111 and C112:

[0679] Compound C111-5 (28 mg, 0.05 mmol) was separated using the following separation method: instrument: Agilent 1260 Infinity II, column: phenomenex 5 μm cellulose-4 (250×21.2 mm), mobile phase: n-hexane:ethanol = 1:9, column temperature: 25°C.

[0680] C111 (9.5 min, 10.95 mg) [M+H] + :571.3 1 HNMR: (DMSO-d6, 400Hz), δ7.89~7.87(m,2H),7.71~7.68(m,2H),7.64~7.60(m,2H),7.43~7.41(m,1H),7.29~7.25(m,1H),6.74~.6.70(m ,1H),6.60~6.58(m,1H),5.13~5.10(m,1H),4.31~4.24(m,2H),3.44~3.39(m,1H),3.28~3.21(m,5H),2.35(s,3H),1.62(d,J=7.8Hz,3H)

[0681] C112 (10.2 min, 11.94 mg) [M+H] + :571.3 1 HNMR: (DMSO-d6, 400Hz), δ7.89~7.87(m,2H),7.71~7.68(m,2H),7.64~7.60(m,2H),7.43~7.41(m,1H),7.29~7.25(m,1H),6.74~.6.70( m,1H),6.60~6.58(m,1H),5.13~5.10(m,1H),4.31~4.24(m,2H),3.44~3.39(m,1H),3.28~3.21(m,5H),2.35(s,3H)1.62(d,J=7.8Hz,3H)

[0682] Example 13

[0683] Compounds of the present invention

[0684] The synthetic route and experimental process are as follows:

[0685] 1. Synthesis of Compound C163-2

[0686] Dissolve C163-1 (1.01 g, 2.65 mmol) in 30 mL of dioxane, add trimethylboroxine in tetrahydrofuran (3.5 N, 5.4 mL), potassium carbonate (2.62 g, 7.95 mmol), and DPPF-PdCl2 (463 mg, 0.265 mmol). Heat the reaction mixture to 105°C overnight. After completion, purify by column chromatography to yield 236 mg of the product.

[0687] 1 H NMR (400MHz, Chloroform-d) δ10.45(s,1H),8.50(d,J=4.9Hz,1H),7.53(t,J=4.9Hz,1H),2.65(d,J=3.2Hz,3H).

[0688] 2. Synthesis of Compound C163-3

[0689] Dissolve C163-2 (54 mg, 0.39 mmol) in 1.5 mL of N,N-dimethylformamide, add 2-bromo-4-fluorophenol (112 mg, 0.59 mmol) and cesium carbonate (198 mg, 0.78 mmol). Heat the reaction to 100°C for 3 hours. After completion of the reaction, purify by column chromatography to yield 24 mg of the product.

[0690] 3. Synthesis of Compound C163-4

[0691] C163-3 (24 mg, 0.078 mmol) was dissolved in a mixture of 0.5 mL of tetrahydrofuran and 0.5 mL of aqueous ammonia, and iodine (29.7 mg, 0.117 mmol) was added. The mixture was reacted at room temperature overnight under nitrogen. After completion of the reaction, 11 mg of the product was obtained.

[0692] 1 H NMR (400MHz, Chloroform-d) δ8.55(d,J=5.0Hz,1H),7.52–7.40(m,2H),6.98(ddd,J=9.1,7.5,3.0Hz,1H),6.54(dd,J=9.0,4.6Hz,1H),2.52(s,3H).

[0693] 4. Synthesis of Compound C163-5

[0694] C163-4 (4.4 g) was added to a reaction flask, followed by polyphosphoric acid (50 g), and the temperature was raised to 220°C. The reaction was completed, cooled, quenched with aqueous sodium bicarbonate solution, adjusted to alkalinity, extracted three times with dichloromethane, dried, and concentrated to obtain 3.6 g of crude product, which was used directly in the next reaction.

[0695] 5. Synthesis of Compound C163-6

[0696] Dissolve C163-5 (3.6 g, 11.7 mmol) in acetonitrile, add potassium iodide (4.28 g, 25.8 mmol) and p-methoxybenzyl chloride (3.67 g, 23.5 mmol). Heat the reaction to 80°C for 1 h. After the reaction is complete, spin dry the product and use it in the next step.

[0697] 6. Synthesis of Compound C163-7

[0698] Dissolve C163-6 in ethanol (150 ml), add acetic acid (211 mg, 3.5 mmol) and sodium cyanoborohydride (887 mg, 14.1 mmol), and react at room temperature for 10 min. After completion of the reaction, 1.3 g of the product was purified by column chromatography.

[0699] 7. Synthesis of Compound C163-8

[0700] C163-7 (650 mg, 1.51 mmol) was dissolved in dioxane (10 ml), and tributyl(1-ethoxyethylene)tin (653.3 mg, 1.81 mmol) and Pd(PPh3)Cl2 (106 mg, 0.15 mmol) were added. The mixture was reacted at 80°C overnight under nitrogen. After completion of the reaction, the product was purified by column chromatography to obtain 540 mg.

[0701] 8. Synthesis of Compound C163-9

[0702] Dissolve C163-8 (540 mg, 1.37 mmol) in tetrahydrofuran (20 ml), add R-tert-butylsulfenamide (331 mg, 2.73 mmol) and tetraethyl titanate (1.25 g, 5.47 mmol). Keep the reaction mixture under nitrogen at 70°C overnight. After completion of the reaction, purify by column chromatography to obtain 630 mg of the product.

[0703] 9. Synthesis of Compound C163-10

[0704] C163-9 (630 mg, 1.27 mmol) was added to 10 ml of methanol, followed by cerium chloride heptahydrate (236 mg, 0.63 mmol), stirred for 5 min, and sodium borohydride (72 mg, 1.90 mmol) was added portionwise. After completion of the reaction, the product was purified by column chromatography to obtain 540 mg.

[0705] 10. Synthesis of Compound C163-11

[0706] C163-10 (540 mg) was dissolved in ethanol (5 ml), and a 2 M ethanolic solution of hydrochloric acid (5 ml) was added. The mixture was reacted at room temperature for 10 min. After completion, the product was purified by column chromatography to obtain 450 mg.

[0707] 11. Synthesis of Compound C163-12

[0708] Dissolve C163-11 (450 mg, 1.14 mmol) in toluene and add tert-butyl 2-bromobenzoate (350 mg, 1.36 mmol), Pd(OAc)2 (25.5 mg, 0.11 mmol), Xantphos (131.6 mg, 0.23 mmol), and Cs2CO3 (1.00 g, 3.10 mmol). Under nitrogen, react at 100°C overnight. After completion of the reaction, 500 mg of the product was purified by column chromatography.

[0709] 12. Synthesis of Compound C163-13

[0710] Dissolve C163-12 (500 mg, 0.87 mmol) in 1,2-dichloroethane, add 1-chloroethyl chloroformate (250 mg, 1.75 mmol), and react at 80°C for 1 h. Concentrate, add methanol and triethylamine (353 mg, 3.50 mmol), and heat to 65°C for 1 h. After completion of the reaction, 300 mg of the product was purified by column chromatography.

[0711] 13. Synthesis of Compound C163-14

[0712] C163-13 (150 mg, 0.33 mmol) was dissolved in dichloromethane, and DBU (252 mg, 1.66 mmol) and isopropylsulfonyl chloride (142 mg, 1.00) were added. The mixture was reacted at room temperature for 1 h. After completion of the reaction, the product was purified by column chromatography to obtain 100 mg.

[0713] 14. Synthesis of Compounds C163 and C164

[0714] Dissolve C163-14 in dichloromethane (4 ml), add trifluoroacetic acid (4 ml), and react at room temperature overnight. After the reaction is complete, concentrate and separate using the following separation method: instrument: Agilent 1260 Infinity II, column: phenomenex 5 μm cellulose-4 (250×21.2 mm), mobile phase: n-hexane:ethanol = 3:7, column temperature: 25°C.

[0715] C163 (11.2 min, 23.26 mg) [M+H] + :502.6 1H NMR(400MHz,DMSO-d6)δ8.41(br,1H),7.84(dd,J=8.0,1.6Hz,1H),7.62-7.6 0(m,1H),7.51-7.48(m,1H),7.25–7.20(m,1H),6.58(t,J=7.6Hz,1H),6.50( d,J=8.4Hz,1H),5.27(br,1H),4.91(q,J=6.8Hz,1H),3.87-3.82(m,1H),3.4 9–3.46(m,1H),2.66–2.54(m,2H),1.62(d,J=6.8Hz,6H),1.28-1.22(m,8H).

[0716] C164 (13.4 min, 23.60 mg) [M+H] + :502.6 1 H NMR(400MHz, DMSO-d6)δ8.48(br,1H),7.81(dd,J=8.0,1.6Hz,1H),7.66-7.60(m,2H),7.25–7.20(m,1H),6.56(t,J=7.6Hz,1H),6.50(d,J=8.4Hz,1H) ,5.21-5.18(m,1H),4.87(q,J=6.8Hz,1H),3.87-3.82(m,1H),3.47–3.43( m,1H),2.68–2.52(m,2H),1.66-1.63(m,6H),1.23(dd,J=20.0,6.8Hz,8H).

[0717] Example 14

[0718] Compounds of the present invention

[0719] The synthetic route and experimental process are as follows:

[0720] 1. Synthesis of Compound C166-1

[0721] Dissolve intermediate int7 (200 mg, 0.46 mmol) in 5 mL of N,N-dimethylformamide, add methylbenzyl chloride (189 mg, 1.34 mmol), triethylamine (270 mg, 2.67 mmol), and potassium iodide (120 mg, 0.72 mmol). Seal the tube and react overnight at 80°C. After completion of the reaction, purify by column chromatography to yield 183 mg of the product.

[0722] 2. Synthesis of Compounds C166 and C167

[0723] Dissolve C166-1 (50 mg) in dichloromethane (10 mL), add trifluoroacetic acid (10 mL), and react at room temperature overnight. After the reaction is complete, concentrate and separate using the following separation method: instrument: Agilent 1260 Infinity II, column: phenomenex 5 μm cellulose-4 (250×21.2 mm), mobile phase: n-hexane:ethanol = 95:5, column temperature: 25°C.

[0724] C166 (10.4 min, 19.28 mg) [M+H] + :483.3 1 H NMR (400MHz, DMSO-d6) δ12.78(br,1H),8.42(d,J=7.0Hz,1H),7.82(dd,J=7.9,1. 7Hz,1H),7.73(d,J=2.1Hz,1H),7.66–7.31(m,6H),7.24-7.17(m,1H),6.55(t,J= 7.5Hz,1H),6.46(d,J=8.5Hz,1H),5.15(t,J=6.6Hz,1H),4.75-4.04(m,3H),3.28 -3.16(m,2H),2.76-2.57(m,2H),2.35(s,3H),1.68(s,3H),1.59(d,J=6.6Hz,3H).

[0725] C167 (13.6 min, 19.52 mg) [M+H] + :483.3 1 H NMR (400MHz, DMSO-d6) δ12.79(br,1H),8.42(d,J=6.9Hz,1H),7.82(dd,J=8.0,1. 7Hz,1H),7.73(d,J=2.1Hz,1H),7.66–7.37(m,6H),7.25-7.17(m,1H),6.56(t,J= 7.5Hz,1H),6.47(d,J=8.5Hz,1H),5.17(t,J=6.7Hz,1H),4.87-4.02(m,3H),3.27 -2.89(m,2H),2.82–2.56(m,2H),2.35(s,3H),1.69(s,3H),1.59(d,J=6.7Hz,3H).

[0726] Example 15

[0727] Compounds of the present invention

[0728] The synthetic route and experimental process are as follows:

[0729] 1. Synthesis of C185-1

[0730] Compound int-12 (2.1 g, 6.03 mmol), tert-butyl 2-bromobenzoate (1.86 g, 7.24 mmol), palladium acetate (134 mg, 0.6 mmol), Xantphos (694 mg, 1.2 mmol), and cesium carbonate (5.9 g, 18.9 mmol) were dissolved in dry toluene (21 mL) and stirred at 100°C for 12 h. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography to yield 2.4 g of the product.

[0731] 2. Synthesis of C185 and C186:

[0732] Compound C185-1 (100 mg) was dissolved in dichloromethane (3 mL) / trifluoroacetic acid (3 mL) and stirred at 30°C under nitrogen for 12 h. After the reaction was complete, the crude product (60 mg) was purified by column chromatography and separated by the following separation method: instrument: Agilent 1260 Infinity II, column: phenomenex 5 μm Amylose-1 (250×21.2 mm), mobile phase: n-hexane:ethanol = 9:1, column temperature: 25°C.

[0733] C185 (18.7 min 15 mg) 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),7.80(d,J=7.8Hz,1H),7.59(d,J=3.3Hz,1H),7 .43–7.32(m,4H),7.32–7.23(m,1H),7.23–7.09(m,1H),6.52(d,J=3.5Hz,1H),6.30 (d,J=8.5Hz,1H),5.30(d,J=6.6Hz,1H),3.73(s,2H),3.58(s,2H),3.14(d,J=3.4Hz ,3H),2.82–2.73(m,2H),2.68(d,J=5.6Hz,2H),2.28(s,3H),1.54(d,J=6.6Hz,3H).

[0734] C186 (22 min 5 mg) 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.45(d,J=6.5Hz,1H),7.80(d,J=7.9Hz,1H),7.6 1(d,J=2.1Hz,1H),7.46–7.32(m,4H),7.29(t,J=6.9Hz,1H),7.17(t,J=7.8Hz,1H),6. 53(t,J=7.5Hz,1H),6.30(d,J=8.5Hz,1H),5.30(q,J=6.1Hz,1H),3.73(s,2H),3.57(s ,2H),2.75(q,J=5.7Hz,2H),2.66(t,J=5.8Hz,2H),2.30(s,3H),1.54(d,J=6.6Hz,3H).

[0735] The following compounds were synthesized using similar synthetic methods as described above:

[0736] Cell proliferation inhibition assay

[0737] 1. Experimental Materials

[0738] 2. Experimental Plan

[0739] 1. Cell plating

[0740] a) Preparation of cell suspension

[0741] b) removing the culture medium from the culture flask;

[0742] c) Rinse the cells once with PBS;

[0743] d) adding trypsin for digestion and collecting by centrifugation;

[0744] e) Resuspend in culture medium, count and adjust to the appropriate concentration.

[0745] f) Add the cell suspension to a 96-well plate at a volume of 100 μl per well, place one plate for each cell type, and culture overnight in a 37° C., 5% CO 2 incubator.

[0746] 2. Compound treatment

[0747] Compound dilution

[0748] a) Prepare a serial dilution of the test compound: Prepare a 10 mM stock solution of the compound. Dissolve 18 μl of the stock solution in 982 μl of DMSO medium. Perform a 4-fold serial dilution in 0.5% DMSO medium for a total of 9 concentrations. The compound concentrations after dilution are as follows:

[0749] 180000nM, 45000nM, 11250nM, 2812.5nM, 703.13nM, 175.78nM, 43.95nM, 10.99nM, 2.75nM

[0750] b) After thorough mixing, add 20 μl of compound solution to each well containing 100 μl of cells, using three replicates for each concentration. The final compound concentrations are as follows:

[0751] 30000nM, 7500nM, 1875nM, 468.75nM, 117.188nM, 29.30nM, 7.32nM, 1.83nM, 0.46nM

[0752] c) Transfer the cells to an incubator and incubate for 3 days.

[0753] 3. CTG test

[0754] Remove the cell culture plate and add 25ul CTG to a 96-well plate, shake at room temperature for 10 minutes, and read the plate.

[0755] 4. Data Analysis

[0756] The following formula was used to calculate the cell survival rate (%Cell Survival):

[0757] %Cell Survival=100%×(OD_Sample-OD_LCave) / (OD_HC-OD_LCave)

[0758] OD_HC: 0.1‰ DMSO control group cell reading

[0759] OD_Sample: Cell readings after compound addition

[0760] OD_LCave: blank culture medium reading

[0761] Analyed by Prizm:Dose-response-Inhibition-Log(inhibitor)vs response(three parameters for the best fit)

[0762] The results of the cell proliferation inhibition test are shown in Table 1 below.

[0763] Table 1 A stands for IC 50 ≤500nM; B means 500nM<IC 50 ≤2000nM; C means 2000nM<IC 50 ≤5000nM; D means 5000nM<IC 50 .

[0764] The present invention provides a series of compounds having selective inhibitory activity on PI3Kα H1047R mutation activity and a synthesis method thereof, which have broad application prospects.

[0765] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

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 selected from the following group: N, O, S, NR 11 , C(R 11 ) q ; X2 and X3 are each independently selected from the following group: N, C; X4 is N or CR; X5 is selected from the group consisting of: absent, O, NR 51 , C 1-6 Alkylene, C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene containing 1-4 heteroatoms selected from N, O or S, wherein the C 1-6 Alkylene, C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene, optionally substituted by 1, 2, 3, 4, 5 or 6 R 52 replace; X6 is selected from the group consisting of: absent, NR 61 , C 1-6 Alkylene, wherein the C 1-6 The alkylene group is optionally substituted with 1, 2, 3, 4, 5 or 6 R 62 replace; X7 is selected from the following group: C=O, C=S, CR 71 ; Ring B is: a 5-7 membered heterocycloalkyl group containing 1 N atom and 0-3 heteroatoms selected from N, O or S, optionally substituted by one or more R5; Ring A is selected from the following group: C 6-10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, 5-10 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; wherein the C 6-10 Aryl, 5-10 membered heteroaryl is optionally substituted by m R6; R, R2, R3, R 11 , R 52 , R 62 Each independently selected from the group consisting of H, deuterium, halogen, oxo (=O), -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, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, deuterated C 3-6 Cycloalkyl; Alternatively, R together with R2 and the atom to which it is attached forms C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; wherein the C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 or 6 R6; Alternatively, R2 and R3 together with the atom to which they are attached form a C 4-6 Cycloalkyl or containing 1-4 selected from N, O or S heteroatom 4-6 membered heterocycloalkyl; wherein said C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 or 6 R6; R 51 , R 61 Each independently selected from the following group: H, -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, deuterated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl; R 71 Selected from the following group: H, halogen, -CN, -NO2, 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, -C(O)R8; R4 is selected from the following group: -L-(C 1-6 Alkyl), -LC 6-10 Aryl, -L-(5-10 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, 5-10 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, 3-12 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 by 0-6 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 selected from the following group: C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, 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)-, wherein the C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, 1-6 membered heteroalkylene are optionally substituted with 0-6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NR8R9, =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 1-6 Alkylamino, halogenated C 1-6 Alkylamino, C 1-6 Alkylthio, halo 1-6 Alkylthio, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, halogenated C 3-6 Cycloalkyl, halogenated 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; Alternatively, R8, R9 and the heteroatom to which they are connected together form a 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocycloalkyl is 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, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, C 1-6 Alkylthio, halo 1-6 Alkylthio, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, halogenated C 3-6 Cycloalkyl, halogenated 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; Or, R9, R 10 The heteroatoms connected thereto form a 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocycloalkyl is 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, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, C 1-6 Alkylthio, halo 1-6 Alkylthio, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, halogenated C 3-6 Cycloalkyl, halogenated 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; each are each independently a single bond or a double bond; Each m, n, q is independently selected from the following group: 0, 1, 2, 3, 4, 5.

2. A compound, characterized in that The compound is a compound of formula (I-a), or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, in: X1 is selected from the following group: N, O, C (R 11 ) q ; 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, 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, R 11 Each is independently selected from the group consisting of 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 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 attached 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, n, q is independently selected from the following group: 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: in: X1 is selected from the following group: N, O, C (R 11 ) q ; 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, R3, R 11 Each is independently selected from the group consisting of 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-membered 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), 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; Each R6 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, Deuterium Generation 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 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 attached 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, n, and q are independently selected from: 0, 1, 2, 3, 4, and 5.

4. The compound according to claim 3, 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: Among them, R1, R2, R3, R4, R 11 , Y1, Y2, Y3, Y4, Ring A are as defined in claim 1 or 2; structure Contains the following configurations:

5. The compound according to claim 1 or 2, 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)R8, -C(O)OR8, -C(O)NR8R9, -SO2R8, -S(O)(NR8)R9, -SO2NR8R9, -P(O)R8R9; Each R8, R9 is as defined in claim 1 or 2; m is selected from: 0, 1, 2, 3, 4, 5.

6. The compound according to claim 1 or 2, 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 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, containing 1-4 3-6 membered heterocycloalkyl from N, O or S heteroatom, -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; Each R8, R9, R 10 As defined in claim 1 or 2; n is selected from the following group: 0, 1, 2, 3, 4, 5.

7. The compound according to claim 3, 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 4; X8 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)R8, -C(O)OR8, -C(O)NR8R9, -SO2R8, -S(O)(NR8)R9, -SO2NR8R9, -P(O)R8R9; m is selected from the following group: 0, 1, 2, 3, 4.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, characterized in that: The compound is selected from the group consisting of:

9. A pharmaceutical composition, characterized in that Comprising a safe and effective amount of the compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, deuterated substance, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

10. Use of a compound according to claim 1 or 2, 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.

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