PI3K inhibitor and application thereof

Abstract

The invention discloses a PI3K allosteric inhibitor and application thereof. The present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The phosphoinositide 3-kinase allosteric inhibitor disclosed by the invention can effectively inhibit PI3K alpha mutation in an allosteric targeting manner, particularly PI3K alpha H1047R mutation and PI3K alpha E545K mutation, has relatively good selectivity, and is expected to treat related diseases or obstacles. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly to a PI3K inhibitor and its use. Background Art

[0002] Phosphoinositide 3-kinase (PI3K) is an intracellular phosphatidylinositol kinase that plays a regulatory role in key cellular processes such as cell growth, proliferation, differentiation, and intracellular trafficking. PI3K can be divided into three classes (Class I, II, and III), among which the most widely studied is Class I PI3K. Class I PI3K can be further divided into two subclasses, IA and IB, based on the signaling pathway and regulatory proteins. Class IA PI3K (PI3Kα, PI3Kβ, and PI3Kδ) is located downstream of receptor tyrosine kinases (RTKs) and is a heterodimeric complex composed of a catalytic subunit p110 (p110α, p110β, and p110δ respectively) and a regulatory subunit p85 (such as p85α, p85β, p55δ, p55α, and p50α); Class IB PI3K (PI3Kγ) is located downstream of G protein-coupled receptors (GPCRs) and is a heterodimer composed of a catalytic subunit p110γ and a regulatory subunit p101 or p84. Class I PI3K is activated by receptor tyrosine kinases or G protein-coupled receptors to generate PIP3, which binds to downstream effectors such as Akt / PDKl, mTOR, Tec family kinases, and effectors in the Rho family GTPase pathway. The regulatory subunit contains domains that allow anchoring to cell surface receptors and other regulatory proteins; the catalytic subunit (p110α, p110β, p110γ, p110δ) contains an ATP binding domain. The catalytic subunit, especially its ATP binding site, has been the focus of research on small molecule inhibitors of PI3K.

[0003] PI3Kα and PI3Kβ are ubiquitously expressed in vivo, while PI3Kγ and PI3Kδ are mainly present in leukocytes. Dysregulation of PI3Kα and PI3Kβ is associated with the occurrence and development of solid tumor diseases; while dysregulation of PI3Kγ and PI3Kδ is associated with inflammatory and immune system diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma, and hematological malignancies.

[0004] Mutations in the PI3Kα-encoding gene or mutations that cause upregulation of PI3Kα occur in many human cancers, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and skin cancer. Mutations in the PI3Kα-encoding gene are point mutations clustered within several hotspots in the helical and kinase domains, such as E542K, E545K, and H1047R. Most of these mutations have been shown to be gain-of-function oncogenic mutations. Because of the high mutation rate of PI3Kα, targeting this pathway can provide valuable therapeutic opportunities.

[0005] Due to the central role of PI3Kα in regulating systemic glucose homeostasis, PI3Kα inhibition in patients often results in hyperglycemia and / or hyperinsulinemia. High levels of circulating insulin may have mitogenic and / or anti-apoptotic effects on cancer cells, thereby offsetting the anti-proliferative effects of PI3K inhibitors. In the case of cancers with mutant PI3Kα, one way to overcome the problem of compensatory production of insulin and / or glucose after systemic PI3Kα inhibition is to develop inhibitors that are more selective for mutant PI3Kα than wild-type PI3Kα, thereby limiting toxicity and allowing higher doses and more complete inhibition of the drug target.

[0006] A variety of PI3K inhibitors that have been developed to date (such as Taselisib, Buparlisib, etc.) are small molecule compounds that competitively bind to the ATP-binding site to block the phosphorylation of PIP2 and the formation of PIP3. These inhibitors inhibit multiple class IA PI3K isoforms and are referred to as "pan-PI3K" inhibitors. Pan-PI3K inhibitors have certain target-related toxicities, including diarrhea, rash, fatigue, and hyperglycemia. The toxicity of PI3K inhibitors depends on their isoform selectivity. Inhibition of PI3Kα is associated with hyperglycemia and rash, while inhibition of PI3Kδ or PI3Kγ is associated with diarrhea, myelosuppression, and transaminases (Hanker et al., Cancer Discovery (2019) PMID: 30837161). PI3Kα inhibitors that have been developed to date (such as Alpelisib), small molecule compounds also bind to the ATP-binding site of PI3K and are almost equivalent for wild-type and mutant PI3Kα, with side effects such as hyperglycemia. Therefore, there is still a need to continue to develop small molecule PI3Kα-selective inhibitors that abandon binding to the ATP-binding site of PI3K and allosterically target and inhibit PI3Kα mutants (such as PI3Kα H1047R mutation, PI3Kα E545K mutation) to treat related diseases (such as cancer) while avoiding dose-limiting toxicity. Summary of the Invention

[0007] The present invention aims to solve the problem of the single structure of PI3K inhibitors in the prior art, and provides an allosteric inhibitor of phosphoinositide 3-kinase for treating diseases or disorders related to PI3K regulation. The allosteric inhibitor of phosphoinositide 3-kinase of the present invention can effectively allosterically target and inhibit PI3Kα mutations, especially PI3Kα H1047R mutation and PI3Kα E545K mutation, has good selectivity, and is expected to treat related diseases or disorders.

[0008] The present invention solves the above technical problems through the following technical solutions.

[0009] The present invention provides a compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts,

[0010] ;

[0011] wherein,

[0012] X is CR 2 or N;

[0013] Y is CR 2 or N;

[0014] Each R 2 independently is hydrogen, deuterium, halogen, cyano, -N(R 7 )2, hydroxy, C 1-6 alkyl, C 2a alkyl substituted with one or more R 1-6 -O-C 1-6 alkyl, -O-C 2b alkyl substituted with one or more R 1-6 C 2-6 alkenyl, C 2c alkenyl substituted with one or more R 2-6 C 2-6 alkynyl, C 2d alkynyl substituted with one or more R 2-6 C 3-12 cycloalkyl, C 2e cycloalkyl substituted with one or more R 3-12 C 3-12 cycloalkenyl, C 2f cycloalkenyl substituted with one or more R 3-12 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted with one or more R 2g 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted with one or more R 2h C 6-10 aryl, C 2i aryl substituted with one or more R 6-10An aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl substituted with one or more R 2j ;

[0015] Each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , and R 2j is independently deuterium, a halogen, cyano, -NH2, hydroxy, C 1-6 alkyl, or -O-C 1-6 alkyl;

[0016] Each R 7 is independently hydrogen or C 1-6 alkyl;

[0017] R 1 is -N(R 8 )2, -NR 8 N(R 8 )2, or -NR 8 NR 8 C(=O)R 9 ;

[0018] Each R 8 is independently hydrogen, C 1-6 alkyl, C 8a alkyl substituted with one or more R 1-6 , C 2-6 alkenyl, C 8b alkenyl substituted with one or more R 2-6 , C 2-6 alkynyl, C 8c alkynyl substituted with one or more R 2-6 , C 3-12 cycloalkyl, C 8d cycloalkyl substituted with one or more R 3-12 , C 3-12 cycloalkenyl, C 8e cycloalkenyl substituted with one or more R 3-12 , 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkyl substituted with one or more R 8f , 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocycloalkenyl substituted with one or more R 8g , C 6-10 aryl, C 8h aryl substituted with one or more R 6-10 , 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl substituted with one or more R 8iSubstituted 5- to 10-membered heteroaryl;

[0019] Each R 8a 、R 8b 、R 8c 、R 8d 、R 8e 、R 8f 、R 8g 、R 8h and R 8i is independently deuterium, halogen, cyano, -NH2, hydroxy, C 1-6 alkyl or -O-C 1-6 alkyl;

[0020] R 9 is hydrogen, cyano, -N(R 10 )2, C 1-6 alkyl, C 9a alkyl substituted with one or more R 1-6 -O-C 1-6 alkyl, -O-C 9b alkyl substituted with one or more R 1-6 C 2-6 alkenyl, C 9c alkenyl substituted with one or more R 2-6 C 2-6 alkynyl, C 9d alkynyl substituted with one or more R 2-6 C 3-12 cycloalkyl, C 9e cycloalkyl substituted with one or more R 3-12 C 3-12 cycloalkenyl, C 9f cycloalkenyl substituted with one or more R 3-12 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkyl substituted with one or more R 9g 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocycloalkenyl substituted with one or more R 9h C 6-10 aryl, C 9i aryl substituted with one or more R 6-10 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl substituted with one or more R 9j ;

[0021] Each R 9a 、R 9b 、R 9c 、R 9d 、R 9e 、R 9f 、R 9g 、R 9h 、R 9i and R9j Each independently is deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, -C(=O)OR 12 , -C(=O)N(R 12 )2, C 1-6 alkyl, C 9-a alkyl substituted by one or more R 1-6 or -O-C 1-6 alkyl;

[0022] Each R 9-a is independently deuterium, a halogen, a cyano group, -N(R 13 )2, a hydroxyl group, C 3-12 cycloalkyl, C 9-aa cycloalkyl substituted by one or more R 3-12 , C 3-12 cycloalkenyl, C 9-bb cycloalkenyl substituted by one or more R 3-12 , a 3- to 12-membered heterocycloalkyl, a 3- to 12-membered heterocycloalkyl substituted by one or more R 9-cc , a 3- to 12-membered heterocycloalkenyl, a 3- to 12-membered heterocycloalkenyl substituted by one or more R 9-dd , C 6-10 aryl, C 9-ee aryl substituted by one or more R 6-10 , a 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl substituted by one or more R 9-ff ;

[0023] Each R 9-aa , R 9-bb , R 9-cc , R 9-dd , R 9-ee and R 9-ff are each independently deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, C 1-6 alkyl or -O-C 1-6 alkyl;

[0024] Each R 10 is independently hydrogen or C 1-6 alkyl;

[0025] Each R 12 is independently hydrogen, C 1-6 alkyl or C 12a alkyl substituted by one or more R 1-6 ;

[0026] Each R 12a is independently deuterium, a halogen, a cyano group, -NH2 or a hydroxyl group;

[0027] Each R 13 is independently hydrogen or C1-6 Alkyl;

[0028] R 3 independently is deuterium, halogen, cyano, -N(R 7 )2, hydroxy, C 1-6 alkyl, C 3a alkyl substituted by one or more R 1-6 -O-C 1-6 alkyl, -O-C 3b alkyl substituted by one or more R 1-6 alkyl, C 2-6 alkenyl, C 3c alkenyl substituted by one or more R 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 3d alkynyl, C 2-6 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 3e cycloalkyl, C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 3f 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkyl substituted by one or more R 3-12 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocycloalkenyl substituted by one or more R 3g aryl, C 3h aryl substituted by one or more R 6-10 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl substituted by one or more R 3i 6-10 3j ;

[0029] Each R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j and R 1-6 is independently deuterium, halogen, cyano, -NH2, hydroxy, C 1-6 alkyl or -O-C 1-6 alkyl;

[0030] Cy is or ;

[0031] Z is O or S;

[0032] R 4-1 and R4-2 Each independently is deuterium, a halogen, a cyano group, -N(R 11 )2, a hydroxyl group, C 1-6 alkyl, C 4a alkyl substituted with one or more R 1-6 -O-C 1-6 alkyl, -O-C 4b alkyl substituted with one or more R 1-6 -C 2-6 alkenyl, C 4c alkenyl substituted with one or more R 2-6 -C 2-6 alkynyl, C 4d alkynyl substituted with one or more R 2-6 -C 3-12 cycloalkyl, C 4e cycloalkyl substituted with one or more R 3-12 -C 3-12 cycloalkenyl, C 4f cycloalkenyl substituted with one or more R 3-12 -a 3- to 12-membered heterocycloalkyl, a 3- to 12-membered heterocycloalkyl substituted with one or more R 4g -a 3- to 12-membered heterocycloalkenyl, a 3- to 12-membered heterocycloalkenyl substituted with one or more R 4h -C 6-10 aryl, C 4i aryl substituted with one or more R 6-10 -a 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl substituted with one or more R 4j ;

[0033] Each R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , R 4h , R 4i and R 4j each independently is deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, C 1-6 alkyl or -O-C 1-6 alkyl;

[0034] R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , R 5-7 , R 5-8 and R 5-9 each independently is hydrogen, deuterium, a halogen, a cyano group, -N(R11 ) 2, hydroxy, C 1-6 alkyl, C substituted by one or more R 5a alkyl 1-6 -O-C 1-6 alkyl, -O-C substituted by one or more R 5b alkyl 1-6 alkyl, C 2-6 alkenyl, C substituted by one or more R 5c alkenyl 2-6 alkenyl, C 2-6 alkynyl, C substituted by one or more R 5d alkynyl 2-6 alkynyl, C 3-12 cycloalkyl, C substituted by one or more R 5e cycloalkyl 3-12 cycloalkyl, C 3-12 cycloalkenyl, C substituted by one or more R 5f cycloalkenyl 3-12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkyl substituted by one or more R 5g 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocycloalkenyl substituted by one or more R 5h 41, C 6-10 aryl, C substituted by one or more R 5i aryl 6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl substituted by one or more R 5j 5- to 10-membered heteroaryl, -S-C 1-6 alkyl or -S-C substituted by one or more R 5k alkyl 1-6 alkyl;

[0035] Each R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h , R 5i , R 5j and R 5k are each independently deuterium, halogen, cyano, -NH2, hydroxy, C 1-6 alkyl or -O-C 1-6 alkyl;

[0036] R 6 is hydrogen, deuterium, halogen, cyano, -N(R 11 )2, hydroxy, C 1-6 alkyl, C substituted by one or more R 6a alkyl 1-6Alkyl, -OC 1-6 Alkyl, with one or more R 6b Replaced-OC 1-6 Alkyl, C 2-6 Alkenyl, one or more R 6c Substituted C 2-6 Alkenyl, C 2-6 Alkynyl, with one or more R 6d Substituted C 2-6 Alkynyl, C 3-12 Cycloalkyl, with one or more R 6e Substituted C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, with one or more R 6f Substituted C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 6g substituted 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, substituted by one or more R 6h Substituted 3-12 membered heterocycloalkenyl, C 6-10 Aryl, one or more R 6i Substituted C 6-10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 6j Substituted 5-10 membered heteroaryl, -SC 1-6 Alkyl or one or more R 6k Substituted-SC 1-6 alkyl;

[0037] Each R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i , R 6j and R 6k are independently deuterium, halogen, cyano, -NH2, hydroxyl, C 1-6 Alkyl or -OC 1-6 alkyl;

[0038] Each R 11 are independently hydrogen or C 1-6 alkyl;

[0039] Furthermore, the compound of formula (I) satisfies at least one of the following conditions:

[0040] (1) R 1 For-NR 8 N(R 8 )2 or -NR8 NR 8 C(=O)R 9 ;

[0041] (2) Cy is ;

[0042] (3) R 6 is deuterium, cyano, -N(R 11 )2, hydroxy, C 1-6 alkyl, C 6a alkyl substituted with one or more R 1-6 -O-C 1-6 alkyl, -O-C 6b alkyl substituted with one or more R 1-6 C 2-6 alkenyl, C 6c alkenyl substituted with one or more R 2-6 C 2-6 alkynyl, C 6d alkynyl substituted with one or more R 2-6 C 3-12 cycloalkyl, C 6e cycloalkyl substituted with one or more R 3-12 C 3-12 cycloalkenyl, C 6f cycloalkenyl substituted with one or more R 3-12 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkyl substituted with one or more R 6g 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocycloalkenyl substituted with one or more R 6h C 6-10 aryl, C 6i aryl substituted with one or more R 6-10 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl substituted with one or more R 6j -S-C 1-6 alkyl or -S-C 6k alkyl substituted with one or more R 1-6 ;

[0043] (4) R 4-1 and R 4-2 are each independently deuterium, halogen, cyano, -N(R 11 )2, hydroxy, C 4a alkyl substituted with one or more R 1-6 -O-C 1-6 alkyl, -O-C 4b alkyl substituted with one or more R 1-6 C 2-6 alkenyl, C 4cSubstituted C 2-6 alkenyl, C 2-6 alkynyl, substituted by one or more R 4d substituted C 2-6 alkynyl, C 3-12 cycloalkyl, substituted by one or more R 4e substituted C 3-12 cycloalkyl, C 3-12 cycloalkenyl, substituted by one or more R 4f substituted C 3-12 cycloalkenyl, 3- to 12-membered heterocycloalkyl, substituted by one or more R 4g substituted 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, substituted by one or more R 4h substituted 3- to 12-membered heterocycloalkenyl, C 6-10 aryl, substituted by one or more R 4i substituted C 6-10 aryl, 5- to 10-membered heteroaryl or substituted by one or more R 4j substituted 5- to 10-membered heteroaryl;

[0044] * The configuration of the carbon atom at the position is R configuration, S configuration or a mixture of R configuration and S configuration;

[0045] In each "3- to 12-membered heterocycloalkyl", the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2, 3, 4 or 5;

[0046] In each "3- to 12-membered heterocycloalkenyl", the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2, 3, 4 or 5;

[0047] In each "5- to 10-membered heteroaryl", the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2, 3, 4 or 5.

[0048] In one embodiment, in the compound of formula I or its pharmaceutically acceptable salt, certain groups have the following definitions, and the definitions of the groups not mentioned are as described in any embodiment of the present invention (the content of this paragraph is hereinafter simply referred to as "in one embodiment").

[0049] In one embodiment, each halogen may independently be fluorine, chlorine, bromine or iodine, for example fluorine.

[0050] In one embodiment, each C 1-6 alkyl may independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl.

[0051] In one embodiment, each -O-C 1-6 alkyl group can independently be -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl or -O-sec-butyl.

[0052] In one embodiment, each -S-C 1-6 alkyl group can independently be -S-methyl, -S-ethyl, -S-n-propyl, -S-isopropyl, -S-n-butyl, -S-tert-butyl, -S-isobutyl or -S-sec-butyl, such as -S-methyl.

[0053] In one embodiment, each C 2-6 alkenyl group can independently be vinyl, propenyl, allyl, butenyl or pentenyl, such as .

[0054] In one embodiment, each C 2-6 alkynyl group can independently be ethynyl, propynyl, propargyl, butynyl or pentynyl, such as or .

[0055] In one embodiment, each C 3-12 cycloalkyl group can independently be C 3-8 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0056] In one embodiment, each C 3-12 cycloalkenyl group can independently be C 3-8 cycloalkenyl, preferably C 5-6 cycloalkenyl.

[0057] In one embodiment, each C 3-12 cycloalkenyl group independently contains one or more carbon-carbon sp 2 double bonds.

[0058] In one embodiment, each 3-12 membered heterocycloalkyl group can independently be a 3-8 membered heterocycloalkyl group; in the "3-8 membered heterocycloalkyl group", the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3.

[0059] In one embodiment, each 3-12 membered heterocycloalkyl group can independently be monocyclic or polycyclic, the polycyclic group can be a bridged ring, a fused ring or a spiro ring, and the polycyclic group can also be a bicyclic or tricyclic ring.

[0060] In one embodiment, each 3-12 membered heterocycloalkenyl group can independently be a 3-8 membered heterocycloalkenyl group; in the "3-8 membered heterocycloalkenyl group", the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3.

[0061] In one embodiment, each 3-12 membered heteroalkenyl may independently be monocyclic or polycyclic, and the polycycle may be a bridged ring, a fused ring or a spiro ring, and the polycycle may also be a bicyclic or a tricyclic ring.

[0062] In one embodiment, each 3-12 membered heteroalkenyl independently contains one or more carbon-carbon sp 2 double bonds.

[0063] In one embodiment, each C 6-10 aryl may independently be phenyl or naphthyl, such as phenyl.

[0064] In one embodiment, each 5-10 membered heteroaryl may independently be a 5-6 membered heteroaryl; in the “5-6 membered heteroaryl”, the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3.

[0065] In one embodiment, each 5-10 membered heteroaryl may independently be monocyclic or polycyclic, and the polycycle may be a bridged ring, a fused ring or a spiro ring; the polycycle may be a bicyclic or a tricyclic ring.

[0066] In one embodiment, X is CR 2 , preferably CH.

[0067] In one embodiment, Y is N.

[0068] In one embodiment, R 2 is hydrogen, deuterium, a halogen or C 1-6 alkyl, preferably hydrogen.

[0069] In one embodiment, R 1 is -NR 8 N(R 8 )2 or -NR 8 NR 8 C(=O)R 9 .

[0070] In one embodiment, each R 8 is independently hydrogen or C 1-6 alkyl, preferably hydrogen.

[0071] In one embodiment, R 9 is hydrogen, cyano, -N(R 10 )2, C 1-6 alkyl, C 9a alkyl substituted with one or more R 1-6 alkyl, C 2-6 alkenyl, C 9c alkenyl substituted with one or more R 2-6 alkenyl, C 2-6Alkynyl, C substituted with one or more R 9d Alkynyl or C 2-6 Alkynyl or C 3-12 Cycloalkyl, preferably hydrogen, cyano, -N(R 10 )2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C substituted with one or more R 9d Alkynyl, more preferably C 2-6 Alkynyl or C substituted with one or more R 2-6 Alkynyl or C 9d Alkynyl substituted with one or more R 2-6 Alkynyl.

[0072] In one embodiment, each R 9a , R 9c and R 9d is independently deuterium, halogen, cyano, -NH2, hydroxy, C 1-6 Alkyl, C alkyl substituted with one or more R 9-a or -O-C 1-6 Alkyl, preferably hydroxy, C 1-6 Alkyl or C alkyl substituted with one or more R 1-6 or -O-C 9-a Alkyl substituted with one or more R 1-6 Alkyl.

[0073] In one embodiment, each R 9-a is independently deuterium, halogen or hydroxy, preferably hydroxy.

[0074] In one embodiment, each R 10 is independently hydrogen or C 1-6 Alkyl, preferably hydrogen.

[0075] In one embodiment, R 3 is independently halogen, C 1-6 Alkyl or C alkyl substituted with one or more R 3a or -O-C 1-6 Alkyl, preferably C 1-6 Alkyl or C alkyl substituted with one or more R 3a or -O-C 1-6 Alkyl substituted with one or more R 3a or -O-C 1-6 Alkyl substituted with one or more R

[0076] In one embodiment, each R 3a is independently deuterium or halogen, preferably halogen.

[0077] In one embodiment, Z is O.

[0078] In one embodiment, R 4-1 and R4-2 Each independently is deuterium, a halogen, a cyano group, -N(R 11 )2, a hydroxyl group, C 1-6 alkyl, C 4a alkyl substituted by one or more R 1-6 alkyl or -O-C 1-6 alkyl, preferably -N(R 11 )2 or C 1-6 alkyl, more preferably C 1-6 alkyl.

[0079] In one embodiment, each R 4a is independently deuterium or a halogen.

[0080] In one embodiment, R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , R 5-7 , R 5-8 and R 5-9 are each independently hydrogen, deuterium, a halogen, C 1-6 alkyl or -O-C 1-6 alkyl, preferably hydrogen or a halogen;

[0081] More preferably, R 5-1 is a halogen, and R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , R 5-7 , R 5-8 and R 5-9 are hydrogen.

[0082] In one embodiment, R 6 is hydrogen, a halogen, a cyano group, -N(R 11 )2, a hydroxyl group, C 1-6 alkyl, C 6a alkyl substituted by one or more R 1-6 alkyl, -O-C 1-6 alkyl, C 2-6 alkenyl, C 6c alkenyl substituted by one or more R 2-6 alkenyl, C 2-6 alkynyl, C 6d alkynyl substituted by one or more R 2-6 alkynyl, C 3-12 cycloalkyl, -S-C 1-6 alkyl or -S-C 6k alkyl substituted by one or more R 1-6 alkyl, preferably hydrogen, a halogen, C2-6 alkenyl, C 2-6 alkynyl or -S-C 1-6 alkyl, more preferably C 2-6 alkenyl, C 2-6 alkynyl or -S-C 1-6 alkyl.

[0083] In one embodiment, each R 6a , R 6c , R 6d and R 6k are each independently deuterium, halogen, hydroxy or C 1-6 alkyl.

[0084] In one embodiment, each R 11 is independently hydrogen.

[0085] In one embodiment, the configuration of the carbon atom at the * position is the R configuration.

[0086] In one embodiment, the compound of formula (I) above satisfies at least one of the following conditions:

[0087] (1) R 1 is -NR 8 N(R 8 )2 or -NR 8 NR 8 C(=O)R 9 ;

[0088] (2) R 6 is deuterium, cyano, -N(R 11 )2, hydroxy, C 1-6 alkyl, C 6a alkyl substituted with one or more R 1-6 -O-C 1-6 alkyl, -O-C 6b alkyl substituted with one or more R 1-6 C 2-6 alkenyl, C 6c alkenyl substituted with one or more R 2-6 C 2-6 alkynyl, C 6d alkynyl substituted with one or more R 2-6 C 3-12 cycloalkyl, C 6e cycloalkyl substituted with one or more R 3-12 C 3-12 cycloalkenyl, C 6f cycloalkenyl substituted with one or more R 3-12 3- to 12-membered heterocycloalkyl, substituted with one or more R 6gSubstituted 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, or a group having one or more R 6h substituted 3- to 12-membered heterocycloalkenyl, C 6-10 aryl, or a group having one or more R 6i substituted C 6-10 aryl, 5- to 10-membered heteroaryl, or a group having one or more R 6j substituted 5- to 10-membered heteroaryl, -S-C 1-6 alkyl, or a group having one or more R 6k substituted -S-C 1-6 alkyl.

[0089] In one embodiment, the compound of formula (I) satisfies at least one of the following conditions:

[0090] (1) R 1 is -NR 8 N(R 8 )2 or -NR 8 NR 8 C(=O)R 9 ;

[0091] (2) Cy is ;

[0092] (3) R 6 is C 2-6 alkenyl, C 2-6 alkynyl, or -S-C 1-6 alkyl;

[0093] (4) R 4-1 and R 4-2 are each independently -N(R 11 )2.

[0094] In one embodiment, the compound of formula (I) satisfies at least one of the following conditions:

[0095] (1) R 1 is -NR 8 N(R 8 )2 or -NR 8 NR 8 C(=O)R 9 ;

[0096] (2) Cy is ;

[0097] (3) R 6 is C 2-6 alkenyl, C 2-6 alkynyl, or -S-C 1-6 alkyl.

[0098] In one embodiment, R1 -NH2, , , , , , , , or .

[0099] In one embodiment, X is CH or N.

[0100] In one embodiment, Y is CH or N.

[0101] In one embodiment, R 3 is -CF3.

[0102] In one embodiment, R 4-1 and R 4-2 are each independently methyl or -NH2.

[0103] In one embodiment, R 5-1 is F, R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , R 5-7 , R 5-8 and R 5-9 are hydrogen.

[0104] In one embodiment, R 6 is F, -S-Me, or .

[0105] In one embodiment, Cy is , , , , or .

[0106] In one embodiment,

[0107] X is CR 2 or N;

[0108] Y is CR 2 or N;

[0109] Each R 2 is independently hydrogen, deuterium, a halogen, or a C 1-6 alkyl;

[0110] R 1 is -N(R 8 )2, -NR 8N(R 8 )2 or -NR 8 NR 8 C(=O)R 9 ;

[0111] Each R 8 is independently hydrogen or C 1-6 alkyl;

[0112] R 9 is hydrogen, cyano, -N(R 10 )2, C 1-6 alkyl, C 9a alkyl substituted with one or more R 1-6 alkyl, C 2-6 alkenyl, C 9c alkenyl substituted with one or more R 2-6 alkenyl, C 2-6 alkynyl, C 9d alkynyl substituted with one or more R 2-6 alkynyl or C 3-12 cycloalkyl;

[0113] Each R 9a , R 9c and R 9d are each independently deuterium, halogen, cyano, -NH2, hydroxy, C 1-6 alkyl, C 9-a alkyl substituted with one or more R 1-6 alkyl or -O-C 1-6 alkyl;

[0114] Each R 9-a is independently deuterium, halogen or hydroxy;

[0115] Each R 10 is independently hydrogen or C 1-6 alkyl;

[0116] R 3 is independently halogen, C 1-6 alkyl or C 3a alkyl substituted with one or more R 1-6 alkyl;

[0117] Each R 3a is independently deuterium or halogen;

[0118] Cy is or ;

[0119] Z is O;

[0120] R 4-1 and R 4-2 are each independently deuterium, halogen, cyano, -N(R11 ) 2, hydroxy, C 1-6 alkyl, C alkyl substituted by one or more R 4a alkyl or -O-C 1-6 alkyl; 1-6 alkyl;

[0121] Each R 4a is independently deuterium or halogen;

[0122] Each R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , R 5-7 , R 5-8 and R 5-9 are each independently hydrogen, deuterium, halogen, C 1-6 alkyl or -O-C 1-6 alkyl;

[0123] R 6 is hydrogen, halogen, cyano, -N(R 11 )2, hydroxy, C 1-6 alkyl, C alkyl substituted by one or more R 6a alkyl, -O-C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C alkenyl substituted by one or more R 6c alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C alkynyl substituted by one or more R 6d alkyl, C 2-6 alkynyl, C 3-12 cycloalkyl, -S-C 1-6 alkyl or -S-C alkyl substituted by one or more R 6k alkyl; 1-6 alkyl;

[0124] Each R 6a , R 6c , R 6d and R 6k are each independently deuterium, halogen, hydroxy or C 1-6 alkyl;

[0125] Each R 11 is independently hydrogen;

[0126] And, the compound of formula (I) satisfies at least one of the following conditions:

[0127] (1) R 1 is -NR 8 N(R 8 )2 or -NR8 NR 8 C(=O)R 9 ;

[0128] (2) Cy is ;

[0129] (3) R 6 is C 2-6 alkenyl, C 2-6 alkynyl or -S-C 1-6 alkyl;

[0130] (4) R 4-1 and R 4-2 are each independently -N(R 11 )2;

[0131] The configuration of the carbon atom at the * position is the R configuration, the S configuration, or a mixture of the R configuration and the S configuration;

[0132] In each "3- to 12-membered heterocycloalkyl", the types of heteroatoms are each independently selected from one, two, or more of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3;

[0133] In each "3- to 12-membered heterocycloalkenyl", the types of heteroatoms are each independently selected from one, two, or more of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3;

[0134] In each "5- to 10-membered heteroaryl", the types of heteroatoms are each independently selected from one, two, or more of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3;

[0135] Preferably, the compound in this scheme is not , , , , or .

[0136] In one scheme,

[0137] X is CR 2 or N;

[0138] Y is CR 2 or N;

[0139] Each R 2 is independently hydrogen, deuterium, halogen, or C 1-6 alkyl;

[0140] R 1 is -NR 8 N(R 8 )2 or -NR8 NR 8 C(=O)R 9 ;

[0141] Each R 8 is independently hydrogen or C 1-6 alkyl;

[0142] R 9 is hydrogen, cyano, -N(R 10 )2, C 1-6 alkyl, C 9a alkyl substituted with one or more R 1-6 alkyl, C 2-6 alkenyl, C 9c alkenyl substituted with one or more R 2-6 alkenyl, C 2-6 alkynyl, C 9d alkynyl substituted with one or more R 2-6 alkynyl or C 3-12 cycloalkyl;

[0143] Each R 9a , R 9c and R 9d are each independently deuterium, halogen, cyano, -NH2, hydroxy, C 1-6 alkyl, C 9-a alkyl substituted with one or more R 1-6 alkyl or -O-C 1-6 alkyl;

[0144] Each R 9-a is independently deuterium, halogen or hydroxy;

[0145] Each R 10 is independently hydrogen or C 1-6 alkyl;

[0146] R 3 is independently halogen, C 1-6 alkyl or C 3a alkyl substituted with one or more R 1-6 alkyl;

[0147] Each R 3a is independently deuterium or halogen;

[0148] Cy is or ;

[0149] Z is O;

[0150] R 4-1 and R 4-2 are each independently deuterium, halogen, cyano, -N(R 11 )2, hydroxy, C1-6 An alkyl group, a C alkyl group substituted with one or more R 4a alkyl group, or -O-C 1-6 alkyl group; 1-6

[0151] Each R 4a is independently deuterium or a halogen;

[0152] Each R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , R 5-7 , R 5-8 and R 5-9 are each independently hydrogen, deuterium, a halogen, a C 1-6 alkyl group, or -O-C 1-6 alkyl group;

[0153] R 6 is hydrogen, a halogen, a cyano group, -N(R 11 )2, a hydroxyl group, a C 1-6 alkyl group, a C alkyl group substituted with one or more R 6a alkyl group, -O-C 1-6 alkyl group, a C 1-6 alkenyl group, a C alkenyl group substituted with one or more R 2-6 alkenyl group, a C 6c alkynyl group, a C alkynyl group substituted with one or more R 2-6 alkynyl group, a C 2-6 cycloalkyl group, -S-C 6d alkyl group, or a -S-C alkyl group substituted with one or more R 2-6 alkyl group; 3-12 1-6 6k 1-6 6a 6c 6d 6k

[0154] Each R 6a , R 6c , R 6d and R 6k are each independently deuterium, a halogen, a hydroxyl group, or a C 1-6 alkyl group;

[0155] Each R 11 is independently hydrogen;

[0156] The configuration of the carbon atom at the * position is the R configuration, the S configuration, or a mixture of the R configuration and the S configuration;

[0157] In each "3- to 12-membered heterocycloalkyl group", the types of heteroatoms are each independently selected from one, two, or more of N, O, and S, and the number of heteroatoms is each independently 1, 2, or 3;​

[0158] In each “3- to 12-membered heteroalkenyl”, the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3;

[0159] In each “5- to 10-membered heteroaryl”, the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3.

[0160] In one embodiment, the compound of formula (I) above is a compound of formula (II) below,

[0161] ;

[0162] wherein,

[0163] R 1 is -NHNH2 or -NHNHC(=O)R 9 ;

[0164] R 9 is hydrogen, cyano, -NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 9d alkynyl substituted with one or more R 2-6 ;

[0165] Each R 9d is independently hydroxy, C 1-6 alkyl or C 1-6 alkyl substituted with one or more hydroxy groups;

[0166] R 3 is C 1-6 alkyl or C 1-6 alkyl substituted with one or more halogens;

[0167] R 4-1 is -NH2 or C 1-6 alkyl;

[0168] R 5-1 is halogen;

[0169] R 6 is hydrogen, halogen, C 2-6 alkenyl, C 2-6 alkynyl or -S-C 1-6 alkyl;

[0170] X is CH or N;

[0171] Y is CH or N;

[0172] The configuration of the carbon atom at the * position is R configuration, S configuration, or a mixture of R configuration and S configuration.

[0173] In one embodiment, the compound of formula (I) above is the compound of formula (III) below,

[0174] ;

[0175] wherein,

[0176] R 1 is -NH2, -NHNH2 or -NHNHC(=O)R 9 ;

[0177] R 9 is hydrogen, cyano, -NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C alkynyl substituted by one or more R 9d ; 2-6 Each R

[0178] is independently hydroxy, C 9d alkyl or C alkyl substituted by one or more hydroxy groups 1-6 ; 1-6 R

[0179] is C 3 alkyl or C alkyl substituted by one or more halogens 1-6 ; 1-6 R

[0180] is -NH2 or C 4-2 alkyl; 1-6 X is CH or N;

[0181] Y is CH or N;

[0182] The configuration of the carbon atom at the * position is R configuration, S configuration, or a mixture of R configuration and S configuration;

[0183] Preferably, the compound in this embodiment is not

[0184] or ; or ;

[0185] In one embodiment, the compound of formula (I) above is the compound of formula (II) below,

[0186] ;

[0187] wherein,

[0188] R 1-NH2, -NHNH2 or -NHNHC(=O)R 9 ;

[0189] R 9 is hydrogen, cyano, -NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C alkynyl substituted with one or more R 9d ; 2-6 alkynyl;

[0190] Each R 9d is independently hydroxy, C 1-6 alkyl or C alkyl substituted with one or more hydroxy groups 1-6 ;

[0191] R 3 is C 1-6 alkyl or C alkyl substituted with one or more halogens 1-6 ;

[0192] R 4-1 is -NH2 or C 1-6 alkyl;

[0193] R 5-1 is halogen;

[0194] R 6 is C 2-6 alkenyl, C 2-6 alkynyl or -S-C 1-6 alkyl;

[0195] X is CH or N;

[0196] Y is CH or N;

[0197] The configuration of the carbon atom at the * position is R configuration, S configuration or a mixture of R configuration and S configuration.

[0198] In one embodiment, the compound of formula (I) above is the compound of formula (IV) below,

[0199] ;

[0200] wherein,

[0201] R 1 is -NHNH2 or -NHNHC(=O)R 9 ;

[0202] R 9 is C 2-6 alkynyl or C alkynyl substituted with one or more R 9d ; 2-6 alkynyl;

[0203] Each R 9d is independently a hydroxyl group, C 1-6 alkyl, or C 1-6 alkyl substituted by one or more hydroxyl groups;

[0204] R 3 is C 1-6 alkyl substituted by one or more halogens;

[0205] R 4-1 is -NH2 or C 1-6 alkyl;

[0206] R 5-1 is a halogen;

[0207] R 6 is hydrogen, a halogen, C 2-6 alkenyl, C 2-6 alkynyl, or -S-C 1-6 alkyl;

[0208] The configuration of the carbon atom at the * position is the R configuration, the S configuration, or a mixture of the R configuration and the S configuration.

[0209] In one embodiment, the compound of formula (I) is any of the following compounds:

[0210] , , , , , , , , , , , , , or .

[0211] In one embodiment, the compound of formula (I) is any of the following compounds:

[0212] or .

[0213] In one embodiment, the compound of formula (I) is any of the following compounds:

[0214] and The compound that elutes first under the following conditions: Instrument: SFC-150 (Waters), Chiral column: IG 25*250mm, 10µm (Daicel), Column temperature: 35 ºC, Mobile phase: CO2 / MeOH[0.2%NH3(7M in MeOH) ] = 70 / 30, Flow rate: 100mL / min, Detection wavelength: 214 nm; Preferably, under the above conditions, the retention time of the compound that elutes first is 1.86 min;

[0215] and The compound that elutes later under the following conditions: Instrument: SFC-150 (Waters), Chiral column: IG 25*250mm, 10µm (Daicel), Column temperature: 35 ºC, Mobile phase: CO2 / MeOH[0.2%NH3(7M in MeOH) ] = 70 / 30, Flow rate: 100mL / min, Detection wavelength: 214 nm; Preferably, under the above conditions, the retention time of the compound that elutes later is 2.6 min.

[0216] The present invention also provides any of the intermediates described in the present invention.

[0217] The present invention also provides a method for preparing the compound represented by Formula I as described above, which is any of the following routes:

[0218] Synthesis Route 1:

[0219] When R 1 is -NHNH2 or -NHNHC(=O)R 9 , and Cy is , it can be prepared by the following method:

[0220] ;

[0221] Step 1: Perform a substitution reaction in the presence of a base or under neutral conditions. The operating conditions of the substitution reaction can be the conventional operations and conditions of this type of reaction in the art. The base can be N,N-diisopropylethylamine, sodium carbonate, etc.;

[0222] Step 2: Perform a reduction reaction in the presence of a reducing agent. The operating conditions of the reduction reaction can be the conventional operations and conditions of this type of reaction in the art. The reducing agent can be iron powder, zinc powder, etc.;

[0223] Step 3: Perform an acylation reaction in the presence of a base or under neutral conditions. The operating conditions of the acylation reaction can be the conventional operations and conditions of this type of reaction in the art. The base can be N,N-diisopropylethylamine, sodium carbonate, etc.;

[0224] Step 4: Transamidation reaction in the presence of a base. The operating conditions of the transamidation reaction can be the conventional operations and conditions for this type of reaction in the art. The base can be N,N-diisopropylethylamine, pyridine, etc.;

[0225] Step 5: Deprotection reaction in the presence of an acid. The operating conditions of the deprotection reaction can be the conventional operations and conditions for this type of reaction in the art. The acid can be hydrochloric acid, trifluoroacetic acid, etc.;

[0226] Step 6: Acid-amine condensation reaction in the presence of a condensing agent. The operating conditions of the condensation reaction can be the conventional operations and conditions for this type of reaction in the art. The condensing agent can be 2-(7-azabenzotriazol)-N,N,N ， N ， -tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, etc.;

[0227] Synthetic route two:

[0228] When R 1 is -NH2, Cy is and R 6 is -S-C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, it can be prepared by the following method:

[0229] ;

[0230] Step 1: Acetylation reaction in the presence of a base. The operating conditions of the acetylation reaction can be the conventional operations and conditions for this type of reaction in the art. The base can be triethylamine, N,N-diisopropylethylamine, etc.;

[0231] Step 2: Rearrangement reaction in the presence of a Lewis acid. The operating conditions of the rearrangement reaction can be the conventional operations and conditions for this type of reaction in the art. The Lewis acid can be trifluoromethanesulfonic acid, anhydrous aluminum trichloride, etc.;

[0232] Step 3: Substitution and ring-closing reaction in the presence of a base. The operating conditions of the reaction can be the conventional operations and conditions for this type of reaction in the art. The base can be potassium carbonate, N,N-diisopropylethylamine, etc.;

[0233] Step 4: Addition and dehydration reaction in the presence of a base or under neutral conditions. The operating conditions of the addition and dehydration reaction can be the conventional operations and conditions for this type of reaction in the art. The base can be sodium acetate, potassium carbonate, etc.;

[0234] Step 5: Perform a reduction reaction in the presence of a reducing agent. The operating conditions of the reduction reaction can be the conventional operations and conditions for this type of reaction in the art. The reducing agent can be iron powder, zinc powder, etc.;

[0235] Step 6: A coupling reaction catalyzed by a palladium reagent or a copper reagent. The operating conditions of the coupling reaction can be the conventional operations and conditions for this type of reaction in the art. The palladium reagent can be tris(dibenzylideneacetone)palladium, palladium acetate, etc., and the copper reagent can be cuprous iodide, etc.;

[0236] Step 7: An amine transesterification reaction in the presence of a base. The operating conditions of the amine transesterification reaction can be the conventional operations and conditions for this type of reaction in the art. The base can be N,N-diisopropylethylamine, sodium carbonate, etc.;

[0237] Synthetic Route 3:

[0238] When R 1 is -NH2, Cy is and R 4-1 is -NH2, it can be prepared by the following method:

[0239] ;

[0240] Step 1: A substitution and ring - closing reaction in the presence of a base. The operating conditions of the reaction can be the conventional operations and conditions for this type of reaction in the art. The base can be potassium carbonate, N,N - diisopropylethylamine, etc.;

[0241] Step 2: An amino - protection reaction in the presence of a base. The operating conditions of the amino - protection reaction can be the conventional operations and conditions for this type of reaction in the art. The base can be triethylamine, sodium bicarbonate, etc.;

[0242] Step 3: An addition - dehydration reaction in the presence of a base or under neutral conditions. The operating conditions of the addition - dehydration reaction can be the conventional operations and conditions for this type of reaction in the art. The base can be sodium acetate, potassium carbonate, etc.;

[0243] Step 4: A reduction reaction in the presence of a reducing agent. The operating conditions of the reduction reaction can be the conventional operations and conditions for this type of reaction in the art. The reducing agent can be iron powder, zinc powder, etc.;

[0244] Step 5: An amine transesterification reaction in the presence of a base. The operating conditions of the amine transesterification reaction can be the conventional operations and conditions for this type of reaction in the art. The base can be N,N - diisopropylethylamine, sodium carbonate, etc.;

[0245] Step 6: Perform a de - protection reaction in the presence of a de - protection reagent. The operating conditions of the de - protection reaction can be the conventional operations and conditions for this type of reaction in the art. The de - protection reagent can be hydrochloric acid, trifluoroacetic acid, etc.;

[0246] Synthetic Route Four:

[0247] When R 1 is -NH2 and Cy is it can be prepared by the following method:

[0248] ;

[0249] Step 1a: Transamination reaction in the presence of a base, the operating conditions of the transamination reaction can be the conventional operations and conditions of this type of reaction in the art, and the base can be N,N - diisopropylethylamine, sodium carbonate, etc.;

[0250] Step 1b: Urea synthesis reaction in the presence of a base, the operating conditions of the urea synthesis reaction can be the conventional operations and conditions of this type of reaction in the art, and the base can be N,N - diisopropylethylamine, sodium carbonate, etc.;

[0251] Step 2: Coupling reaction in the presence of a palladium catalyst, the operating conditions of the coupling reaction can be the conventional operations and conditions of this type of reaction in the art, and the palladium catalyst can be palladium acetate, tris(dibenzylideneacetone)palladium, etc.;

[0252] Step 3: Deprotection reaction in the presence of a deprotection reagent, the operating conditions of the deprotection reaction can be the conventional operations and conditions of this type of reaction in the art, and the deprotection reagent can be hydrochloric acid, trifluoroacetic acid, etc.

[0253] The present invention also provides a pharmaceutical composition, which comprises the compound represented by formula (I) as described in any one of the above - mentioned schemes, its stereoisomers or its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient; preferably, the compound represented by formula (I), its stereoisomers or its pharmaceutically acceptable salts are in a therapeutically effective amount.

[0254] The present invention also provides the use of the compound represented by formula (I), its stereoisomers or its pharmaceutically acceptable salts or the above - mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing tumors; the tumors are preferably endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer; the breast cancer is preferably ductal carcinoma of the breast; preferably, the compound represented by formula (I), its stereoisomers or its pharmaceutically acceptable salts are in a therapeutically effective amount.

[0255] The present invention also provides the use of a compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts, or the above-mentioned pharmaceutical composition, in the preparation of a medicament for treating and / or preventing diseases or disorders related to PI3Kα regulation; the diseases or disorders related to PI3Kα regulation are preferably tumors, such as endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer; the breast cancer is preferably ductal carcinoma of the breast; preferably, the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts are in a therapeutically effective amount.

[0256] The present invention also provides the use of a compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts, or the above-mentioned pharmaceutical composition, in the preparation of a medicament for treating and / or preventing diseases or disorders related to PI3Kα regulation; the diseases or disorders related to PI3Kα regulation are preferably CLOVES syndrome (such as manifested as congenital lipomatosis overgrowth, vascular malformation, epidermal nevus, scoliosis, skeletal abnormalities or spinal abnormalities) or PI3Kα-related overgrowth syndrome (PROS); preferably, the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts are in a therapeutically effective amount.

[0257] The present invention also provides the use of a compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts, or the above-mentioned pharmaceutical composition, in the preparation of a medicament for treating and / or preventing CLOVES syndrome (such as manifested as congenital lipomatosis overgrowth, vascular malformation, epidermal nevus, scoliosis, skeletal abnormalities or spinal abnormalities) or PI3Kα-related overgrowth syndrome (PROS); preferably, the compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts are in a therapeutically effective amount.

[0258] The present invention also provides the use of a compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts, or the above-mentioned pharmaceutical composition, in the preparation of a PI3Kα inhibitor.

[0259] The said PI3Kα inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: provided as a standard or control sample for comparison, or made into a kit according to the conventional methods in the art to provide a rapid detection for the effect of inhibiting PI3Kα.

[0260] The present invention also provides a method for treating and / or preventing tumors, which comprises administering to a patient a therapeutically effective amount of a compound represented by formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition; the tumor is preferably endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer; the breast cancer is preferably ductal carcinoma of the breast.

[0261] The present invention also provides a method for treating and / or preventing a disease or disorder related to PI3Kα regulation, which comprises administering to a patient a therapeutically effective amount of a compound represented by formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition; the disease or disorder related to PI3Kα regulation is preferably a tumor, such as endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer; the breast cancer is preferably ductal carcinoma of the breast.

[0262] The present invention also provides a method for treating and / or preventing a disease or disorder related to PI3Kα regulation, which comprises administering to a patient a therapeutically effective amount of a compound represented by formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition; the disease or disorder related to PI3Kα regulation is preferably CLOVES syndrome (such as manifested by congenital lipomatosis overgrowth, vascular malformation, epidermal nevus, scoliosis, skeletal abnormalities or spinal abnormalities) or PI3Kα-related overgrowth syndrome (PROS).

[0263] The present invention also provides a method for treating and / or preventing CLOVES syndrome (such as manifested by congenital lipomatosis overgrowth, vascular malformation, epidermal nevus, scoliosis, skeletal abnormalities or spinal abnormalities) or PI3Kα-related overgrowth syndrome (PROS), which comprises administering to a patient a therapeutically effective amount of a compound represented by formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0264] The present invention also provides a method for inhibiting PI3Kα, which comprises administering to a patient a therapeutically effective amount of a compound represented by formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0265] The PI3Kα as described above is a PI3Kα mutation, preferably a PI3Kα H1047R mutation or a PI3Kα E545K mutation, more preferably a PI3Kα H1047R mutation.

[0266] Unless otherwise specifically indicated, the following terms have the meanings shown below.

[0267] The total number of carbon atoms present in certain chemical groups defined herein is indicated by a simplified symbol in front of the group. For example, C1-C6 alkyl or C1-6 alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5, or 6 carbon atoms.

[0268] In this document, numerical ranges defined for substituents such as 0 to 10, 1-6, 1-3, etc. indicate integers within that range, e.g., 1-6 being 1, 2, 3, 4, 5, or 6.

[0269] The term "comprising" is an open-ended expression, i.e., it includes what is specified in the present invention but does not exclude other aspects.

[0270] The term "substituted by" or "substituted with" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence of the particular atom is normal and the resulting compound is stable.

[0271] Generally, the term "substituted" or "substitution" means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Further, when the group is substituted by more than one of the said substituents, the substituents are independent of each other, i.e., the more than one substituents can be different from each other or the same. Unless otherwise indicated, a substituent group can substitute at each substitutable position of the group being substituted. When there is more than one position in the given structural formula that can be substituted by one or more substituents selected from a specific group, then the substituents can substitute at each position either identically or differently.

[0272] Those skilled in the art will understand that, according to the convention used in the art, the " " used in the structural formula describing the group in the present invention means that the corresponding group R is connected to other fragments and groups in the compound through this site.

[0273] As used herein, the terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" refer to a specific fragment or functional group in a molecule.

[0274] When it is not specified which atom of a listed substituent is connected to the general chemical structure formula (including compounds not specifically mentioned), such a substituent can be bonded through any of its atoms. Combinations of substituents and / or their variants are only allowed if such combinations result in a stable compound.

[0275] When it is not explicitly indicated that a listed group has a substituent, such a group only refers to being unsubstituted. For example, when "C 1-6 alkyl" has no limitation of "substituted or unsubstituted", it only refers to "C 1-6"Alkyl" per se or "unsubstituted C" 1-6 "alkyl".

[0276] The term "plurality" means 2, 3, 4 or 5.

[0277] When the term "one or more" is used to define the number of a certain group, it means 1, 2, 3, 4 or more.

[0278] In the claims, "one or more of the following conditions are satisfied", the "one or more" means 1, 2, 3, 4 or more, and the maximum value of the "more" is based on the numerical value of the maximum number of conditions recited in each claim. For example, if a claim recites 8 conditions, the "one or more" in "it satisfies one or more of the following conditions" in this claim is any integer from 1 to 8, such as 1, 2, 3, 4, 5, 6, 7 or 8.

[0279] In the claims, "one or more of the following conditions are satisfied", the "one or more" means 1, 2, 3, 4 or more, and the maximum value of the "more" is based on the numerical value of the maximum number of conditions recited in each claim. For example, if a claim recites 8 conditions, the "one or more" in "it satisfies one or more of the following conditions" in this claim is any integer from 1 to 8, such as 1, 2, 3, 4, 5, 6, 7 or 8.

[0280] "Halogen" means F, Cl, Br, I.

[0281] In the present invention, the term "alkyl" means a saturated straight-chain or branched-chain monovalent hydrocarbon group. C 1-6 The alkyl is an alkyl having 1-6 carbon atoms, preferably a C alkyl having 1-4 carbon atoms 1-4 alkyl, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0282] In the present invention, the term "-O-C" 1-6 "alkyl" means an alkoxy group, where "C" 1-6 "alkyl" is defined as above. Preferably, it is an alkoxy group having 1-4 carbon atoms, such as -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl or -O-sec-butyl.

[0283] In the present invention, the term "-S-C" 1-6 "alkyl" in "C" 1-6 "alkyl" is defined as above. Preferably, it is -S-C 1-4Alkyl groups, such as -S-methyl, -S-ethyl, -S-n-propyl, -S-isopropyl, -S-n-butyl, -S-tert-butyl, -S-isobutyl or -S-sec-butyl.

[0284] In the present invention, the term "C 2-6 alkynyl" refers to a straight-chain or branched-chain, unsaturated monovalent hydrocarbon group having from C2 to C6 carbon atoms and having one or more (e.g., 1, 2 or 3) carbon-carbon sp 3 triple bonds, preferably C 2-4 alkynyl; alkynyl groups include but are not limited to: or .

[0285] In the present invention, the term "C 2-6 alkenyl" refers to a straight-chain or branched-chain, unsaturated monovalent hydrocarbon group having from C2 to C6 carbon atoms and having one or more (e.g., 1, 2 or 3) carbon-carbon sp 2 double bonds, preferably C 2-4 alkenyl. Alkenyl groups include but are not limited to: etc.

[0286] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (spiro, bridged or fused) cyclic group having a specified number of ring carbon atoms (e.g., C 3-8 or C 3-12 ), the ring atoms of which consist only of carbon atoms; the polycyclic ring can be 2 or 3. Cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0287] In the present invention, the term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more ring bridged, fused (condensed) or spiro systems) non-aromatic carbocyclic substituent having at least one carbon-carbon sp 2 double bond; such as C 3-12 cycloalkenyl having 3 to 12 carbon atoms, more preferably C 3-8 cycloalkenyl having 3 to 8 carbon atoms, and most preferably C 5-6 cycloalkenyl having 5 to 6 carbon atoms. Examples of cycloalkenyl groups include but are not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, etc.

[0288] In the present invention, the term "heterocycloalkyl" refers to a saturated monovalent group having a specified number of ring atoms (e.g., 3 - 12 membered, 3 - 8 membered, 4 - 6 membered, 7 - 10 membered), a specified number of heteroatoms (e.g., 1, 2, 3, 4 or 5), a specified type of heteroatoms (one, two or more of N, O and S), which is monocyclic or polycyclic (e.g., bicyclic, tricyclic or more ring bridged, fused (condensed) or spiro ring systems), and is connected to the rest of the molecule through a carbon atom or a heteroatom. Examples of heterocycloalkyl include, but are not limited to, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl, oxetanyl, azetidinyl, etc.

[0289] In the present invention, the term "heterocycloalkenyl" refers to a cyclic, unsaturated monovalent hydrocarbon group having a specified number of ring atoms (e.g., 3 - 12 membered, 3 - 8 membered, 4 - 6 membered, 7 - 10 membered), a specified number of heteroatoms (e.g., 1, 2, 3, 4 or 5), a specified type of heteroatoms (one, two or more of N, O and S), which has one or more (e.g., 1, 2 or 3) carbon - carbon sp 2 double bonds, and is monocyclic or polycyclic (e.g., bicyclic, tricyclic or more ring bridged, fused (condensed) or spiro ring systems), and is not aromatic. The heterocycloalkenyl is connected to the rest of the molecule through a carbon atom or a heteroatom.

[0290] The term "aryl" refers to an aromatic group having a specified number of ring carbon atoms (e.g., C 6-10 )). Examples of aryl include, but are not limited to, phenyl or naphthyl.

[0291] In the present invention, the term "heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5 - 10 membered, 5 - 6 membered, 9 - 10 membered), a specified number of heteroatoms (e.g., 1, 2, 3, 4 or 5), a specified type of heteroatoms (one, two or more of N, O and S), which is monocyclic or polycyclic; when it is polycyclic, two atoms and one bond are shared between every two monocycles, and at least one ring has aromaticity. The heteroaryl is connected to the rest of the molecule through a carbon atom or a heteroatom; the heteroaryl is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; the heteroaryl is connected to the rest of the molecule through an aromatic ring or a non - aromatic ring. Examples of heteroaryl include, but are not limited to, pyridyl, pyrimidinyl, pyrazolyl, thienyl, pyrrolyl, quinolinyl, quinazolinyl, indolyl, etc.

[0292] The term "pharmaceutically acceptable salt" refers to salts prepared from the compounds of the present invention with relatively non-toxic, pharmaceutically acceptable acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.

[0293] The term "stereoisomer" refers to cis-trans isomers or optical isomers. Cis-trans isomers are isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely, and optical isomers are stereoisomers with different optical rotation properties caused by the absence of anti-axis symmetry in the molecule. They can be defined as (R)- / (S)- or (D)- / (L)- or (R,R)- / (R,S)- / (S,S)- according to the absolute stereochemistry of amino acids. Optical (+) and (-), (R)- and (S)-, and (R,R)- / (R,S)- / (S,S)- or (D)- and (L)- isomers can be synthesized using chiral starting materials, prepared by chiral resolution, or can be resolved using conventional techniques such as, but not limited to, high performance liquid chromatography (HPLC) using chiral columns. In the chemical structure, the bond " " does not specify the configuration, that is, if there is configurational isomerism in the chemical structure, the bond " " can be " " or " ", or can contain both " " and " " two configurations.

[0294] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, and are all substances contained in pharmaceutical preparations except for the active ingredients. See the fourth part of the Pharmacopoeia of the People's Republic of China (2020 edition), or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0295] The term "treatment" refers to therapeutic treatment. When referring to a specific disease or disorder, treatment means: (1) alleviating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade that causes or gives rise to the disorder or (b) one or more biological manifestations of the disorder, (3) improving one or more symptoms, effects, or side effects associated with the disorder, or one or more symptoms, effects, or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.

[0296] The term "prevention" means a reduction in the risk of acquiring or developing a disease or disorder.

[0297] The term "therapeutically effective amount" means an amount of a compound that is sufficient to effectively treat a disease or disorder described herein when administered to a patient. A "therapeutically effective amount" will vary depending on the compound, the disorder and its severity, and the age of the patient to be treated, but can be adjusted by those skilled in the art as needed.

[0298] The term "patient" means any animal that is about to or has received administration of the compound or composition according to an embodiment of the present invention, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.

[0299] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0300] The reagents and raw materials used in the present invention are all commercially available.

[0301] The positive and progressive effects of the present invention are as follows: The allosteric inhibitor of phosphoinositide 3-kinase of the present invention can effectively allosterically target and inhibit PI3Kα mutations, especially PI3Kα H1047R mutations and PI3Kα E545K mutations, has good selectivity, and is expected to treat related diseases or disorders. Detailed Description of the Invention

[0302] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the examples described herein. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0303] Synthesis of Intermediates

[0304] Intermediate 1: 1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-amine

[0305]

[0306] 1-(5,7-Difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-amine (4.5 g) was synthesized according to Examples 60 and 126 of the reference patent WO2022265993.

[0307] MS: m / z: 266[M+H] +

[0308] Intermediate 2: [(2-Aminopyrimidin-5-yl)amino]methanic acid 4-nitrophenyl ester

[0309] Step 1: 5-Nitropyrimidin-2-amine

[0310] 2-Chloro-5-nitropyrimidine (1.0 g, 6.3 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), ammonia water (1.0 ml, 6.3 mmol, 1.0 eq) was added, and the reaction was carried out at room temperature for 1 hour. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL) three times. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 5-nitropyrimidin-2-amine (0.8 g, yield 91.1%).

[0311] MS: m / z: 141.1[M+H] +

[0312] Step 2: Pyrimidine-2,5-diamine

[0313] 5-Nitropyrimidin-2-amine (0.6 g, 4.3 mmol, 1.0 eq) was dissolved in ethanol (10 mL), iron powder (2.39 g, 43 mmol, 10.0 eq) and saturated ammonium chloride aqueous solution (1.0 mL) were added, and the reaction was carried out at 90 °C for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to obtain pyrimidine-2,5-diamine (0.47 g, yield 99.6%).

[0314] MS: m / z: 111.1[M+H] +

[0315] Step 3: [(2-Aminopyrimidin-5-yl)amino]methanic acid 4-nitrophenyl ester

[0316] Pyrimidine-2,5-diamine (0.1 g, 0.9 mmol, 1.0 eq) was dissolved in tetrahydrofuran (6.0 mL), and chloroformic acid 4-nitrophenyl ester (0.18 g, 0.9 mmol, 1.0 eq) was added. The mixture was stirred for 1 hour, and the reaction solution was directly used for the next step.

[0317] MS: m / z: 276.1 [M+H] +

[0318] Intermediate 3: 2,2,2-trifluoro-1-(3-methylnaphthalen-2-yl)ethan-1-amine

[0319]

[0320] Step 1: 3-(Methoxycarbonyl)naphthalen-2-yl trifluoromethanesulfonate

[0321] Methyl 3-hydroxynaphthalene-2-carboxylate (1.0 g, 4.95 mmol, 1.0 eq), 4-dimethylaminopyridine (1.2 g, 9.89 mmol, 2.0 eq) and dichloromethane (20 mL) were added to a 100 mL three-necked flask. Under argon protection, trifluoromethanesulfonic anhydride (1.95 g, 6.92 mmol, 1.4 eq) was added dropwise at 0 °C. The reaction was carried out at 0 °C for 1 hour, diluted with water (50 mL), and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 3-(methoxycarbonyl)naphthalen-2-yl trifluoromethanesulfonate (1.64 g, yield 99%), a white solid.

[0322] Step 2: Methyl 3-methylnaphthalene-2-carboxylate

[0323] 3-(Methoxycarbonyl)naphthalen-2-yl trifluoromethanesulfonate (1.0 g, 3.0 mmol, 1.0 eq) was dissolved in N-methylpyrrolidone (3.0 mL), and iron(III) acetylacetonate (105 mg, 0.3 mmol, 0.1 eq) was added. Under argon protection, methylmagnesium bromide (3.3 mL, 3.0 mmol, 1.0 eq) was added dropwise at 0 °C. After addition, the mixture was stirred at room temperature for 2 hours, water (50 mL) was added, and the mixture was extracted 3 times with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography to obtain methyl 3-methylnaphthalene-2-carboxylate (0.5 g, yield 84%).

[0324] MS m / z: 201 [M+H] +

[0325] Step 3: (3-Methylnaphthalen-2-yl)methanol

[0326] (3-Methylnaphthalen-2-yl)methanol (0.5 g, 2.5 mmol, 1.0 eq) was dissolved in THF (5 mL). At 0 °C, lithium aluminum hydride (2.5 mL, 2.5 mmol, 1.0 eq) was added dropwise. After the addition, the mixture was stirred for 2 hours. At 0 °C, water (1.0 mL) and 15% sodium hydroxide (2.0 mL) were added to quench the reaction. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain (3-methylnaphthalen-2-yl)methanol (412 mg, yield 96%), a white solid.

[0327] MS: m / z: 155.1 [M - H2O + H] +

[0328] Step 4: 3-Methylnaphthalene-2-carbaldehyde

[0329] (3-Methylnaphthalen-2-yl)methanol (412 mg, 2.4 mmol, 1.0 eq), Dess-Martin reagent (1.1 g, 2.64 mmol, 1.1 eq), and dichloromethane (10 mL) were added to a 100 mL eggplant-shaped flask. The mixture was stirred at room temperature for 2 hours, filtered through diatomaceous earth, and the filtrate was concentrated. The product was purified by column chromatography to obtain 3-methylnaphthalene-2-carbaldehyde (376 mg, yield 92.1%), a white solid.

[0330] MS m / z: 171.2 [M + H] +

[0331] 1 1H NMR (400 MHz, chloroform-d) δ 10.36 (s, 1H), 8.33 (s, 1H), 7.98 (dd, J = 8.2, 1.1 Hz, 1H), 7.83 (dd, J = 8.3, 1.1 Hz, 1H), 7.68 (s, 1H), 7.63 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.54 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 2.82 (d, J = 1.0 Hz, 3H).

[0332] Step 5: 2,2,2-Trifluoro-1-(3-methylnaphthalen-2-yl)ethan-1-ol

[0333] 3-Methylnaphthalene-2-carbaldehyde (3.0 g, 17.6 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (30 mL). Potassium carbonate (1.22 g, 8.8 mmol, 0.5 eq) was added. At 0 °C, (trifluoromethyl)trimethylsilane (5.0 g, 35.25 mmol, 2.0 eq) was added. The mixture was stirred at room temperature for 0.5 h. Potassium carbonate (2.44 g, 17.6 mmol, 1.0 eq) was added and the mixture was stirred at room temperature overnight. It was cooled to 0 °C, water (1.0 mL) was added and stirred for 1.0 h. Then water (100 mL) was added and the mixture was extracted with ethyl acetate (80 mL) three times. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was directly used for the next reaction.

[0334] MS m / z: 241.1 [M+H] +

[0335] Step 6: 2,2,2-Trifluoro-1-(3-methylnaphthalen-2-yl)ethan-1-one

[0336] 2,2,2-Trifluoro-1-(3-methylnaphthalen-2-yl)ethan-1-ol (3.8 g, 15.8 mmol, 1.0 eq) was dissolved in dichloromethane (50 mL). Dess-Martin periodinane (7.4 g, 17.45 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through diatomaceous earth and concentrated. The crude product was purified by column chromatography to obtain 2,2,2-trifluoro-1-(3-methylnaphthalen-2-yl)ethan-1-one (3.2 g, yield 84.7%), a white solid.

[0337] MS m / z: 238.1 [M+H] +

[0338] Step 7: [(1Z)-2,2,2-Trifluoro-1-(3-methylnaphthalen-2-yl)ethylidene]hydroxylamine

[0339] 2,2,2-Trifluoro-1-(3-methylnaphthalen-2-yl)ethan-1-one (3.2 g, 13.4 mmol, 1.0 eq) was dissolved in ethanol (60 mL). Hydroxylamine hydrochloride (9.33 g, 134 mmol, 10 eq) and sodium acetate (27.4 g, 201 mmol, 15.0 eq) were added. The mixture was refluxed and stirred overnight, concentrated, water (50 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain [(1Z)-2,2,2-trifluoro-1-(3-methylnaphthalen-2-yl)ethylidene]hydroxylamine (3.1 g, yield 91%), a white solid, which was directly used for the next step.

[0340] MS m / z: 254.1 [M+H]+

[0341] Step 8: 2,2,2-Trifluoro-1-(3-methylnaphthalen-2-yl)ethan-1-amine

[0342] In a 250 mL eggplant-shaped flask, [(1Z)-2,2,2-trifluoro-1-(3-methylnaphthalen-2-yl)ethylidene]hydroxylamine (3.1 g, 12.2 mmol, 1.0 eq), zinc powder (4.0 g, 61.2 mmol, 10.0 eq), ethanol (50 mL), water (10 mL) and ammonium chloride (13.1 g, 244.85 mmol, 20.0 eq) were added. The mixture was refluxed for 5 hours, cooled to room temperature, the zinc powder was filtered off, 50 mL of water was added, and the mixture was extracted 3 times with 60 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain 2,2,2-trifluoro-1-(3-methylnaphthalen-2-yl)ethan-1-amine (1.1 g, yield 38%), a colorless oil.

[0343] MS m / z: 223 [M-NH2+H] +

[0344] 1 1H NMR (400 MHz, chloroform-d) δ 8.06 (s, 1H), 7.86 (dd, J = 7.5, 1.7 Hz, 1H), 7.81 – 7.75 (m, 1H), 7.70 (s, 1H), 7.49 (pd, J = 6.9, 1.5 Hz, 2H), 4.85 (q, J = 7.2 Hz, 1H), 2.59 (s, 3H), 1.92 (s, 2H).

[0345] Example 1: 1-[(2-Ethylaminopyrimidin-5-yl)amino]-N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (Compound 1)

[0346]

[0347] Prepared according to Synthesis Route 1:

[0348] Step 1: 2-Methylprop-2-yl [2-(5-nitropyrimidin-2-yl)ethylamino]methanoate

[0349]

[0350] 2-Chloro-5-nitropyrimidine (1.5 g, 9.4 mmol, 1.0 eq) was dissolved in ethanol (20 mL). tert-Butyl hydrazinecarboxylate (3.1 g, 23.5 mmol, 2.5 eq) was added, and the mixture was heated at 80 °C for 3 hours. After cooling to room temperature, water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to obtain [2-(5-nitropyrimidin-2-yl)ethylamino]methyl 2-methylprop-2-yl carbonate (2.1 g, yield 87.5%), a yellow solid.

[0351] MS m / z: 256.1 [M+H] +

[0352] Step 2: [2-(5-Aminopyrimidin-2-yl)ethylamino]methyl 2-methylprop-2-yl carbonate

[0353]

[0354] [2-(5-Nitropyrimidin-2-yl)ethylamino]methyl 2-methylprop-2-yl carbonate (0.3 g, 1.2 mmol, 1.0 eq) was dissolved in ethanol (10 mL). Iron powder (0.65 g, 12 mmol, 10.0 eq) and saturated aqueous ammonium chloride solution (4 mL) were added, and the reaction mixture was stirred at 80 °C for 4 hours. The iron powder was filtered off, the filtrate was concentrated, and the residue was separated by column chromatography to obtain [2-(5-aminopyrimidin-2-yl)ethylamino]methyl 2-methylprop-2-yl carbonate (200 mg, yield 75.5%).

[0355] MS m / z: 226.1 [M+H] +

[0356] Step 3: {[2-(2-{[(2-Methylprop-2-yl)oxy]carbonyl}ethylamino)pyrimidin-5-yl]amino}methyl 4-nitrophenyl carbonate

[0357]

[0358] [2-(5-Aminopyrimidin-2-yl)ethylamino]methyl 2-methylprop-2-yl carbonate (100 mg, 0.44 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL). 4-Nitrophenyl chloroformate (90 mg, 0.44 mmol, 1.0 eq) was added, and the reaction was carried out under argon protection at room temperature for 1 hour. The reaction mixture was directly used for the next step.

[0359] MS m / z: 335.1 [M+H-56] +

[0360] Step 4: (2-{5-[({[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]amino}carbonyl)amino]pyrimidin-2-yl}ethylamino)methanoic acid 2-methylpropan-2-yl ester

[0361]

[0362] To a solution of {[2-(2-{[(2-methylpropan-2-yl)oxy]carbonyl}ethylamino)pyrimidin-5-yl]amino}methanoic acid 4-nitrophenyl ester (170 mg, 0.44 mmol, 1.0 eq) in tetrahydrofuran was added 1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-amine (116 mg, 0.44 mmol, 1.0 eq) and pyridine (0.41 mL, 2.2 mmol, 5.0 eq). The mixture was stirred at 50 °C for 4 h, water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the residue was separated by column chromatography to give (2-{5-[({[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]amino}carbonyl)amino]pyrimidin-2-yl}ethylamino)methanoic acid 2-methylpropan-2-yl ester (86 mg, yield 38.1%).

[0363] MS m / z: 461.1 [M+H-56] +

[0364] Step 5: 1-[(2-ethylaminopyrimidin-5-yl)amino]-N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide

[0365]

[0366] (2-{5-[({[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]amino}carbonyl)amino]pyrimidin-2-yl}ethylamino)methanoic acid 2-methylpropan-2-yl ester (500 mg, 0.97 mmol, 1.0 eq) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 h. The pH was adjusted to greater than 7 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (10 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography gave 1-[(2-ethylaminopyrimidin-5-yl)amino]-N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (250 mg, yield 60%).

[0367] MS m / z: 417 [M+H] +

[0368] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 14.3 Hz, 3H), 7.98 (s, 1H), 7.85 (d, J = 9.4 Hz, 1H), 7.49 - 7.37 (m, 2H), 6.06 (p, J = 8.3 Hz, 1H), 4.12 (s, 2H), 2.30 (s, 3H).

[0369] Example 2: 1-{[2-(2-Acetylethylamino)pyrimidin-5-yl]amino}-N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (Compound 2)

[0370]

[0371] 1-[(2-Ethylaminopyrimidin-5-yl)amino]-N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (50 mg, 0.12 mmol, 1.0 eq) was dissolved in dichloromethane (8 mL). Triethylamine (0.05 mL, 0.36 mmol, 3.0 eq) and acetyl chloride (9 μL, 0.12 mmol, 1.0 eq) were added. The mixture was stirred at room temperature for 2 hours, water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to obtain 1-{[2-(2-acetylethylamino)pyrimidin-5-yl]amino}-N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (20 mg, yield 36%), a white solid.

[0372] MS m / z: 459.1 [M+H] +

[0373] 11H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.45 - 8.35 (m, 3H), 7.88 (d, J = 9.5 Hz, 1H), 7.48 - 7.39 (m, 2H), 6.11 - 6.00 (m, 1H), 2.30 (s, 3H), 1.86 (s, 3H).

[0374] Example 3: N-[1-(5,7-Difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-({2-[2-(1-oxopropyl-2-enyl)ethylamino]pyrimidin-5-yl}amino)methanamide (Compound 3)

[0375]

[0376] 1-[(2-Ethylaminopyrimidin-5-yl)amino]-N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (80 mg, 0.19 mmol, 1.0 eq) was dissolved in dichloromethane (8 mL). Triethylamine (58 mg, 0.57 mmol, 3.0 eq) and acryloyl chloride (17.2 mg, 0.19 mmol, 1.0 eq) were added. The mixture was stirred at room temperature for 2 hours, then water (10 mL) was added. The mixture was extracted with dichloromethane (20 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to obtain N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-({2-[2-(1-oxopropyl-2-enyl)ethylamino]pyrimidin-5-yl}amino)methanamide (10 mg, yield 11%), a white solid.

[0377] MS m / z: 471.1 [M+H] +

[0378] 1 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.81 (s, 1H), 8.41 (d, J = 18.6 Hz, 3H), 7.90 (d, J = 9.4 Hz, 1H), 7.52 - 7.24 (m, 2H), 6.38 - 6.00 (m, 3H), 5.70 (dd, J = 10.2, 2.2 Hz, 1H), 2.30 (s, 3H).

[0379] Example 4: N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-({2-[2-(1-oxopropyl-2-ynyl)ethylamino]pyrimidin-5-yl}amino)methanamide (Compound 4)

[0380]

[0381] 1-[(2-ethylaminopyrimidin-5-yl)amino]-N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (20 mg, 0.05 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL), and propargylic acid (3.37 mg, 0.05 mmol, 1.0 eq), N,N-diisopropylethylamine (18.6 mg, 0.15 mmol, 3.0 eq) and 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (54.8 mg, 0.15 mmol, 3.0 eq) were added. The mixture was stirred at room temperature for 2 hours, water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to obtain N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-({2-[2-(1-oxopropyl-2-ynyl)ethylamino]pyrimidin-5-yl}amino)methanamide (20 mg, yield 88.9%), a white solid.

[0382] MS m / z: 469.1 [M+H] +

[0383] 1 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.89 (s, 1H), 8.77 - 8.25(m, 3H), 7.99 (d, J = 29.3 Hz, 1H), 7.56 - 7.21 (m, 2H), 6.06 (p, J = 8.2 Hz,1H), 4.24 (s, 1H), 2.30 (s, 3H).

[0384] N-[(1S)-1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-({2-[2-(1-oxopropylidene-prop-2-ynyl)ethylamino]pyrimidin-5-yl}amino)methanamide and N-[(1R)-1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-({2-[2-(1-oxopropylidene-prop-2-ynyl)ethylamino]pyrimidin-5-yl}amino)methanamide (Compound 4-P1 and Compound 4-P2)

[0385]

[0386] Compound 4 was separated by SFC to prepare N-[(1S)-1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-({2-[2-(1-oxopropylidene-prop-2-ynyl)ethylamino]pyrimidin-5-yl}amino)methanamide (6 mg, pale yellow solid) and N-[(1R)-1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-({2-[2-(1-oxopropylidene-prop-2-ynyl)ethylamino]pyrimidin-5-yl}amino)methanamide (7 mg, pale yellow solid). The retention times of Compound 4-P1 and Compound 4-P2 were 1.86 minutes and 2.6 minutes respectively.

[0387] Chiral separation method:

[0388] Instrument: SFC-150 (Waters)

[0389] Chiral column: IG 25*250mm, 10µm (Daicel)

[0390] Column temperature: 35 ºC

[0391] Mobile phase: CO2 / MeOH[0.2%NH3(7M in MeOH) ]=70 / 30

[0392] Flow rate: 100 mL / min

[0393] Detection wavelength: 214 nm

[0394] Example 5: 1-{5-[({[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]amino}carbonyl)amino]pyrimidin-2-yl}semicarbazide (Compound 5)

[0395]

[0396] 1-[(2-Ethylaminopyrimidin-5-yl)amino]-N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (60 mg, 0.14 mmol, 1.0 eq) was dissolved in water (5 mL), potassium cyanate (35.1 mg, 0.43 mmol, 3.0 eq) and 1.0 mol / L hydrochloric acid (0.14 mL, 0.14 mmol, 1.0 eq) were added. The mixture was stirred at room temperature for 3 hours, water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to obtain 1-{5-[({[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]amino}carbonyl)amino]pyrimidin-2-yl}semicarbazide (15 mg, yield 22.6%), a white solid.

[0397] MS m / z: 460.1[M+H] +

[0398] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 28.1 Hz, 4H), 7.91 (s, 1H),7.67 (s, 1H), 7.50 -7.34 (m, 2H), 6.06 (p, J = 8.2 Hz, 1H), 5.85 (s, 2H),2.30 (s, 3H).

[0399] Example 6: 1-[(2-Aminopyrimidin-5-yl)amino]-N-[2,2,2-trifluoro-1-(7-fluoro-3-methyl-5-vinyl-1-benzofuran-2-yl)ethyl]methanamide (Compound 6)

[0400]

[0401] Prepared according to Synthetic Route 2:

[0402] Step 1: 4-Bromo-2-fluorophenyl acetate

[0403]

[0404] 4-Bromo-2-fluorophenol (15 g, 78.5 mmol, 1.0 eq) was dissolved in THF (200 mL), and triethylamine (11.9 g, 117.8 mmol, 1.5 eq) was added. Acetyl chloride (9.3 g, 117.5 mmol, 1.5 eq) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 1 h. Water (300 mL) was added, and the mixture was extracted three times with ethyl acetate (300 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4-bromo-2-fluorophenyl acetate (17 g, yield 93%), a pale yellow oil.

[0405] 1 H NMR (400 MHz, chloroform-d) δ 7.36 (dd, J = 9.4, 2.3 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.04 (dd, J = 8.6, 8.0 Hz, 1H), 2.35 (s, 3H).

[0406] Step 2: 1-(5-Bromo-3-fluoro-2-hydroxyphenyl)ethan-1-one

[0407]

[0408] To 4-bromo-2-fluorophenyl acetate (10 g, 42.9 mmol, 1.0 eq) was added anhydrous aluminum trichloride (8.6 g, 64.4 mmol, 1.5 eq). Under argon protection, the mixture was stirred at 150 °C for 20 min, cooled to 0 °C, ice water (300 mL) was added, and the mixture was extracted three times with ethyl acetate (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the residue was separated by column chromatography to obtain 1-(5-bromo-3-fluoro-2-hydroxyphenyl)ethan-1-one (11.8 g, yield 79.5%).

[0409] MS m / z: 231.1 / 233.1 [M-H] -

[0410] 1 H NMR (400 MHz, chloroform-d) δ 12.22 (d, J = 0.6 Hz, 1H), 7.67 (dd, J = 2.3, 1.7 Hz, 1H), 7.46 (ddd, J = 9.7, 2.3, 0.6 Hz, 1H), 2.67 (s, 3H).

[0411] Step 3: 1-(5-Bromo-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-one

[0412]

[0413] 1-(5-Bromo-3-fluoro-2-hydroxyphenyl)ethan-1-one (4.0 g, 17.2 mmol, 1.0 eq) was dissolved in ethanol (50 mL). 3-Bromo-1,1,1-trifluoropropan-2-one (4.92 g, 25.7 mmol, 1.5 eq), potassium carbonate (4.74 g, 34.3 mmol, 2.0 eq) and potassium iodide (0.85 g, 5.2 mmol, 0.3 eq) were added. Under argon protection, the mixture was refluxed overnight. The reaction solution was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the residue was separated by column chromatography to obtain 1-(5-bromo-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-one (1.5 g, yield 26.8%).

[0414] MS m / z: 325.1 / 327.1 [M+H] +

[0415] Step 4: [(1Z)-1-(5-Bromo-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethylidene]hydroxylamine

[0416]

[0417] To a solution of 1-(5-bromo-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-one (1.5 g, 4.6 mmol, 1.0 eq) in ethanol (90 mL), hydroxylamine hydrochloride (3.2 g, 46.1 mmol, 10.0 eq) and sodium acetate (3.78 g, 46.1 mmol, 10.0 eq) were added. The mixture was stirred at 80 °C overnight, cooled to room temperature, water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the residue was separated by column chromatography to obtain [(1Z)-1-(5-bromo-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethylidene]hydroxylamine (1.4 g, yield 84.7%), a white solid.

[0418] MS m / z: 340.1 / 342.1 [M+H] +

[0419] Step 5: 1-(5-Bromo-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-amine

[0420]

[0421] [(1Z)-1-(5-Bromo-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethanimidoyl]hydroxylamine (1.4 g, 4.1 mmol, 1.0 eq) was dissolved in ethanol (50 mL) and water (10 mL). Ammonium chloride (2.24 g, 41.1 mmol, 10.0 eq) and zinc powder (2.68 g, 41.1 mmol, 10.0 eq) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1-(5-bromo-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-amine (900 mg, yield 63%), a white solid.

[0422] MS m / z: 309.1 / 310.1 [M+H-17] +

[0423] Step 6: 2,2,2-Trifluoro-1-(7-fluoro-3-methyl-5-vinyl-1-benzofuran-2-yl)ethan-1-amine

[0424]

[0425] 1-(5-Bromo-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-amine (325 mg, 1.0 mmol, 1.0 eq) was dissolved in dioxane (20 mL). Tributylvinylstannane (411 mg, 1.3 mmol, 1.3 eq) and bis(triphenylphosphine)palladium(II) dichloride (140 mg, 0.2 mmol, 0.2 eq) were added. Under argon protection, the mixture was stirred at 110 °C for 2 hours, cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2,2,2-trifluoro-1-(7-fluoro-3-methyl-5-vinyl-1-benzofuran-2-yl)ethan-1-amine (175 mg, yield 59.7%), a white solid.

[0426] MS m / z: 257.1 [M+H-17] +

[0427] Step 7: 1-[(2-Aminopyrimidin-5-yl)amino]-N-[2,2,2-trifluoro-1-(7-fluoro-3-methyl-5-vinyl-1-benzofuran-2-yl)ethyl]methanamide

[0428]

[0429] To a solution of [(2-aminopyrimidin-5-yl)amino]methanoic acid 4-nitrophenyl ester (94 mg, 0.34 mmol, 1.1 eq) in tetrahydrofuran (10 mL), 2,2,2-trifluoro-1-(7-fluoro-3-methyl-5-vinyl-1-benzofuran-2-yl)ethan-1-amine (85 mg, 0.31 mmol, 1.0 eq) and pyridine (123 mg, 1.6 mmol, 5.0 eq) were added. Under argon protection, the mixture was stirred at 50 °C for 3 hours, cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain 1-[(2-aminopyrimidin-5-yl)amino]-N-[2,2,2-trifluoro-1-(7-fluoro-3-methyl-5-vinyl-1-benzofuran-2-yl)ethyl]methanamide (9 mg, yield 7.1%), a white solid.

[0430] MS m / z: 410.1 [M+H] +

[0431] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 9.7 Hz, 1H), 8.22(s, 2H),7.83 (d, J = 9.2 Hz, 1H), 7.64 -7.42 (m, 2H), 6.84 (dd,J = 17.6, 11.0 Hz,1H), 6.36 (s, 2H), 6.07 -5.86 (m, 2H), 5.32(d, J = 11.0 Hz, 1H), 2.32 (s,3H).

[0432] Example 7: 1-[(2-aminopyrimidin-5-yl)amino]-N-{2,2,2-trifluoro-1-[7-fluoro-3-methyl-5-(methylthio)-1-benzofuran-2-yl]ethyl}methanamide (Compound 7)

[0433]

[0434] Step 1: 2,2,2-trifluoro-1-[7-fluoro-3-methyl-5-(methylthio)-1-benzofuran-2-yl]ethan-1-amine

[0435]

[0436] 1-(5-Bromo-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-amine (42 mg, 0.13 mmol, 1.0 eq) was dissolved in toluene (10 mL), and sodium methanethiolate (10 mg, 0.14 mmol, 1.1 eq), N,N-diisopropylethylamine (33 mg, 0.26 mmol, 2.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.5 mg, 0.013 mmol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium (5.9 mg, 0.01 mmol, 0.05 eq) were added. Under argon protection, the mixture was stirred at 90 °C for 12 h, cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2,2,2-trifluoro-1-[7-fluoro-3-methyl-5-(methylthio)-1-benzofuran-2-yl]ethan-1-amine (19 mg, yield 50.3%), a white solid.

[0437] MS m / z: 277.1 [M+H-17] +

[0438] Step 2: 1-[(2-Aminopyrimidin-5-yl)amino]-N-{2,2,2-trifluoro-1-[7-fluoro-3-methyl-5-(methylthio)-1-benzofuran-2-yl]ethyl}methanamide

[0439]

[0440] To a solution of [(2-aminopyrimidin-5-yl)amino]methanoic acid 4-nitrophenyl ester (258 mg, 0.94 mmol, 1.1 eq) in tetrahydrofuran (10 mL), 2,2,2-trifluoro-1-[7-fluoro-3-methyl-5-(methylthio)-1-benzofuran-2-yl]ethan-1-amine (250 mg, 0.85 mmol, 1.0 eq) and triethylamine (339 mg, 2.5 mmol, 3.0 eq) were added. Under argon protection, the mixture was stirred at 50 °C for 3 h, cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain 1-[(2-aminopyrimidin-5-yl)amino]-N-{2,2,2-trifluoro-1-[7-fluoro-3-methyl-5-(methylthio)-1-benzofuran-2-yl]ethyl}methanamide (29 mg, yield 7.9%), a white solid.

[0441] MS m / z: 430.1 [M+H] +

[0442] 1 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 6.5 Hz, 1H), 8.22 (s, 2H), 7.85 (d, J = 9.6 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.31 (dd, J = 11.7, 1.6 Hz, 1H), 6.40 (s, 2H), 6.01 (p, J = 8.3 Hz, 1H), 2.56 (s, 3H), 2.30 (s, 3H).

[0443] Example 8: 1-[(2-Aminopyrimidin-5-yl)amino]-N-[1-(5-ethynyl-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (Compound 8)

[0444]

[0445] Step 1: 2,2,2-Trifluoro-1-(7-fluoro-3-methyl-5-{[tris(propan-2-yl)silyl]ethynyl}-1-benzofuran-2-yl)ethan-1-amine

[0446]

[0447] 1-(5-Bromo-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-amine (126 mg, 0.39 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL). Ethynyl[tris(propan-2-yl)]silane (77 mg, 0.43 mmol, 1.1 eq), copper(I) iodide (15 mg, 0.08 mmol, 0.2 eq), triethylamine (117 mg, 1.16 mmol, 3.0 eq) and bis(triphenylphosphine)palladium(II) chloride (27 mg, 0.04 mmol, 0.1 eq) were added. Under argon protection, the mixture was stirred at 80 °C for 5 h, cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography gave 2,2,2-trifluoro-1-(7-fluoro-3-methyl-5-{[tris(propan-2-yl)silyl]ethynyl}-1-benzofuran-2-yl)ethan-1-amine (110 mg, yield 64.3%), a white solid.

[0448] Step 2: 1-(5-Ethynyl-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-amine

[0449]

[0450] 2,2,2-Trifluoro-1-(7-fluoro-3-methyl-5-{[tris(propan-2-yl)silyl]ethynyl}-1-benzofuran-2-yl)ethan-1-amine (1.3 g, 3.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL) and tetrabutylammonium fluoride (5 mL), stirred at room temperature for 1 hour, saturated sodium thiosulfate solution (10 mL) was added, extracted with ethyl acetate (20 mL) three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1-(5-ethynyl-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-amine (570 mg, yield 69.5%), a yellow solid.

[0451] MS m / z: 255[M+H-17] +

[0452] Step 3: 1-[(2-Aminopyrimidin-5-yl)amino]-N-[1-(5-ethynyl-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide

[0453]

[0454] To a solution of [(2-aminopyrimidin-5-yl)amino]methanoic acid 4-nitrophenyl ester (390 mg, 1.42 mmol, 1.1 eq) in tetrahydrofuran (10 mL), 1-(5-ethynyl-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-amine (350 mg, 1.29 mmol, 1.0 eq) and triethylamine (391 mg, 3.87 mmol, 3.0 eq) were added, protected by argon, stirred at 50 °C for 3 hours, cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (20 mL) three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain 1-[(2-aminopyrimidin-5-yl)amino]-N-[1-(5-ethynyl-7-fluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (65 mg, yield 12.3%), a white solid.

[0455] MS m / z: 408.2 [M+H] +

[0456] 11H NMR (400 MHz, DMSO-d6) δ 8.32 -8.25 (m, 1H),8.22 (s, 2H), 7.89 -7.82 (m, 1H), 7.70 (d, J = 1.4 Hz,1H), 7.48 (d, J = 11.6 Hz, 1H), 6.41 (s,2H), 6.04 (q, J =8.4 Hz, 1H), 4.28 (s, 1H), 2.31 (s, 3H).

[0457] Example 9: N-[1-(3-Amino-5,7-difluoro-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-[(2-aminopyrimidin-5-yl)amino]methanamide (Compound 9)

[0458]

[0459] Prepared according to Synthetic Method III:

[0460] Step 1: 1-(3-Amino-5,7-difluoro-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-one

[0461]

[0462] 3,5-Difluoro-2-hydroxybenzonitrile (5.1 g, 32.9 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (50 mL), and 3-bromo-1,1,1-trifluoropropan-2-one (6.9 g, 36 mmol, 1.1 eq), potassium iodide (5.46 g,32.9 mmol, 1.0 eq) and potassium carbonate (10.0 g, 72 mmol, 2.2 eq) were added. The mixture was stirred overnight at room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL) three times. The organic phase was dried over sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography to obtain 1-(3-amino-5,7-difluoro-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-one (1.4 g, yield 16%).

[0463] Step 2: {[5,7-Difluoro-2-(trifluoroacetyl)-1-benzofuran-3-yl]amino}methanoic acid 2-methylpropan-2-yl ester

[0464]

[0465] 1-(3-Amino-5,7-difluoro-1-benzofuran-2-yl)-2,2,2-trifluoroethan-1-one (1.4 g, 5.3 mmol, 1.0 eq), di-tert-butyl dicarbonate (1.73 g, 7.9 mmol, 1.5 eq), 4-dimethylaminopyridine (0.65 g, 5.3 mmol, 1.0 eq) and triethylamine (1.6 g, 15.8 mmol, 3.0 eq) were added to dichloromethane (20 mL). The mixture was stirred at room temperature for 3 h, water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain [(5,7-difluoro-2-(trifluoroacetyl)-1-benzofuran-3-yl)amino]carbamic acid 2-methylpropan-2-yl ester (1.9 g, yield 98.5%).

[0466] MS m / z: 310[M+H-56] +

[0467] Step 3: [(5,7-Difluoro-2-[(1Z)-2,2,2-trifluoro-1-(hydroxyimino)ethyl]-1-benzofuran-3-yl)amino]carbamic acid 2-methylpropan-2-yl ester

[0468]

[0469] [(5,7-Difluoro-2-(trifluoroacetyl)-1-benzofuran-3-yl)amino]carbamic acid 2-methylpropan-2-yl ester (100 mg, 0.21 mmol, 1.0 eq) was dissolved in ethanol (10 mL), hydroxylamine hydrochloride (149 mg, 2.2 mmol, 10.0 eq) and sodium acetate (176 mg, 2.2 mmol, 10.0 eq) were added, and the mixture was stirred at 80 °C for 6 h. Water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain [(5,7-difluoro-2-[(1Z)-2,2,2-trifluoro-1-(hydroxyimino)ethyl]-1-benzofuran-3-yl)amino]carbamic acid 2-methylpropan-2-yl ester (73 mg, yield 91.5%), a white solid.

[0470] MS m / z: 281.1[M+H-100] +

[0471] Step 4: [(2-(1-Amino-2,2,2-trifluoroethyl)-5,7-difluoro-1-benzofuran-3-yl)amino]carbamic acid 2-methylpropan-2-yl ester

[0472]

[0473] ({5,7-difluoro-2-[(1Z)-2,2,2-trifluoro-1-(hydroxyimino)ethyl]-1-benzofuran-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester (950 mg, 2.5 mmol, 1.0 eq) was dissolved in ethanol (50 mL) and water (10 mL). Zinc powder (1.62 g, 25 mmol, 10.0 eq) and ammonium chloride (1.35 gmg, 25 mmol, 10.0 eq) were added. The reaction was carried out at 80 °C for 2 h, cooled to room temperature, water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain {[2-(1-amino-2,2,2-trifluoroethyl)-5,7-difluoro-1-benzofuran-3-yl]amino}methanoic acid 2-methylpropan-2-yl ester (410 mg, yield 44.5%), a white solid.

[0474] MS m / z: 311[M+H-56] +

[0475] 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.39 (ddd, J = 11.6, 9.6, 2.4 Hz, 1H), 7.20 (dd, J = 8.3, 2.5 Hz, 1H), 4.96 (q, J = 9.4, 8.6 Hz, 1H), 2.67 (d, J = 8.6 Hz, 2H), 1.48 (s, 9H).

[0476] Step 5: ({2-[1-({[(2-aminopyrimidin-5-yl)amino]carbonyl}amino)-2,2,2-trifluoroethyl]-5,7-difluoro-1-benzofuran-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester

[0477]

[0478] To a solution of [(2-aminopyrimidin-5-yl)amino]methanoic acid 4-nitrophenyl ester (83 mg, 0.3 mmol, 1.1 eq) in tetrahydrofuran (10 mL), add {[2-(1-amino-2,2,2-trifluoroethyl)-5,7-difluoro-1-benzofuran-3-yl]amino}methanoic acid 2-methylpropan-2-yl ester (100 mg, 0.27 mmol, 1.0 eq) and triethylamine (83 mg, 0.82 mmol, 3.0 eq). Protect with argon and stir at 50 °C for 3 hours. Cool to room temperature, add water (10 mL), and extract with ethyl acetate (20 mL) three times. Combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography to obtain ({2-[1-({[(2-aminopyrimidin-5-yl)amino]carbonyl}amino)-2,2,2-trifluoroethyl]-5,7-difluoro-1-benzofuran-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester (35 mg, yield 25.5%), a white solid.

[0479] MS m / z: 403.2 [M+H-100] +

[0480] Step 6: N-[1-(3-Amino-5,7-difluoro-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-[(2-aminopyrimidin-5-yl)amino]methanamide

[0481]

[0482] ({2-[1-({[(2-aminopyrimidin-5-yl)amino]carbonyl}amino)-2,2,2-trifluoroethyl]-5,7-difluoro-1-benzofuran-3-yl}amino)methanoic acid 2-methylpropan-2-yl ester (35 mg, 0.07 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), HCl / dioxane solution (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure, adjust the pH to greater than 7 with saturated sodium bicarbonate solution, extract with dichloromethane (10 mL) three times, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography to obtain N-[1-(3-amino-5,7-difluoro-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-[(2-aminopyrimidin-5-yl)amino]methanamide (13 mg, yield 46%).

[0483] MS m / z: 403.1[M+H] +

[0484] Example 10: 1-[(2-Aminopyrimidin-5-yl)amino]-N-[2,2,2-trifluoro-1-(3-methylnaphthalen-2-yl)ethyl]methanamide (Compound 10)

[0485]

[0486] Prepared according to Synthesis Method 4:

[0487] To a solution of [(2-aminopyrimidin-5-yl)amino]methanoic acid 4-nitrophenyl ester (166 mg, 0.6 mmol, 1.0 eq) in tetrahydrofuran (10 mL), 2,2,2-trifluoro-1-(3-methylnaphthalen-2-yl)ethan-1-amine (144 mg, 0.6 mmol, 1.0 eq) and triethylamine (61 mg, 0.6 mmol, 1.0 eq) were added. Under argon protection, the mixture was stirred at room temperature for 3 hours, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain 1-[(2-aminopyrimidin-5-yl)amino]-N-[2,2,2-trifluoro-1-(3-methylnaphthalen-2-yl)ethyl]methanamide (16.7 mg, yield 7.4%), a white solid.

[0488] MS m / z: 376.1 [M+H] +

[0489] 1 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 2H), 8.05 (d, J = 21.7 Hz, 2H), 7.95 – 7.91 (m, 1H), 7.88 – 7.82 (m, 3H), 7.57 – 7.50 (m, 2H), 6.38 (s, 2H), 5.94 (q, J = 8.5 Hz, 1H), 2.56 (s, 3H).

[0490] Example 11: 1-[(5-Aminopyrazin-2-yl)amino]-N-[2,2,2-trifluoro-1-(3-methylnaphthalen-2-yl)ethyl]methanamide (Compound 11)

[0491]

[0492] Prepared according to Synthesis Method 4:

[0493] Step 1: 1-[(5-Bromopyrazin-2-yl)amino]-N-[2,2,2-trifluoro-1-(3-methylnaphthalen-2-yl)ethyl]methanamide

[0494]

[0495] 5-Bromopyrazin-2-amine (174 mg, 1.0 mmol, 1.0 eq), triethylamine (0.21 mL, 1.5 mmol, 1.5 eq) and N,N-dimethylformamide (10 mL) were added to a 100 mL eggplant-shaped flask. Under argon protection, at 0 °C, triphosgene (118.7 mg, 0.4 mmol) was added. Stirring was continued at 0 °C for 0.5 h, then 2,2,2-trifluoro-1-(naphthalen-2-yl)ethan-1-amine (239 mg, 1.0 mmol, 1.0 eq) was added. Stirring was carried out at room temperature for 1 h, then water (50 mL) was added. The mixture was extracted 3 times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1-[(5-bromopyrazin-2-yl)amino]-N-[2,2,2-trifluoro-1-(naphthalen-2-yl)ethyl]methanamide (301 mg, yield 68.3%), a white solid.

[0496] MS m / z: 439.1 / 441.1 [M+H] +

[0497] Step 2: (5-[({[2,2,2-Trifluoro-1-(naphthalen-2-yl)ethyl]amino}carbonyl)amino]pyrazin-2-yl)amino)methanoic acid 2-methylpropan-2-yl ester

[0498]

[0499] 1-[(5-Bromopyrazin-2-yl)amino]-N-[2,2,2-trifluoro-1-(naphthalen-2-yl)ethyl]methanamide (150 mg, 0.34 mmol, 1.0 eq), 2-methylpropan-2-yl aminomethanoate (120 mg, 1.02 mmol, 3.0 eq), palladium(II) acetate (7.6 mg, 0.03 mmol, 0.1 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (39.5 mg, 0.07 mmol, 0.2 eq), cesium carbonate (333.8 mg, 1.1 mmol, 3.0 eq) and dioxane (10 mL) were added to a 100 mL eggplant-shaped flask. Under nitrogen protection, stirring was carried out at 80 °C for 8 h, then water (50 mL) was added. The mixture was extracted 3 times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain (5-[({[2,2,2-trifluoro-1-(naphthalen-2-yl)ethyl]amino}carbonyl)amino]pyrazin-2-yl)amino)methanoic acid 2-methylpropan-2-yl ester (153 mg, yield 94.2%), a white solid.

[0500] MS m / z: 476.1 [M+H] +

[0501] 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.29 (s, 1H), 8.69 (s, 2H), 8.42 (d, J = 9.3 Hz, 1H), 7.97 (d, J = 9.7 Hz, 2H), 7.90 – 7.83 (m, 2H), 7.58 – 7.49 (m, 2H), 5.98 (q, J = 8.4 Hz, 1H), 2.61 – 2.55 (m, 3H), 1.47 (s, 9H).

[0502] Step 3: 1-[(5-Aminopyrazin-2-yl)amino]-N-[2,2,2-trifluoro-1-(3-methylnaphthalen-2-yl)ethyl]methanamide

[0503]

[0504] ({5-[({[2,2,2-Trifluoro-1-(3-methylnaphthalen-2-yl)ethyl]amino}carbonyl)amino]pyrazin-2-yl}amino)methanoic acid 2-methylpropan-2-yl ester (150 mg, 0.32 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL), stirred at room temperature for 2 h, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 1-[(5-aminopyrazin-2-yl)amino]-N-[2,2,2-trifluoro-1-(3-methylnaphthalen-2-yl)ethyl]methanamide (54 mg, yield 45.6%), a white solid.

[0505] MS m / z: 376.1 [M+H] +

[0506] 11H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.32 (s, 1H), 8.25 – 8.18(m, 1H), 7.95 (d, J = 7.7 Hz, 2H), 7.89 – 7.82 (m, 2H), 7.60 (s, 1H), 7.57 –7.49 (m, 2H), 5.98 (dd, J = 17.1, 8.5 Hz, 3H), 2.57 (s, 3H).

[0507] Example 12: N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-({2-[2-(4-hydroxy-1-oxobut-2-ynyl)ethylamino]pyrimidin-5-yl}amino)methanamide (Compound 12)

[0508]

[0509] 1-[(2-Ethylaminopyrimidin-5-yl)amino]-N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (30 mg, 0.07 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.8 mg, 0.07 mmol, 1.0 eq) and 1-hydroxybenzotriazole (9.74 mg, 0.07 mmol, 1.0 eq) were added, and the mixture was stirred at room temperature for 10 minutes. 4-Hydroxybut-2-ynoic acid (7.21 mg, 0.07 mmol, 1.0 eq) was added, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to obtain N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-({2-[2-(4-hydroxy-1-oxobut-2-ynyl)ethylamino]pyrimidin-5-yl}amino)methanamide (15 mg, yield 41.5%), a yellow solid.

[0510] MS m / z: 499.1 [M+H] +

[0511] 11H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.43 (d, J = 21.1 Hz, 3H), 7.91 (d, J = 9.5 Hz, 1H), 7.51 - 7.35 (m, 2H), 6.07 (p, J = 8.5 Hz, 1H), 5.54 (d, J = 6.2 Hz, 1H), 4.26 (d, J = 6.0 Hz, 2H), 2.27 (s, 3H).

[0512] Example 13: N-[1-(5,7-Difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-({2-[2-(1-oxobut-2-ynyl)ethylamino]pyrimidin-5-yl}amino)methanamide (Compound 13)

[0513]

[0514] 1-[(2-Ethylaminopyrimidin-5-yl)amino]-N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (50 mg, 0.12 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol, 1.0 eq) and 1-hydroxybenzotriazole (16.22 mg, 0.12 mmol, 1.0 eq) were added, and the mixture was stirred at room temperature for 10 minutes. But-2-ynoic acid (10.1 mg, 0.07 mmol, 1.0 eq) was added, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to obtain N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-({2-[2-(1-oxobut-2-ynyl)ethylamino]pyrimidin-5-yl}amino)methanamide (10 mg, yield 17.5%), a white solid.

[0515] MS m / z: 483.1 [M+H] +

[0516] 11H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.82 (s, 1H), 8.42 (d, J =19.3 Hz, 3H), 7.90 (d, J= 9.5 Hz, 1H), 7.48-7.38 (m, 2H), 6.07 (p, J = 8.3Hz, 1H), 2.30 (s, 3H), 2.01 (s, 3H).

[0517] Example 14: N-[1-(5,7-Difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-{[2-(2-formylethylamino)pyrimidin-5-yl]amino}methanamide (Compound 14)

[0518]

[0519] 1-[(2-Ethylaminopyrimidin-5-yl)amino]-N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]methanamide (50 mg, 0.12 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol, 1.0 eq) and 1-hydroxybenzotriazole (16.22 mg, 0.12 mmol, 1.0 eq) were added. The mixture was stirred at room temperature for 10 minutes, then formic acid (5 μL, 0.12 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 2 hours, then water (10 mL) was added. The mixture was extracted with dichloromethane (10 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by preparative HPLC to obtain N-[1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]-1-{[2-(2-formylethylamino)pyrimidin-5-yl]amino}methanamide (11 mg, yield 50.1%), a white solid.

[0520] MS m / z: 445.1 [M+H] +

[0521] 11H NMR (400 MHz, DMSO-d6) δ 9.81 (d, J = 1.9 Hz, 0.65H), 9.44 (d, J = 12 Hz, 0.35H), 9.07 (s, 0.32H), 8.79 (d, J = 1.9 Hz, 0.68H), 8.64 – 8.31 (m, 3H), 8.08 – 7.83 (m, 2H), 7.50 – 7.34 (m, 2H), 6.06 (p, J = 8.2 Hz, 1H), 2.30 (s, 3H).

[0522] Synthesis of reference compounds

[0523] Compound A was prepared according to the method of Example 80 of Patent WO2022265993.

[0524]

[0525] Test Example 1: Inhibitory activity against PI3K-Alpha enzymes (PI3K H1047R mutation, PI3K E545K mutation, and PI3KWT)

[0526] The N-terminal GST-tagged full-length PIK3CA protein / PIK3R1 co-expressed protein (hereinafter abbreviated as PIK3CA[WT] / PIK3R1), the N-terminal BTN-tagged full-length PIK3CA H1047R mutant protein and PIK3R1 co-expressed protein (hereinafter abbreviated as PIK3CA [H1047R] / PIK3R1), and the N-terminal BTN-tagged full-length PIK3CA E545K mutant protein and PIK3R1 co-expressed protein (hereinafter abbreviated as PIK3CA [E545K] / PIK3R1) were all from Carna, with the catalog numbers 11-101, 11-415-20N, and 11-414-20N respectively; the PIP2:3PS lipid kinase substrate was composed of 1 mg / mL phosphatidylinositol-4,5-bisphosphate (PIP2) and 3 mg / mL phosphoserine (PS), which is a selective substrate for type I PI3Ks and was from Promega, catalog number V1701.

[0527] Each test compound was first prepared as a 20 mmol / L stock solution in dimethyl sulfoxide (DMSO), then 60 μL per well was added to a 384-well dilution plate, and then serially diluted 1:3 with DMSO for a total of 10 concentrations, and the plate was heated to room temperature.

[0528] Add 0.1 μL of each concentration of the compound to be tested after dilution (add 0.1 μL of DMSO to the DMSO control group and the substrate-free control group) to the 384-well detection plate, and set two replicates for each compound concentration. Then add 5 μL of 1 ng / μL PIK3CA[WT] / PIK3R1, PIK3CA [H1047R] / PIK3R1, PIK3CA [E545K] / PIK3R1 enzyme buffer (this buffer contains 50 mmol / L 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 50 mmol / L NaCl, 3 mmol / L MgCl2, 0.025 mg / mL bovine serum albumin (BSA), pH 7.5) to each well, briefly vortex at 1500 rpm for 1 minute, and incubate at 25 °C for 10 minutes. Then add 5 μL of 0.1 mg / mL substrate assay buffer (this assay buffer contains 50 mmol / L HEPES, 0.5 mmol / L ethylene glycol bis(2-aminoethyl ether) tetraacetic acid (EGTA), 50 μmol / L adenosine triphosphate (ATP), pH 7.5) to the 384-well detection plate to initiate the reaction (add 5 μL of the assay buffer to the substrate-free control group), and incubate at 25 °C for 180 minutes. Then add 10 μL of ADP-Glo reagent (Promega, catalog number: V912C) to terminate the generation of adenosine diphosphate (ADP) and remove ATP, and incubate at 25 °C for 40 minutes. Finally, add 10 μL of ADP-Glo detection reagent (Promega, catalog number: V917A) to convert ADP to ATP, and introduce luciferase and luciferin to detect ATP, and incubate at 25 °C for 40 minutes. Read the relative light units (RLU) of the 384-well detection plate on a PHERAstar FSX (BMG). Calculate the inhibition rate of each concentration of the compound according to the following formula.

[0529]

[0530] Use XLfit 5.5.0 software to analyze the data, use non-linear S-curve regression to fit the data to obtain the dose-effect curve, and calculate the IC 50 value, and the results are shown in Table 1.

[0531] Table 1

[0532]

[0533] The test results show that the compounds of the present invention have good inhibitory activity against PIK3CA [H1047R] enzyme and PIK3CA [E545K] enzyme, while the inhibitory activity against PIK3CA [WT] enzyme is relatively weak, and has good selectivity. Compared with compound A, compounds 1, 4, 12, and 13 of the present invention have better inhibitory activity against PIK3CA[H1047R] enzyme.

[0534] Test Example 2: Proliferation Inhibitory Activity against Human Mammary Duct Carcinoma Cells T-47D

[0535] The proliferation inhibitory activity of the compound against human mammary duct carcinoma cells T-47D in vitro was determined by the PrestoBlue method.

[0536] T-47D (WuXi AppTec) cells were cultured in RPMI 1640 complete medium supplemented with 10% fetal bovine serum and 10 μg / ml insulin (Insulin). T-47D cells in the logarithmic growth phase were inoculated into 96-well plates at a cell density of 1500 cells / 135 μl complete medium / well and cultured in a constant temperature incubator at 37°C with 5% CO2 for 24 hours. Each compound was previously dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution of 10 mmol / L, and then diluted with DMSO and complete medium in sequence. The 96-well plate inoculated with cells was taken out, and one of them was used as a blank control group (culture medium control without cells); in the other 96-well plates, 15 μl of different concentrations of the compound were added to each well to make the final concentration 10000, 2500, 625, 156.3, 39.1, 9.8, 2.4, 0.6, 0.15, 0.04 nmol / L. Three replicates were set for each compound concentration, and a negative control group (culture medium control with cells but without the compound added) was set, and the concentration of DMSO in each well was 0.5%. The PrestoBlue TM HS Cell Viability Assay Reagent (Thermo Fisher, Invitrogen™ Cat. No.: P50201) was immediately added to the non-growth control group and subsequent detections were carried out. The other 96-well plates were continued to be cultured in a constant temperature incubator at 37°C with 5% CO2 for 72 hours and then PrestoBlue TM HS Cell Viability Assay Reagent was added and subsequent detections were carried out.

[0537] Add PrestoBlue TM HS Cell Viability Assay Reagent and the subsequent detection steps are as follows: Take out the 96-well cell culture plate from the CO2 constant temperature incubator, and add PrestoBlue TM HS Cell Viability Assay Reagent 15 μl to each well, and continue to incubate in a constant temperature incubator at 37°C with 5% CO2 for 3 hours. Take out the 96-well cell culture plate and measure the relative fluorescence intensity (RFU) at an excitation wavelength of 560 nm and an emission wavelength of 590 nm with an enzyme-linked immunosorbent assay reader. Calculate the cell inhibition rate of each concentration of the compound according to the following formula.

[0538]

[0539] Data were analyzed using GraphPad Prism 8.3 software. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC 50 value was calculated from this curve. The results are shown in Table 2.

[0540] Table 2

[0541]

[0542] The test results show that the compound of the present invention has a good inhibitory effect on the proliferation of human mammary duct carcinoma cell line T-47D with PI3KCA[H1047R] mutation.

Claims

1. A compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts, ； wherein, X is CR 2 or N; Y is CR 2 or N; Each R 2 is independently hydrogen, deuterium, halogen, cyano, -N(R 7 )2, hydroxy, C 1-6 alkyl, C 2a alkyl substituted with one or more R 1-6 -O-C 1-6 alkyl, -O-C 2b alkyl substituted with one or more R 1-6 C 2-6 alkenyl, C 2c alkenyl substituted with one or more R 2-6 C 2-6 alkynyl, C 2d alkynyl substituted with one or more R 2-6 C 3-12 cycloalkyl, C 2e cycloalkyl substituted with one or more R 3-12 C 3-12 cycloalkenyl, C 2f cycloalkenyl substituted with one or more R 3-12 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkyl substituted with one or more R 2g 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocycloalkenyl substituted with one or more R 2h C 6-10 aryl, C 2i aryl substituted with one or more R 6-10 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl substituted with one or more R 2j ; Each R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i and R 2j is independently deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, C 1-6 alkyl or -O-C 1-6 alkyl; Each R 7 is independently hydrogen or a C 1-6 alkyl group; R 1 is -N(R 8 )2, -NR 8 N(R 8 )2 or -NR 8 NR 8 C(=O)R 9 ; Each R 8 is independently hydrogen, C 1-6 alkyl, C 8a alkyl substituted with one or more R 1-6 groups, C 2-6 alkenyl, C 8b alkenyl substituted with one or more R 2-6 groups, C 2-6 alkynyl, C 8c alkynyl substituted with one or more R 2-6 groups, C 3-12 cycloalkyl, C 8d cycloalkyl substituted with one or more R 3-12 groups, C 3-12 cycloalkenyl, C 8e cycloalkenyl substituted with one or more R 3-12 groups, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkyl substituted with one or more R 8f groups, 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocycloalkenyl substituted with one or more R 8g groups, C 6-10 aryl, C 8h aryl substituted with one or more R 6-10 groups, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl substituted with one or more R 8i groups; Each R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8g , R 8h , and R 8i is independently deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, C 1-6 alkyl or -O-C 1-6 alkyl; R 9 is hydrogen, cyano group, -N(R 10 )2, C 1-6 alkyl group, C 9a alkyl group substituted by one or more R 1-6 alkyl group, -O-C 1-6 alkyl group, -O-C 9b alkyl group substituted by one or more R 1-6 alkyl group, C 2-6 alkenyl group, C 9c alkenyl group substituted by one or more R 2-6 alkenyl group, C 2-6 alkynyl group, C 9d alkynyl group substituted by one or more R 2-6 alkynyl group, C 3-12 cycloalkyl group, C 9e cycloalkyl group substituted by one or more R 3-12 cycloalkyl group, C 3-12 cycloalkenyl group, C 9f cycloalkenyl group substituted by one or more R 3-12 cycloalkenyl group, 3-12 membered heteroalkyl group, 3-12 membered heteroalkyl group substituted by one or more R 9g 3-12 membered heteroalkenyl group, 3-12 membered heteroalkenyl group substituted by one or more R 9h heteroalkenyl group, C 6-10 aryl group, C 9i aryl group substituted by one or more R 6-10 aryl group, 5-10 membered heteroaryl group or 5-10 membered heteroaryl group substituted by one or more R 9j ; Each R 9a 、R 9b 、R 9c 、R 9d 、R 9e 、R 9f 、R 9g 、R 9h 、R 9i and R 9j are each independently deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, -C(=O)OR 12 、-C(=O)N(R 12 )2、C 1-6 alkyl, C 9-a alkyl substituted with one or more R 1-6 or -O-C 1-6 alkyl; Each R 9-a is independently deuterium, halogen, cyano, -N(R 13 )2, hydroxy, C 3-12 cycloalkyl, C 9-aa cycloalkyl substituted with one or more R 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted with one or more R 9-bb 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkyl substituted with one or more R 3-12 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocycloalkenyl substituted with one or more R 9-cc 3- to 12-membered heterocycloalkenyl, C 9-dd aryl, C 6-10 aryl substituted with one or more R 9-ee 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl substituted with one or more R 6-10 9-ff 9-ff ; Each R 9-aa 、R 9-bb 、R 9-cc 、R 9-dd 、R 9-ee and R 9-ff is independently deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, C 1-6 alkyl or -O-C 1-6 alkyl; Each R 10 is independently hydrogen or a C 1-6 alkyl group; Each R 12 is independently hydrogen, C 1-6 alkyl or C 12a alkyl substituted by one or more R 1-6 alkyl; Each R 12a is independently deuterium, a halogen, a cyano group, -NH2 or a hydroxyl group; Each R 13 is independently hydrogen or C 1-6 alkyl; R 3 Independently deuterium, halogen, cyano, -N(R 7 )2, hydroxyl, C 1-6 alkyl, C 3a alkyl substituted with one or more R 1-6 -O-C 1-6 alkyl, -O-C 3b alkyl substituted with one or more R 1-6 C 2-6 alkenyl, C 3c alkenyl substituted with one or more R 2-6 C 2-6 alkynyl, C 3d alkynyl substituted with one or more R 2-6 C 3-12 cycloalkyl, C 3e cycloalkyl substituted with one or more R 3-12 C 3-12 cycloalkenyl, C 3f cycloalkenyl substituted with one or more R 3-12 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkyl substituted with one or more R 3g 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocycloalkenyl substituted with one or more R 3h C 6-10 aryl, C 3i aryl substituted with one or more R 6-10 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl substituted with one or more R 3j ; Each R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h 、R 3i and R 3j is independently deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, C 1-6 alkyl or -O-C 1-6 alkyl; Cy is or ; Z is O or S; R 4-1 and R 4-2 each independently is deuterium, a halogen, a cyano group, -N(R 11 )2, a hydroxyl group, a C 1-6 alkyl group, a C 4a alkyl group substituted by one or more R 1-6 -O-C 1-6 alkyl group, an -O-C 4b alkyl group substituted by one or more R 1-6 alkyl group, a C 2-6 alkenyl group, a C 4c alkenyl group substituted by one or more R 2-6 alkenyl group, a C 2-6 alkynyl group, a C 4d alkynyl group substituted by one or more R 2-6 alkynyl group, a C 3-12 cycloalkyl group, a C 4e cycloalkyl group substituted by one or more R 3-12 cycloalkyl group, a C 3-12 cycloalkenyl group, a C 4f cycloalkenyl group substituted by one or more R 3-12 cycloalkenyl group, a 3- to 12-membered heteroalkyl group, a 3- to 12-membered heteroalkyl group substituted by one or more R 4g a 3- to 12-membered heteroalkenyl group, a 3- to 12-membered heteroalkenyl group substituted by one or more R 4h a 3- to 12-membered heteroalkenyl group, a C 6-10 aryl group, a C 4i aryl group substituted by one or more R 6-10 aryl group, a 5- to 10-membered heteroaryl group or a 5- to 10-membered heteroaryl group substituted by one or more R 4j ; Each R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g 、R 4h 、R 4i and R 4j is independently deuterium, halogen, cyano, -NH2, hydroxy, C 1-6 alkyl or -O-C 1-6 alkyl; R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 、R 5-7 、R 5-8 and R 5-9 each independently is hydrogen, deuterium, halogen, cyano, -N(R 11 )2, hydroxy, C 1-6 alkyl, C 5a alkyl substituted with one or more R 1-6 , -O-C 1-6 alkyl, -O-C 5b alkyl substituted with one or more R 1-6 , C 2-6 alkenyl, C 5c alkenyl substituted with one or more R 2-6 , C 2-6 alkynyl, C 5d alkynyl substituted with one or more R 2-6 , C 3-12 cycloalkyl, C 5e cycloalkyl substituted with one or more R 3-12 , C 3-12 cycloalkenyl, C 5f cycloalkenyl substituted with one or more R 3-12 , 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkyl substituted with one or more R 5g , 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocycloalkenyl substituted with one or more R 5h , C 6-10 aryl, C 5i aryl substituted with one or more R 6-10 , 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl substituted with one or more R 5j , -S-C 1-6 alkyl or -S-C 5k alkyl substituted with one or more R 1-6 ; Each R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h , R 5i , R 5j and R 5k are each independently deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, C 1-6 alkyl or -O-C 1-6 alkyl; R 6 is hydrogen, deuterium, a halogen, a cyano group, -N(R 11 )2, a hydroxyl group, C 1-6 alkyl, C 6a alkyl substituted by one or more R 1-6 alkyl, -O-C 1-6 alkyl, -O-C 6b alkyl substituted by one or more R 1-6 alkyl, C 2-6 alkenyl, C 6c alkenyl substituted by one or more R 2-6 alkenyl, C 2-6 alkynyl, C 6d alkynyl substituted by one or more R 2-6 alkynyl, C 3-12 cycloalkyl, C 6e cycloalkyl substituted by one or more R 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 6f cycloalkenyl substituted by one or more R 3-12 cycloalkenyl, 3- to 12-membered heteroalkyl, 3- to 12-membered heteroalkyl substituted by one or more R 6g 3- to 12-membered heteroalkenyl, 3- to 12-membered heteroalkenyl substituted by one or more R 6h 3- to 12-membered heteroalkenyl, C 6-10 aryl, C 6i aryl substituted by one or more R 6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl substituted by one or more R 6j 5- to 10-membered heteroaryl, -S-C 1-6 alkyl or -S-C 6k alkyl substituted by one or more R 1-6 alkyl; Each R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6i 、R 6j and R 6k are each independently deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, C 1-6 alkyl or -O-C 1-6 alkyl; Each R 11 is independently hydrogen or a C 1-6 alkyl group; and the compound of formula (I) satisfies at least one of the following conditions: (1) R 1 is -NR 8 N(R 8 )2 or -NR 8 NR 8 C(=O)R 9 ; (2) Cy is ; (3) R 6 is deuterium, cyano, -N(R 11 )2, hydroxyl, C 1-6 alkyl, C 6a alkyl substituted by one or more R 1-6 alkyl, -O-C 1-6 alkyl, -O-C 6b alkyl substituted by one or more R 1-6 alkyl, C 2-6 alkenyl, C 6c alkenyl substituted by one or more R 2-6 alkenyl, C 2-6 alkynyl, C 6d alkynyl substituted by one or more R 2-6 alkynyl, C 3-12 cycloalkyl, C 6e cycloalkyl substituted by one or more R 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 6f cycloalkenyl substituted by one or more R 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 6g 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 6h C 6-10 aryl, C 6i aryl substituted by one or more R 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 6j -S-C 1-6 alkyl or -S-C 6k alkyl substituted by one or more R 1-6 alkyl; (4)R 4-1 and R 4-2 each independently is deuterium, a halogen, cyano, -N(R 11 )2, hydroxy, C 4a alkyl substituted by one or more R 1-6 -O-C 1-6 alkyl, -O-C 4b alkyl substituted by one or more R 1-6 C 2-6 alkenyl, C 4c alkenyl substituted by one or more R 2-6 C 2-6 alkynyl, C 4d alkynyl substituted by one or more R 2-6 C 3-12 cycloalkyl, C 4e cycloalkyl substituted by one or more R 3-12 C 3-12 cycloalkenyl, C 4f cycloalkenyl substituted by one or more R 3-12 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkyl substituted by one or more R 4g 3- to 12-membered heterocycloalkenyl, 3- to 12-membered heterocycloalkenyl substituted by one or more R 4h C 6-10 aryl, C 4i aryl substituted by one or more R 6-10 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl substituted by one or more R 4j ; the configuration of the carbon atom at the * position is R configuration, S configuration or a mixture of R configuration and S configuration; in each "3-12 membered heterocycloalkyl", the types of heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5; in each "3-12 membered heterocycloalkenyl", the types of heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5; in each "5-10 membered heteroaryl", the types of heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5.

2. The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that, The compound of formula (I) satisfies one or more of the following conditions: (1) Each halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine; (2) Each C 1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, such as methyl or ethyl; (3) Each -O-C 1-6 alkyl is independently -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl or -O-sec-butyl; (4) Each -S-C 1-6 alkyl group is independently -S-methyl, -S-ethyl, -S-n-propyl, -S-isopropyl, -S-n-butyl, -S-tert-butyl, -S-isobutyl or -S-sec-butyl, such as -S-methyl; (5) Each C 2-6 alkenyl is independently vinyl, propenyl, allyl, butenyl or pentenyl, such as ; (6) Each C 2-6 alkynyl group is independently ethynyl, propynyl, propargyl, butynyl or pentynyl, such as or ; (7) Each C 3-12 cycloalkyl group is independently a C 3-8 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (8) Each C 3-12 cycloalkenyl group is independently a C 3-8 cycloalkenyl group, preferably a C 5-6 cycloalkenyl group; (9) Each C 3-12 cycloalkenyl group independently contains one or more carbon-carbon sp 2 double bonds; (10) Each 3-12 membered heterocycloalkyl is independently a 3-8 membered heterocycloalkyl; in the "3-8 membered heterocycloalkyl", the types of heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; (11) Each 3-12 membered heterocycloalkyl is independently monocyclic or polycyclic, the polycyclic ring can be a bridged ring, a fused ring or a spiro ring, and the polycyclic ring can also be a bicyclic or tricyclic ring; (12) Each 3-12 membered heterocycloalkenyl is independently a 3-8 membered heterocycloalkenyl; in the "3-8 membered heterocycloalkenyl", the types of heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; (13) Each 3-12 membered heterocycloalkenyl is independently monocyclic or polycyclic, the polycyclic ring can be a bridged ring, a fused ring or a spiro ring, and the polycyclic ring can also be a bicyclic or tricyclic ring; (14) Each 3- to 12-membered heteroalkenyl independently contains one or more carbon-carbon sp 2 double bonds; (15) Each C 6-10 The aryl group is independently phenyl or naphthyl, such as phenyl; (16) Each 5-10 membered heteroaryl is independently a 5-6 membered heteroaryl; in the "5-6 membered heteroaryl", the types of heteroatoms are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; and (17) Each 5-10 membered heteroaryl is independently monocyclic or polycyclic, the polycyclic ring can be a bridged ring, a fused ring or a spiro ring; the polycyclic ring can be a bicyclic or tricyclic ring.

3. The compound of formula (I), its stereoisomers or its pharmaceutically acceptable salts according to claim 1, characterized in that, The compound of formula (I) satisfies one or more of the following conditions: (1) X is CR 2 , preferably CH; (2) Y is N; (3) R 2 is hydrogen, deuterium, a halogen or C 1-6 alkyl, preferably hydrogen; (4) R 1 is -NR 8 N(R 8 )2 or -NR 8 NR 8 C(=O)R 9 ; (5) Each R 8 is independently hydrogen or C 1-6 alkyl, preferably hydrogen; (6) R 9 is hydrogen, cyano, -N(R 10 )2, C 1-6 alkyl, C 9a alkyl substituted by one or more R 1-6 alkyl, C 2-6 alkenyl, C 9c alkenyl substituted by one or more R 2-6 alkenyl, C 2-6 alkynyl, C 9d alkynyl substituted by one or more R 2-6 alkynyl or C 3-12 cycloalkyl, preferably hydrogen, cyano, -N(R 10 )2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 9d alkynyl substituted by one or more R 2-6 alkynyl, more preferably C 2-6 alkynyl or C 9d alkynyl substituted by one or more R 2-6 alkynyl; (7) Each R 9a , R 9c and R 9d is independently deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, C 1-6 alkyl, C 9-a alkyl substituted by one or more R 1-6 or -O-C 1-6 alkyl, preferably a hydroxyl group, C 1-6 alkyl or C 9-a alkyl substituted by one or more R 1-6 ; (8) Each R 9-a independently is deuterium, a halogen or a hydroxyl group, preferably a hydroxyl group; (9) Each R 10 is independently hydrogen or C 1-6 alkyl, preferably hydrogen; (10) R 3 Independently a halogen, C 1-6 alkyl or C 3a alkyl substituted by one or more R 1-6 alkyl, preferably C 1-6 alkyl or C 3a alkyl substituted by one or more R 1-6 alkyl, more preferably C 3a alkyl substituted by one or more R 1-6 alkyl; (11) Each R 3a is independently deuterium or a halogen, preferably a halogen; (12) Z is O; (13) R 4-1 and R 4-2 are each independently deuterium, a halogen, a cyano group, -N(R 11 )2, a hydroxyl group, C 1-6 alkyl, C 4a alkyl substituted with one or more R 1-6 or -O-C 1-6 alkyl, preferably -N(R 11 )2 or C 1-6 alkyl, more preferably C 1-6 alkyl; (14) Each R 4a independently is deuterium or a halogen; (15) R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , R 5-7 , R 5-8 and R 5-9 are each independently hydrogen, deuterium, a halogen, C 1-6 alkyl or -O-C 1-6 alkyl, preferably hydrogen or a halogen; More preferably, R 5-1 is a halogen, and R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , R 5-7 , R 5-8 , and R 5-9 are hydrogen; (16)R 6 is hydrogen, halogen, cyano, -N(R 11 )2, hydroxy, C 1-6 alkyl, C 6a alkyl substituted with one or more R 1-6 -O-C 1-6 alkyl, C 2-6 alkenyl, C 6c alkenyl substituted with one or more R 2-6 -C 2-6 alkynyl, C 6d alkynyl substituted with one or more R 2-6 -C 3-12 cycloalkyl, -S-C 1-6 alkyl or -S-C 6k alkyl substituted with one or more R 1-6 , preferably hydrogen, halogen, C 2-6 alkenyl, C 2-6 alkynyl or -S-C 1-6 alkyl; more preferably C 2-6 alkenyl, C 2-6 alkynyl or -S-C 1-6 alkyl; (17) Each R 6a , R 6c , R 6d and R 6k is independently deuterium, a halogen, a hydroxyl group or a C 1-6 alkyl group; (18) Each R 11 is independently hydrogen; (19) The configuration of the carbon atom at the * position is R configuration.

4. The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that, The compound of formula (I) satisfies one or more of the following conditions: (1) R 1 is -NH2, , , , , , , , or ; (2) X is CH or N; (3) Y is CH or N; (4)R 3 is -CF3; (5) R 4-1 and R 4-2 are each independently methyl or -NH2; (6) R 5-1 is F, R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , R 5-7 , R 5-8 and R 5-9 are hydrogen; (7) R 6 is F, -S-Me, or ; (8) Cy is , , , , or .

5. The compound of formula (I), stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound of formula (I) satisfies any one of Scheme 1, Scheme 2, Scheme 3, Scheme 4 and Scheme 5: Scheme 1: X is CR 2 or N; Y is CR 2 or N; Each R 2 is independently hydrogen, deuterium, a halogen or a C 1-6 alkyl group; R 1 is -N(R 8 )2, -NR 8 N(R 8 )2 or -NR 8 NR 8 C(=O)R 9 ; Each R 8 is independently hydrogen or C 1-6 alkyl; R 9 is hydrogen, cyano group, -N(R 10 )2, C 1-6 alkyl group, C 9a alkyl group substituted by one or more R 1-6 alkyl group, C 2-6 alkenyl group, C 9c alkenyl group substituted by one or more R 2-6 alkenyl group, C 2-6 alkynyl group, C 9d alkynyl group substituted by one or more R 2-6 alkynyl group or C 3-12 cycloalkyl group; Each R 9a , R 9c , and R 9d are each independently deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, C 1-6 alkyl, C 9-a alkyl substituted by one or more R 1-6 groups, or -O-C 1-6 alkyl; Each R 9-a is independently deuterium, a halogen, or a hydroxyl group; Each R 10 is independently hydrogen or C 1-6 alkyl; R 3 Independently halogen, C 1-6 alkyl or C 3a alkyl substituted by one or more R 1-6 alkyl; Each R 3a is independently deuterium or a halogen; Cy is or ; Z is O; R 4-1 and R 4-2 each independently is deuterium, a halogen, a cyano group, -N(R 11 )2, a hydroxyl group, a C 1-6 alkyl group, a C 4a alkyl group substituted by one or more R 1-6 or -O-C 1-6 alkyl group; Each R 4a is independently deuterium or a halogen; Each R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 、R 5-7 、R 5-8 and R 5-9 are each independently hydrogen, deuterium, a halogen, C 1-6 alkyl or -O-C 1-6 alkyl; R 6 is hydrogen, a halogen, a cyano group, -N(R 11 )2, a hydroxyl group, C 1-6 alkyl, C 6a alkyl substituted with one or more R 1-6 alkyl, -O-C 1-6 alkyl, C 2-6 alkenyl, C 6c alkenyl substituted with one or more R 2-6 alkenyl, C 2-6 alkynyl, C 6d alkynyl substituted with one or more R 2-6 alkynyl, C 3-12 cycloalkyl, -S-C 1-6 alkyl or -S-C 6k alkyl substituted with one or more R 1-6 alkyl; Each R 6a , R 6c , R 6d and R 6k is independently deuterium, a halogen, a hydroxyl group, or a C 1-6 alkyl group; Each R 11 is independently hydrogen; and the compound of formula (I) satisfies at least one of the following conditions: (1)R 1 is -NR 8 N(R 8 )2 or -NR 8 NR 8 C(=O)R 9 ; (2)Cy is ; (3) R 6 is C 2-6 alkenyl, C 2-6 alkynyl or -S-C 1-6 alkyl; (4) R 4-1 and R 4-2 are each independently -N(R 11 )2; the configuration of the carbon atom at the * position is R configuration, S configuration or a mixture of R configuration and S configuration; In each "3- to 12-membered heterocycloalkyl", the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; In each "3- to 12-membered heterocycloalkenyl", the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; In each "5- to 10-membered heteroaryl", the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; Preferably, the compound in Scheme 1 is not , , , , or ; Scheme Two: The above compound of formula (I) is a compound of the following formula (II), ； wherein, R 1 is -NHNH2 or -NHNHC(=O)R 9 ; R 9 is hydrogen, cyano group, -NH2, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group or C 9d alkynyl group substituted by one or more R 2-6 ; Each R 9d is independently a hydroxyl group, a C 1-6 alkyl group or a C 1-6 alkyl group substituted by one or more hydroxyl groups; R 3 is C 1-6 alkyl or C 1-6 alkyl substituted by one or more halogens; R 4-1 is -NH2 or C 1-6 alkyl; R 5-1 is a halogen; R 6 is hydrogen, halogen, C 2-6 alkenyl, C 2-6 alkynyl or -S-C 1-6 alkyl; X is CH or N; Y is CH or N; The configuration of the carbon atom at the * position is R configuration, S configuration or a mixture of R configuration and S configuration; Scheme Three: The above compound of formula (I) is a compound of the following formula (II), ； wherein, R 1 is -NH2, -NHNH2 or -NHNHC(=O)R 9 ; R 9 is hydrogen, cyano group, -NH2, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group or C 9d alkynyl group substituted by one or more R 2-6 ; Each R 9d is independently a hydroxyl group, C 1-6 alkyl, or C 1-6 alkyl substituted by one or more hydroxyl groups; R 3 is C 1-6 alkyl or C 1-6 alkyl substituted by one or more halogens; R 4-1 is -NH2 or C 1-6 alkyl; R 5-1 is a halogen; R 6 is C 2-6 alkenyl, C 2-6 alkynyl or -S-C 1-6 alkyl; X is CH or N; Y is CH or N; The configuration of the carbon atom at the * position is R configuration, S configuration or a mixture of R configuration and S configuration; Scheme Four: The above compound of formula (I) is a compound of the following formula (III), ； wherein, R 1 is -NH2, -NHNH2 or -NHNHC(=O)R 9 ; R 9 is hydrogen, cyano group, -NH2, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group or C 9d alkynyl group substituted by one or more R 2-6 ; Each R 9d is independently a hydroxyl group, a C 1-6 alkyl group or a C 1-6 alkyl group substituted with one or more hydroxyl groups; R 3 is C 1-6 alkyl or C 1-6 alkyl substituted by one or more halogens; R 4-2 is -NH2 or C 1-6 alkyl; X is CH or N; Y is CH or N; The configuration of the carbon atom at the * position is R configuration, S configuration or a mixture of R configuration and S configuration; Preferably, the compound in Solution 4 is not , or ; Scheme Five: The above compound of formula (I) is a compound of the following formula (IV), ； wherein, R 1 is -NHNH2 or -NHNHC(=O)R 9 ; R 9 is C 2-6 alkynyl or C alkynyl substituted with one or more R 9d substituted; 2-6 alkynyl; Each R 9d is independently a hydroxyl group, a C 1-6 alkyl group or a C 1-6 alkyl group substituted with one or more hydroxyl groups; R 3 C substituted by one or more halogens 1-6 alkyl; R 4-1 is -NH2 or C 1-6 alkyl; R 5-1 is a halogen; R 6 is hydrogen, halogen, C 2-6 alkenyl, C 2-6 alkynyl or -S-C 1-6 alkyl; The configuration of the carbon atom at the * position is R configuration, S configuration or a mixture of R configuration and S configuration; Scheme Six: X is CR 2 or N; Y is CR 2 or N; Each R 2 is independently hydrogen, deuterium, a halogen or a C 1-6 alkyl group; R 1 is -NR 8 N(R 8 )2 or -NR 8 NR 8 C(=O)R 9 ; Each R 8 is independently hydrogen or C 1-6 alkyl; R 9 is hydrogen, cyano, -N(R 10 )2, C 1-6 alkyl, C 9a alkyl substituted with one or more R 1-6 alkyl, C 2-6 alkenyl, C 9c alkenyl substituted with one or more R 2-6 alkenyl, C 2-6 alkynyl, C 9d alkynyl substituted with one or more R 2-6 alkynyl or C 3-12 cycloalkyl; Each R 9a , R 9c and R 9d is independently deuterium, a halogen, a cyano group, -NH2, a hydroxyl group, C 1-6 alkyl, C 9-a alkyl substituted by one or more R 1-6 or -O-C 1-6 alkyl; Each R 9-a is independently deuterium, a halogen or a hydroxyl group; Each R 10 is independently hydrogen or C 1-6 alkyl; R 3 independently halogen, C 1-6 alkyl or C 3a alkyl substituted by one or more R 1-6 alkyl; Each R 3a is independently deuterium or a halogen; Cy is or ; Z is O; R 4-1 and R 4-2 each independently is deuterium, a halogen, a cyano group, -N(R 11 )2, a hydroxyl group, a C 1-6 alkyl group, a C 4a alkyl group substituted with one or more R 1-6 or -O-C 1-6 alkyl; Each R 4a is independently deuterium or a halogen; Each R 5-1 、R 5-2 、R 5-3 、R 5-4 、R 5-5 、R 5-6 、R 5-7 、R 5-8 and R 5-9 is independently hydrogen, deuterium, halogen, C 1-6 alkyl or -O-C 1-6 alkyl; R 6 is hydrogen, halogen, cyano, -N(R 11 )2, hydroxy, C 1-6 alkyl, C 6a alkyl substituted by one or more R 1-6 -O-C 1-6 alkyl, C 2-6 alkenyl, C 6c alkenyl substituted by one or more R 2-6 -C 2-6 alkynyl, C 6d alkynyl substituted by one or more R 2-6 -C 3-12 cycloalkyl, -S-C 1-6 alkyl or -S-C 6k alkyl substituted by one or more R 1-6 alkyl; Each R 6a , R 6c , R 6d and R 6k is independently deuterium, a halogen, a hydroxyl group, or a C 1-6 alkyl group; Each R 11 independently is hydrogen; The configuration of the carbon atom at the * position is R configuration, S configuration or a mixture of R configuration and S configuration; In each "3- to 12-membered heterocycloalkyl", the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; In each "3- to 12-membered heterocycloalkenyl", the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3; In each "5- to 10-membered heteroaryl", the types of heteroatoms are each independently selected from one, two or more of N, O and S, and the number of heteroatoms is each independently 1, 2 or 3.

6. The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that, The compound of formula (I) is any of the following compounds: , , , , , , , , , , , , , or .

7. The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that, The compound of formula (I) is any of the following compounds: or 。 8. A pharmaceutical composition, which comprises the compound of formula (I) shown in any one of claims 1-7, its stereoisomer or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable excipient; Preferably, the compound of formula (I) shown, its stereoisomer or its pharmaceutically acceptable salt is in a therapeutically effective amount.

9. Use of the compound of formula (I) shown in any one of claims 1-7, its stereoisomer or its pharmaceutically acceptable salt or the pharmaceutical composition of claim 8 in the preparation of a drug for treating and / or preventing tumors, CLOVES syndrome or PI3Kα-related overgrowth syndrome; Preferably, the tumor is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer; the breast cancer is preferably ductal carcinoma of the breast; Preferably, the CLOVES syndrome is manifested as congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis, skeletal anomaly or spinal anomaly; Preferably, the compound represented by formula (I), its stereoisomer or its pharmaceutically acceptable salt is in a therapeutically effective amount.

10. Use of a compound represented by formula (I) as claimed in any one of claims 1-7, its stereoisomer or its pharmaceutically acceptable salt or a pharmaceutical composition as claimed in claim 8 in the preparation of a medicament for the treatment and / or prevention of a disease or disorder associated with PI3Kα regulation; Preferably, the disease or disorder associated with PI3Kα regulation is a tumor, such as endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer; the breast cancer is preferably ductal carcinoma of the breast; Preferably, the disease or disorder associated with PI3Kα regulation is CLOVES syndrome (such as manifested as congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis, skeletal anomaly or spinal anomaly) or PI3Kα-related overgrowth syndrome (PROS); Preferably, the compound represented by formula (I), its stereoisomer or its pharmaceutically acceptable salt is in a therapeutically effective amount.

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