CN112789279A - Tricyclic derivative inhibitor, preparation method and application thereof - Google Patents

Tricyclic derivative inhibitor, preparation method and application thereof Download PDF

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CN112789279A
CN112789279A CN201980006386.8A CN201980006386A CN112789279A CN 112789279 A CN112789279 A CN 112789279A CN 201980006386 A CN201980006386 A CN 201980006386A CN 112789279 A CN112789279 A CN 112789279A
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substituted
alkyl
unsubstituted
cycloalkyl
heteroaryl
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CN112789279B (en
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高鹏
修文华
程宇
张福军
刘磊
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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    • C07—ORGANIC CHEMISTRY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Abstract

Provides a tricyclic derivative inhibitor, a preparation method and application thereof. In particular to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound serving as a phosphoinositide 3 kinase (PI3K) inhibitor in treating cancers and diseases or symptoms which mediate or depend on PI3K dysregulation.

Description

Tricyclic derivative inhibitor, preparation method and application thereof Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a tricyclic derivative inhibitor, and a preparation method and application thereof.
Background
The phosphatidylinositol 3 kinase (PI3K) protein family is divided into four major classes I, II, III and IV, and is involved in the regulation of various cell functions such as cell growth, proliferation, differentiation, survival and glucose metabolism. The PI3K four types of proteins have different structures and functions, wherein the most widely researched type I PI3K is the PI3K which is divided into four subtypes, namely PI3K alpha, PI3K beta, PI3K delta and PI3K gamma, wherein the PI3K alpha is subjected to activation mutation and amplification in various tumors and is closely related to the generation and development of the tumors. PI3K beta is reported to activate platelets and plays an important role in the development of diseases such as thrombosis. PI3K δ and PI3K γ are mainly expressed in the blood system, and are closely related to the occurrence of the immune system and inflammation, and in addition, PI3K γ is closely related to blood pressure stabilization and smooth muscle contraction.
PI3K a is an activating mutation and amplification in a variety of tumors, and is the driver for tumorigenesis. PI3K α is a heterodimer consisting of a p110 catalytic subunit and a p85 regulatory subunit. PI3K α is activated by Receptor Tyrosine Kinases (RTKs) and G protein-coupled receptors (GPCRs), and upon activation catalyzes the production of phosphatidylinositol 3 phosphate (PIP3) from phosphatidylinositol 2 phosphate (PIP2), PIP3 further activates protein kinase B (PKB, also known as AKT) and its downstream signaling pathways. Various cell growth factors such as Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), Vascular Endothelial Growth Factor (VEGF), Hepatocyte Growth Factor (HGF) and insulin can activate PI3K alpha, so that downstream proliferation signal channels of cells are activated, and abnormal activation of PI3K alpha can cause cells to rapidly proliferate to cause tumorigenesis.
PI3K alpha is an important target for developing tumor drugs, but most compounds are broad-spectrum inhibitors of PI3Ks, so that the side effects of clinical research are large, and the development of PI3Ks inhibitors is severely limited. Current studies have established that most of the side effects of broad-spectrum inhibitors of PI3Ks are due to inhibition of PI3K β, PI3K δ and PI3K γ subtypes. Wherein PI3K β plays an important role in the mechanism of thrombocytopenia and thrombotic side effects; inhibition of PI3K δ may lead to abnormalities in the immune system; autoimmune and infectious toxicities such as pneumonia, hepatitis and diarrhea/enteritis are closely related to PI3K δ target inhibition; PI3K γ is closely associated with blood pressure stabilization and smooth muscle contraction, and is a major target for the side effects of hypertension. Therefore, the development of the PI3K alpha inhibitor with high activity and high selectivity can further improve the anti-tumor effect of the PI3K alpha inhibitor and reduce or remove serious side effects such as various inflammations, thrombocytopenia and hypertension caused by other subtype inhibition.
BYL-719, a PI3K alpha selective inhibitor, developed by Nowa, is currently in the phase III clinical study, MLN1117, a PI3K alpha selective inhibitor, developed by Wutian, enters the phase II clinical study, and GDC-0077, a selective inhibitor, developed by Genta, is also in the phase I clinical study.
International applications WO2010029082A1 and WO2011022439A1 report compounds related to PI3K alpha selective inhibitors, but later studies show that the compounds have low cell activity and influence the clinical antitumor effect. Therefore, the development of a PI3K alpha inhibitor with high activity and high selectivity is urgently needed, and the PI3K alpha selective inhibitor can be used for treating various multiple tumors with PI3K alpha activation mutation or amplification and has great clinical application value.
Through research, the embodiment of the invention has higher activity and selectivity on PI3K alpha enzyme, better cell activity, better tumor inhibition rate on a mouse pharmacodynamic model and higher safety.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
Figure PCTCN2019104558-APPB-000001
wherein:
q, Y and Z are each independently selected from N or-CRaa；
M is selected from-S-or-NRaa-；
Ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 1selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, - (CH)2) n1R bb、-(CH 2) n1OR bb、-NR aaC(O)(CH 2) n1OR bb、-NR aaC(S)(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl group,Deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl and heteroaryl, optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylhaloalkyl, halogen, substituted or unsubstituted cycloalkylamino, oxo, thioxo, nitro, cyano, hydroxy, substituted or unsubstituted cycloalkylalkenyl, substituted or unsubstituted cycloalkylalkynyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted cycloalkylhaloalkoxy, substituted or unsubstituted cycloalkylhydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH) halo, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, alkoxy, halo2) n1R dd、-(CH 2) n1OR dd、-(CH 2) n1SR dd、-(CH 2) n1C(O)R dd、-(CH 2) n1C(O)OR dd、-(CH 2) n1S(O) m1R dd、-(CH 2) n1NR ddR ee、-(CH 2) n1C(O)NR ddR ee、-(CH 2) n1C(O)NHR dd、-(CH 2) n1NR ddC(O)R eeAnd- (CH)2) n1NR ddS(O) m1R eeIs substituted with one or more substituents of (1);
R xand RyEach independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylhaloalkyl, halogen, substituted or unsubstituted cycloalkylamino, mercapto, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted cycloalkylhaloalkoxy, substituted or unsubstituted cycloalkylhydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH, or C2) n1R dd、-(CH 2) n1OR dd、-(CH 2) n1SR dd、-(CH 2) n1C(O)R dd、-(CH 2) n1C(O)OR dd、-(CH 2) n1S(O) m1R dd、-(CH 2) n1NR ddR ee、-(CH 2) n1C(O)NR ddR ee、-(CH 2) n1C(O)NHR dd、-(CH 2) n1NR ddC(O)R eeAnd- (CH)2) n1NR ddS(O) m1R eeIs substituted with one or more substituents of (1);
or, any two adjacent or non-adjacent RxLinked to form a cycloalkyl, heteroalkyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccIs substituted with one or more substituents of (1);
or, any two adjacent or non-adjacent RyLinked to form a cycloalkyl, heteroalkyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groupsOptionally further substituted with a substituent selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccIs substituted with one or more substituents of (1);
R aaselected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, are optionally further substituted with a substituent selected from the group consisting of deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxySubstituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R bb、R cc、R ddand ReeEach independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
n is 0, 1,2 or 3;
p is 0, 1,2, 3, 4, 5 or 6;
q is 0, 1,2, 3, 4, 5 or 6;
m 1is 0, 1 or 2; and is
n 1Is 0, 1,2, 3, 4 or 5.
The preferable scheme is as follows: rxIs- (CH)2) n1NR bbC(R ffR gg)C(O)R cc；
R ffAnd RggEach independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, and heteroaryl are each optionally substituted with one or more halogen atoms,Haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, preferably hydrogen or C1-3Alkyl, more preferably hydrogen, methyl, ethyl or propyl;
n 1，R bbor RccAs shown in the general formula (I). In a preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formula (II):
Figure PCTCN2019104558-APPB-000002
wherein:
w is selected from oxygen or sulfur; preferably oxygen;
R 9and R10Each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1R dd、-(CH 2) n1OR dd、-(CH 2) n1SR dd、-(CH 2) n1C(O)R dd、-(CH 2) n1C(O)OR dd、-(CH 2) n1S(O) m1R dd、-(CH 2) n1NR ddR ee、-(CH 2) n1C(O)NR ddR ee、-(CH 2) n1C(O)NHR dd、-(CH 2) n1NR ddC(O)R eeAnd- (CH)2) n1NR ddS(O) m1R eeIs substituted with one or more substituents of (1);
or, R9And R10The linkage may form a heterocyclic or heteroaryl group, wherein said heterocyclic and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaryl, and mixtures thereofOr unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccIs substituted with one or more substituents of (1);
A、Q、Y、Z、M、R bb、R cc、R dd、R ee、R x、R y、n、p、q、m 1and n1
As shown in the general formula (I).
In a preferred embodiment of the present invention, the compound represented by the general formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formulae (II-a) and (II-B):
Figure PCTCN2019104558-APPB-000003
wherein:
g is selected from oxygen or sulfur;
l is selected from nitrogen, oxygen, sulfur or-CRaa；
Ring B is selected from heterocyclyl or heteroaryl, preferably thiaheterocyclyl or oxoheterocyclyl;
R zis selected fromHydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl- (CH)2) n1R dd、-(CH 2) n1OR dd、-(CH 2) n1SR dd、-(CH 2) n1C(O)R dd、-(CH 2) n1C(O)OR dd、-(CH 2) n1S(O) m1R dd、-(CH 2) n1NR ddR ee、-(CH 2) n1C(O)NR ddR ee、-(CH 2) n1C(O)NHR dd、-(CH 2) n1NR ddC(O)R eeAnd- (CH)2) n1NR ddS(O) m1R eeIs substituted with one or more substituents of (1);
or, any two adjacent or non-adjacent RzThe groups linked may form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccAnd- (CH)2) n1NR bbS(O) m1R ccIs substituted with one or more substituents of (1);
R 2in the presence or absence of L as a nitrogen atom or-CRaaWhen R is2Selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyanoRadical, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、 -(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R cc；
R 3And R4Each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1R dd、-(CH 2) n1OR dd、-(CH 2) n1SR dd、-(CH 2) n1C(O)R dd、-(CH 2) n1C(O)OR dd、-(CH 2) n1S(O) m1R dd、-(CH 2) n1NR ddR ee、-(CH 2) n1C(O)NR ddR ee、-(CH 2) n1C(O)NHR dd、-(CH 2) n1NR ddC(O)R eeAnd- (CH)2) n1NR ddS(O) m1R eeIs substituted with one or more substituents of (1);
or, the group R2、R 3、R 4And RaaAny two of which are linked to form a cycloalkyl, heteroalkyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccIs substituted with one or more substituents of (1);
m is 0, 1,2, 3, 4, 5 or 6;
t is 0, 1,2, 3, 4, 5 or 6;
q is 0, 1,2, 3, 4, 5 or 6;
Q、Y、Z、M、R bb、R cc、R dd、R ee、R x、R y、n、p、q、m 1and n1As shown in the general formula (I).
In a preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formula (III):
Figure PCTCN2019104558-APPB-000004
wherein:
R 5、R 6and R14Each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclylAryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
or, R5And R6Linked to form a cycloalkyl, heteroalkyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccAnd- (CH)2) n1NR bbS(O) m1R ccIs substituted with one or more substituents of (1);
Q、Y、Z、M、R bb、R cc、R 1、R y、n、p、q、m 1and n1As shown in the general formula (I).
R 2、G、m、R 3And R4As shown in the general formula (II-A).
In a preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formula (IV):
Figure PCTCN2019104558-APPB-000005
wherein:
R 13selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with a substituent selected from the group consisting of deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl; preferably halogen, amino, nitro, cyano, alkyl, haloalkyl or cycloalkyl;
ring B, Q, Z, G, M, R2～R 4、R y、R zM, n, q and t are as described in formula (III).
In a preferred embodiment of the present invention, the compound represented by the general formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formulae (III-a) and (III-B):
Figure PCTCN2019104558-APPB-000006
wherein:
R 7、R 8、R 11and R12Each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccAnd- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, heteroaryl,alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl;
or, the group R7、R 8、R 11And R12Any two of which may be linked to form a cycloalkyl, heteroalkyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
R 9and R10As described in general formula (II).
Q、Z、G、M、R 2～R 6、R 14、R bb、R cc、R y、m、n、q、m 1And n1As described in general formula (III).
R 5、R 6Or R14As described in general formula (III-A).
In a preferred embodiment of the present invention, the compound represented by the general formula (III-a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formula (V):
Figure PCTCN2019104558-APPB-000007
wherein:
ring B is as described in general formula (II-A);
Q、Z、G、M、L、R 2～R 8、R 11、R 12、R 14、R zm and t are as described in formula (III-A).
In a preferred embodiment of the present invention, the compound represented by the general formula (III-a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formula (VI):
Figure PCTCN2019104558-APPB-000008
wherein:
ring B is as described in general formula (II-A);
Q、Z、G、M、L、R 2～R 6、R 14ry, Rz, q, m and t are as described in the general formula (III-A).
In a preferred embodiment of the invention, a compound of any one of the formulae (II-A), (II-B), (IV), (V) or (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is provided, wherein
Ring B is selected from the following groups:
Figure PCTCN2019104558-APPB-000009
in a preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formula (VII):
Figure PCTCN2019104558-APPB-000010
wherein:
R aaselected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further selected from the group consisting of deuterium, alkyl, halogen, hydroxy, amino, oxoSubstituted with one or more substituents selected from the group consisting of aryl, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
L、M、R 2～R 8、R 11、R 12、R 14and m is as described for formula (V).
Preferably, M is selected from-S-or-NRaa-；
L is selected from N;
R aaselected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, aryl and heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-5Cycloalkyl, 3-5 membered heterocyclyl, aryl and heteroaryl, more preferably hydrogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C3-5Cycloalkyl, 3-5 membered heterocyclyl, halogen, hydroxy or amino, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane, cyclopentane, epoxypropyl or epoxybutyl;
R 2～R 8、R 11、R 12or R14Selected from hydrogen, C1-6Alkyl, halogen, cyano, nitro, hydroxy or amino, preferably hydrogen, C1-3Alkyl or halogen, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine, further preferably hydrogen;
m is as described in formula (VII). In a preferred embodiment of the present invention, the compound represented by the general formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formula (VIII-a):
Figure PCTCN2019104558-APPB-000011
wherein:
m is selected from-S-or-NRaa-；
Ring B is selected from the following groups:
Figure PCTCN2019104558-APPB-000012
R aaselected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, aryl and heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-5Cycloalkyl, 3-5 membered heterocyclyl, aryl and heteroaryl, more preferably hydrogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C3-5Cycloalkyl, 3-5 membered heterocyclyl, halogen, hydroxy or amino, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane, cyclopentane, epoxypropyl or epoxybutyl;
R 2～R 6or R14Selected from hydrogen, C1-6Alkyl, halogen, cyano, nitro, hydroxy or amino, preferably hydrogen, C1-3Alkyl or halogen, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine, further preferably hydrogen;
R zselected from hydrogen, C1-6Alkyl or C1-6Haloalkyl, preferably hydrogen, C1-3Alkyl or C1-3Haloalkyl, more preferably hydrogen, C1-3Alkyl or C containing 1-2 halogen atoms1-3Haloalkyl, more preferably hydrogen, methyl, ethyl, propyl, isopropyl, -CH2F、-CHF 2、-CHFCH 3、-CF 2CH 3、-CHFCH 2F、-CH 2Cl、-CHCl 2、-CHClCH 3、-CCl 2CH 3or-CHClCH2Cl；
t is 0, 1,2 or 3.
In a preferred embodiment of the present invention, the compound represented by the general formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formula (VIII):
Figure PCTCN2019104558-APPB-000013
wherein: ring B, M, R3、R 5、R 6、R 14、R ZAnd t is as described for formula (V).
R aaAs shown in the general formula (VII). Preferably, the ring B is selected from
Figure PCTCN2019104558-APPB-000014
R 3Selected from hydrogen, C1-6Alkyl radical, C1-6Alkoxy or alkyl substituted C1-6Alkoxy, preferably hydrogen, C1-3Alkyl radical, C1-3Alkoxy or C1-3Alkoxy-substituted C1-3Alkyl, more preferably hydrogen, methyl, ethyl, propylMethoxy, ethoxy, CH3OCH 2-or CH3CH 2OCH 2-；
R 5、R 6Or R14Each independently selected from hydrogen or halogen, preferably hydrogen;
R zselected from hydrogen, C1-6Alkyl or C1-6Haloalkyl, preferably hydrogen, C1-3Alkyl or C1-3Haloalkyl, more preferably hydrogen, C1-3Alkyl or C containing 1-2 halogen atoms1-3Haloalkyl, more preferably hydrogen, methyl, ethyl, propyl, isopropyl, -CH2F、-CHF 2、-CHFCH 3、-CF 2CH 3、-CHFCH 2F、-CH 2Cl、-CHCl 2、-CHClCH 3、-CCl 2CH 3or-CHClCH2Cl；
t is as described in formula (I).
In a preferred embodiment of the invention, any one of the compounds of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, is further represented by formula (IX):
Figure PCTCN2019104558-APPB-000015
wherein:
m is selected from-S-or-NRaa-；
R aaSelected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, aryl and heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-5Cycloalkyl, 3-5 membered heterocyclyl, aryl and heteroaryl, more preferably hydrogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C3-5Cycloalkyl, 3-5 membered heterocyclyl, halogen, hydroxy or amino, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane, cyclopentane, epoxypropyl or epoxybutyl;
R 2～R 4、R 6or R14Selected from hydrogen, C1-6Alkyl, halogen, cyano, nitro, hydroxy or amino, preferably hydrogen, C1-3Alkyl or halogen, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine, further preferably hydrogen or methyl;
R 15or R16Each independently selected from hydrogen and C1-6Alkyl or C1-6Haloalkyl, preferably hydrogen, C1-3Alkyl or C1-3Haloalkyl, more preferably hydrogen, C1-3Alkyl or C containing 1-2 halogen atoms1-3Haloalkyl, more preferably hydrogen, methyl, ethyl, propyl, isopropyl, -CH2F、-CHF 2、-CHFCH 3、-CF 2CH 3、-CHFCH 2F、-CH 2Cl、-CHCl 2、-CHClCH 3、-CCl 2CH 3or-CHClCH2Cl。
In another preferred embodiment of the present invention, any one of the compounds of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, is further represented by formula (X):
Figure PCTCN2019104558-APPB-000016
wherein:
m is selected from-S-or-NRaa-；
R aaSelected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, aryl and heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-5Cycloalkyl, 3-5 membered heterocyclyl, aryl and heteroaryl, more preferably hydrogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C3-5Cycloalkyl, 3-5 membered heterocyclyl, halogen, hydroxy or amino, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane, cyclopentane, epoxypropyl or epoxybutyl;
R 2～R 4、R 6or R14Selected from hydrogen, C1-6Alkyl, halogen, cyano, nitro, hydroxy or amino, preferably hydrogen, C1-3Alkyl or halogen, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine, further preferably hydrogen or methyl;
R 15or R16Each independently selected from hydrogen and C1-6Alkyl or C1-6Haloalkyl, preferably hydrogen, C1-3Alkyl or C1-3Haloalkyl, more preferably hydrogen, C1-3Alkyl or C containing 1-2 halogen atoms1-3Haloalkyl, more preferably hydrogen, methyl, ethyl, propyl, isopropyl, -CH2F、-CHF 2、-CHFCH 3、-CF 2CH 3、-CHFCH 2F、-CH 2Cl、-CHCl 2、-CHClCH 3、-CCl 2CH 3or-CHClCH2Cl。
In another preferred embodiment of the present invention, any one of the compounds of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein
M is selected from-S-or-NRaa-
Q, Y and Z are each independently selected from N or-CRaa；
Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl, aryl or heteroaryl containing 1-3 heteroatoms, more preferably C5-6Cycloalkyl, 5-6 membered heterocyclyl, aryl or heteroaryl containing 1-3N, O, S heteroatoms, further preferably cyclopentyl, cyclohexyl, pyrrolyl, pyridinyl, phenyl, tetrahydropyrrolyl or piperidinyl;
R 1selected from a substituted or unsubstituted oxoheterocyclic group or a substituted or unsubstituted thioheterocyclic group, preferably a substituted or unsubstituted 5-6-membered oxoheterocyclic group or a substituted or unsubstituted 5-6-membered thioheterocyclic group, more preferably a substituted or unsubstituted 5-6-membered oxoheterocyclic group containing 1-2 heteroatoms of N, O, S or a substituted or unsubstituted 5-6-membered thioheterocyclic group containing 1-2 heteroatoms, further preferably 1-2 heteroatoms of N, O, S
Figure PCTCN2019104558-APPB-000017
Figure PCTCN2019104558-APPB-000018
R xAnd RyEach independently selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyanoAlkenyl, alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, aryl, 3-6 membered heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R cc、-(CH 2) n1NR bbC(R ffR gg)C(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccPreferably hydrogen, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, halogen, amino, C5-6Cycloalkyl, 5-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl or- (CH)2) n1NR bbC(R ffR gg)C(O)R ccMore preferably hydrogen, amino or- (CH)2) n1NR bbC(R ffR gg)C(O)R ccFurther, hydrogen or- (CH) is preferable2) n1NR bbC(R ffR gg)C(O)R cc；
R aa、R bb、R cc、R dd、R ee、R ffOr RggSelected from hydrogen, deuterium, alkyl, cycloalkyl or heterocyclyl, preferably hydrogen, C1-6Alkyl radical, C3-6Cycloalkyl or 3-6 membered heterocyclyl, more preferably hydrogen, C1-3Alkyl radical, C3-5Cycloalkyl or 3-5 membered heterocyclyl, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane, cyclopentane, epoxypropyl or epoxybutyl;
n, p, q, y, n1 or m1 are as described in formula (I). In a preferred embodiment of the invention, any one of the compounds of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein,
R 2in the presence or absence, selected from hydrogen, methoxy, C1-6Alkyl or C1-6A haloalkyl group;
or, R2And R3Or R2And R4Linked to form a 3-8 membered heterocyclic group, preferably pyrrolidinyl or azetidinyl;
R 3and R4Each independently selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or 3-8 membered heterocyclyl;
or R3And R4Link formation C3-8Cycloalkyl or 3-8 membered heterocyclyl, preferably oxetanyl;
R 5and R6Each independently selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy or C1-6A haloalkyl group;
or R5And R6Are linked to form a C3-8Cycloalkyl or 3-8 membered heterocyclyl, preferably cyclobutylalkyl, cyclopentylalkyl and 1, 3-dioxolanyl;
R 14selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C3-8A cycloalkyl group;
R yselected from hydrogen, C1-6Alkyl, aryl, heteroaryl, and heteroaryl,Halogen, C1-6Alkoxy radical, C1-6Haloalkyl and- (CH)2) n1-; preferably a hydrogen atom, C1-3Alkyl radical, C1-3A haloalkyl group; more preferably a hydrogen atom, a methyl group or- (CH)2) n1-；
R aaSelected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl.
In a preferred embodiment of the invention, any one of the compounds of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R iszSelected from hydrogen, halogen, oxo, thio, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl and- (CH)2) n1-, wherein said C1-6Alkyl radical, C1-6Alkoxy and C1-6Haloalkyl, optionally further substituted by hydrogen, halogen, oxo, thio, C1-6Alkyl radical, C1-6Alkoxy and C1-6Substituted by one or more substituents of haloalkyl, preferably halogen, C1-6Alkyl radical, C1-6Haloalkyl or oxo, more preferably halogen, C1-3Alkyl radical, C1-3Haloalkyl or oxo.
In a preferred embodiment of the invention, the compound has the following structure:
Figure PCTCN2019104558-APPB-000019
the invention also relates to a method for preparing the compound shown in the general formula (IV) or the stereoisomer and the pharmaceutically acceptable salt thereof, which comprises the following steps,
Figure PCTCN2019104558-APPB-000020
reacting the general formula (IV-1) with the general formula (IV-2) to obtain a compound shown in the general formula (IV) or a stereoisomer and pharmaceutically acceptable salts thereof;
wherein:
x is selected from halogen;
ring B, Q, Z, G, M, L, R2～R 4、R y、R zQ, m, n and t are as described for formula (VI).
The invention also relates to a method for preparing the compound shown in the general formula (VI) or the stereoisomer and the pharmaceutically acceptable salt thereof, which comprises the following steps,
Figure PCTCN2019104558-APPB-000021
reacting the general formula (VI-1) with the general formula (IV-2) to obtain a compound shown in the general formula (VI) or a stereoisomer and a pharmaceutically acceptable salt thereof;
wherein:
x is selected from halogen;
ring B and t are as described for formula (IV);
Q、Z、G、M、L、R 2～R 6、R 14、R y、R zq, m and n are as described for formula (VI).
The invention also relates to a method for preparing the compound shown in the general formula (IV) or the stereoisomer and the pharmaceutically acceptable salt thereof, which comprises the following steps,
Figure PCTCN2019104558-APPB-000022
wherein:
x is selected from halogen;
ring B, Q, Z, G, M, L, R2～R 6、R y、R zQ, m, n and t are as described for formula (VI).
The invention also relates to a method for preparing the compound shown in the general formula (VI) or the stereoisomer and the pharmaceutically acceptable salt thereof, which comprises the following steps,
Figure PCTCN2019104558-APPB-000023
wherein:
X 1and X2Selected from halogens;
ring B, Q, Z, G, M, L, R2～R 6、R y、R zQ, m, n and t are as described for formula (VI).
The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds of general formula (I), stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to an application of any of the compounds shown in the general formula (I), stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in preparation of PI3K regulator drugs, preferably PI3K alpha inhibitor drugs.
The invention further relates to the use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disease, respiratory disease and cardiac disease, wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, kidney cancer, myelodysplastic syndrome (MDS), Acute Myeloid Leukemia (AML) and colorectal cancer.
The invention further relates to methods of using the compounds of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the treatment of cancer, bone disorders, inflammatory diseases, immune diseases, neurological diseases, metabolic diseases, respiratory diseases and cardiac diseases.
The invention also relates to a method for treating, preventing and/or treating cancer, which comprises the step of administering a therapeutically effective dose of the compound shown as the general formula (I) or the stereoisomer or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof to a patient.
The invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions including, but not limited to, conditions associated with PI3K alpha, PI3K beta, PI3K delta, and PI3K gamma kinase dysfunction.
The present invention also relates to a method of treating a hyperproliferative disorder in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
In some embodiments, the methods relate to the treatment of conditions such as cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disease, respiratory disease, and cardiac disease.
In some embodiments, the present methods relate to the treatment of cancer such as acute myeloid leukemia, myelodysplastic syndrome (MDS), thymus cancer, brain cancer, lung cancer (NSCLC and SCLC), squamous cell cancer, seminoma, melanoma, skin cancer, eye cancer, retinoblastoma, intraocular melanoma, oral and oropharyngeal cancer, bladder cancer, stomach cancer, pancreatic cancer, bladder cancer, breast cancer, cervical cancer, head cancer, neck cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, endometrial cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, CNS cancer, PNS cancer, AIDS-related cancers (e.g., lymphoma and kaposi's sarcoma), or virus-induced cancer. In some embodiments, the method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., Benign Prostatic Hypertrophy (BPH).
The methods of treatment provided herein comprise administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the invention provides a method of treating an inflammatory disorder, including an autoimmune disease, in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Diseases associated with dysfunction of one or more types of ERK include, but are not limited to, Acute Disseminated Encephalomyelitis (ADEM), addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, celiac disease, crohn's disease, diabetes (type 1), goodpasture's syndrome, graves' disease, guillain-barre syndrome (GBS), hashimoto's disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, ocular clonic myoclonic syndrome (OMS), optic neuritis, alder's thyroiditis (Ord's thyroiditis), pemphigus (oemphigus), polyarthritis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, reiter's syndrome, takayasu arteritis, temporal arteritis (also known as "giant cell arteritis"), warm type autoimmune hemolytic anemia (wa-hemolytic rma hemia), Wegener's granulomatosis, alopecia universalis, chagas' disease, chronic fatigue syndrome, autonomic dysfunction, endometriosis, hidradenitis suppurativa, interstitial cystitis, neuromuscular rigidity, sarcoidosis, scleroderma, ulcerative colitis, vitiligo and vulvodynia. Other conditions include bone resorption disorders and thrombotic disorders (thromobsis).
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH2-, "ethylene" means- (CH)2) 2-, "propylene" means- (CH)2) 3-, "butylene" means- (CH)2) 4-and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl groups, more preferably cyclopropyl groups.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2019104558-APPB-000024
spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:
Figure PCTCN2019104558-APPB-000025
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
Figure PCTCN2019104558-APPB-000026
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2019104558-APPB-000027
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. More preferably an oxetanyl group. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.
The term "spiroheterocyclyl" refers to 3 to 20 memberedPolycyclic heterocyclic radicals having a common atom (called spiro atom) between rings, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably a 3-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl group. Non-limiting examples of spiro heterocyclic groups include:
Figure PCTCN2019104558-APPB-000028
Figure PCTCN2019104558-APPB-000029
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-to 5-membered, 4-to 5-membered or 5-to 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2019104558-APPB-000030
the term "bridgeHeterocyclyl "means a 5-to 14-membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure PCTCN2019104558-APPB-000031
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure PCTCN2019104558-APPB-000032
the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure PCTCN2019104558-APPB-000033
the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2019104558-APPB-000034
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"alkynyl" refers to (CH ≡ C-), wherein said alkynyl may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"carboxy" refers to-C (O) OH.
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"EA" ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et 2O "means diethyl ether.
"DCE" refers to 1,2 dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd 2(dba) 3"refers to tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1, 1' -bisdiphenylphosphinoferrocene.
"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bistrimethylsilyl amide.
"MeLi" refers to methyllithium.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc) 3"refers to sodium triacetoxyborohydride.
"DCM" refers to dichloromethane.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that a person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated methanol (CD)3OD) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200 Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh Titai Huanghai silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or can be synthesized according to methods known in the art.
All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.
Intermediate 1
(S) -4- (difluoromethyl) oxazolidin-2-ones
Figure PCTCN2019104558-APPB-000035
The first step is as follows: preparation of (R) -3-benzyl-4- (hydroxymethyl) oxazolidin-2-one
Figure PCTCN2019104558-APPB-000036
(R) -Oxyprop-2-ylcarbinol (3.7g, 50.0mmol), (isocyanatomethyl) benzene (6.66g, 50.0mmol) was mixed in DCM (50mL) and stirred overnight at 45 ℃ under nitrogen. After cooling, 100mL of saturated aqueous sodium bicarbonate was added and extracted with DCM (100 mL. times.2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound (R) -3-benzyl-4- (hydroxymethyl) oxazolidin-2-one (4.14g, yield: 40%).
MS m/z(ESI):208.2[M+H] +.
The second step is that: preparation of (S) -3-benzyl-4- (dimethylol) oxazolidin-2-one
Figure PCTCN2019104558-APPB-000037
(R) -3-benzyl-4- (hydroxymethyl) oxazolidin-2-one (4.14g, 20.0mmol), IBX (16.8g, 60.0mmol) was mixed in EA (100mL) and stirred at 85 ℃ for 3h under nitrogen. After cooling, the mixture is filtered and concentrated under reduced pressure to obtain 4.46g of crude (S) -3-benzyl-4- (dihydroxymethyl) oxazolidine-2-ketone which is directly used for the next reaction.
MS m/z(ESI):224.2[M+H] +.
The third step: preparation of (S) -3-benzyl-4- (difluoromethyl) oxazolidin-2-one
Figure PCTCN2019104558-APPB-000038
Dissolving (S) -3-benzyl-4- (dihydroxymethyl) oxazolidin-2-one (4.46g,20.0mmol) in DCM (100mL), under the protection of nitrogen, in an ice bath, dropwise adding DAST (6.45g,40.0mmol) into the reaction solution, and naturally heating to room temperature for reaction for 3 h. The reaction solution was slowly added dropwise to a pre-cooled saturated aqueous sodium bicarbonate solution. DCM (200mL × 2) extraction, combined organic phases concentrated under reduced pressure and column chromatography gave the title compound (S) -3-benzyl-4- (difluoromethyl) oxazolidin-2-one (1.82g, 40% yield over two steps).
MS m/z(ESI):228.2[M+H] +.
The fourth step: preparation of (S) -4- (difluoromethyl) oxazolidin-2-ones
Figure PCTCN2019104558-APPB-000039
(S) -3-benzyl-4- (difluoromethyl) oxazolidin-2-one (1.82g, 8mmol) dissolved in ethanol (100mL) and Pd (OH) added2C (300mg), stirred overnight at 70 ℃ under hydrogen. Cooled, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (S) -4- (difluoromethyl) oxazolidin-2-one (0.88g, yield: 80%).
1H NMR(400MHz,CDCl 3)δ4.05-4.18(m,1H),4.39-4.45(m,1H),4.54(t,J＝9.3Hz,1H),5.78(td,J＝55.3,4.7Hz,1H),6.07(s,1H).
MS m/z(ESI):138.1[M+H] +.
Example 1
Preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -7-methyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propanamide
Figure PCTCN2019104558-APPB-000040
The first step is as follows: preparation of 5-bromo-2- (1H-imidazol-2-yl) aniline
Figure PCTCN2019104558-APPB-000041
Add aqueous glyoxal (40 wt.%, 18g,124mmol) to a solution of 2-amino-4-bromobenzene (formaldehyde) (4.9g,24.6mmol) in methanol (50mL) and slowly add aqueous ammonia (28 wt.%, 24g,172mmol) dropwise with stirring under a water bath, with the addition lasting for 30 minutes, controlling the temperature of the reaction solution to not exceed 40 ℃. Then, the mixture was stirred at 35 ℃ overnight, cooled, concentrated under reduced pressure and subjected to column chromatography to give the title compound 5-bromo-2- (1H-imidazol-2-yl) aniline (3.5g, yield: 60%).
MS m/z(ESI):238.0[M+H] +.
The second step is that: preparation of 10-bromo-5, 6,7, 8-tetrahydrobenzo [ c ] imidazo [1,2-a ] [1,5] diazacine
Figure PCTCN2019104558-APPB-000042
5-bromo-2- (1H-imidazol-2-yl) aniline (3.3g, 14mmol), 1, 2-dibromoethane (1.38mL, 15.9mmol), cesium carbonate (10.4g,31.8mmol) were mixed in N, N-dimethylformamide (50mL) and stirred at room temperature for 1.5 hours. Water was added, stirred for 5 min and extracted three times with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound 10-bromo-5, 6,7, 8-tetrahydrobenzo [ c ] imidazo [1,2-a ] [1,5] diazacine (1.55g, yield: 40%).
MS m/z(ESI):278.0[M+H] +.
The third step: preparation of 9-bromo-2, 3-diiodo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepine
Figure PCTCN2019104558-APPB-000043
NIS (3.8g, 16.8mmol) was added portionwise to a solution of 10-bromo-5, 6,7, 8-tetrahydrobenzo [ c ] imidazo [1,2-a ] [1,5] diazcin (1.55g, 5.6mmol) in DMF (30mL) at room temperature, then stirred at 60 ℃ overnight. Cooling, adding water, and separating out solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1M aqueous NaOH solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 9-bromo-2, 3-diiodo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepine (2.6g, yield: 90.2%).
MS m/z(ESI):515.8[M+H] +.
The fourth step: preparation of 9-bromo-2-iodo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepine
Figure PCTCN2019104558-APPB-000044
EtMgBr (1.0M THF solution, 10mL, 10mmol) was added slowly dropwise to a solution of 9-bromo-2, 3-diiodo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepine (2.52g,4.9mmol) in THF (20mL) at-20 ℃. After the addition was complete, the mixture was stirred at-15 ℃ for 3 hours. Slowly warmed to room temperature, saturated aqueous ammonium chloride solution was added dropwise, stirred for 15 minutes, and extracted with ethyl acetate 3 times. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give the title compound 9-bromo-2-iodo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepine (1.52g, yield: 80%).
MS m/z(ESI):389.9[M+H] +.
The fifth step: preparation of (S) -3- (9-bromo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptidin-2-yl) -4- (difluoromethyl) oxazolidin-2-one
Figure PCTCN2019104558-APPB-000045
9-bromo-2-iodo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepine (179mg,0.46mmol), (S) -4- (difluoromethyl) oxazolidin-2-one (63mg,0.46mmol), (1R,2R) -N1, N2-dimethylcyclohexane-1, 2-diamine (28.4mg,0.2mmol), cuprous iodide (19.0mg,0.1mmol) and potassium carbonate (138mg,1.0mmol) were mixed in 1, 4-dioxane (4mL), heated to 100 ℃ for 5 hours, cooled to room temperature, 14% ammonia was added, stirred for 5 minutes, and extracted with EtOAc three times. The organic phases were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound (S) -3- (9-bromo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-2-yl) -4- (difluoromethyl) oxazolidin-2-one (111mg, yield: 60%).
MS m/z(ESI):399.1[M+H] +。
And a sixth step: preparation of (S) -3- (9-bromo-7-methyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-2-yl) -4- (difluoromethyl) oxazolidin-2-one
Figure PCTCN2019104558-APPB-000046
(S) -3- (9-bromo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-2-yl) -4- (difluoromethyl) oxazolidin-2-one (111mg, 0.28mmol) is dissolved in methanol (5mL), a catalytic amount of acetic acid and aqueous formaldehyde (37% aq, 50mg, 0.62mmol) is added, stirring is carried out for 30 minutes at room temperature, sodium cyanoborohydride (39mg, 0.62mmol) is added, EtOAc is reacted for 3 hours at room temperature, the reaction is quenched with saturated aqueous ammonium chloride and extracted three times with EtOAc. The organic phases were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound (S) -3- (9-bromo-7-methyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-2-yl) -4- (difluoromethyl) oxazolidin-2-one (81mg, yield: 70%).
MS m/z(ESI):413.1[M+H] +.
The seventh step: preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -7-methyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propanamide
Figure PCTCN2019104558-APPB-000047
(S) -3- (9-bromo-7-methyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-2-yl) -4- (difluoromethyl) oxazolidin-2-one (49.4mg, 0.12mmol), L-alanine (21.4mg,0.24mmol), cuprous iodide (4.6mg,0.024mmol) and potassium phosphate (51.5mg,0.24mmol) were mixed in dimethylsulfoxide (2mL), reacted at 100 ℃ for 5 hours, cooled to room temperature, ammonium chloride (39mg, 0.72mmol), triethylamine (184mg, 1.8mmol) were added, stirred for 5 minutes, 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (418mg, 1.1mmol) was added, after stirring at room temperature for 2 hours, the mixture was filtered, and then saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -7-methyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propionamide (20mg, yield: 40%).
1H NMR(400MHz,CD 3OD)δ1.47(d,J＝7.0Hz,3H),2.95(s,3H),3.43-3.50(m,2H),3.86(q,J＝7.0Hz,1H),4.15(t,J＝5.2Hz,2H),4.54-4.67(m,2H),4.90-4.95(m,1H),6.18(d,J＝2.2Hz,1H),6.27(dd,J＝8.7,2.2Hz,1H),6.35-6.68(m,1H),7.16(s,1H),7.84(d,J＝8.7Hz,1H)；
MS m/z(ESI):421.1[M+H] +.
Example 2
Preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyl oxazolidin-3-yl) -6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propanamide
Figure PCTCN2019104558-APPB-000048
Preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propanamide reference is made to example 1.
1H NMR(400MHz,CD 3OD)δ1.45(d,J＝7.0Hz,3H),3.42-3.49(m,2H),3.78(q,J＝7.0Hz,1H),4.12-4.18(m,2H),4.54-4.67(m,2H),4.90-4.96(m,1H),5.86(d,J＝2.3Hz,1H),6.17(dd,J＝8.8,2.3Hz,1H),6.32-6.62(m,1H),7.05(s,1H),7.91(d,J＝8.8Hz,1H)；
MS m/z(ESI):407.1[M+H] +.
Example 3
Preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -7-ethyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propanamide
Figure PCTCN2019104558-APPB-000049
Preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -7-ethyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propionamide reference is made to example 1.
MS m/z(ESI):435.1[M+H] +.
Example 4
Preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -7-isopropyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propanamide
Figure PCTCN2019104558-APPB-000050
Preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -7-isopropyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propionamide reference is made to example 1.
MS m/z(ESI):449.1[M+H] +.
Example 5
Preparation of (S) -2- ((7-cyclopropyl-2- ((S) -4- (difluoromethyl) -2-carbonyl oxazolidin-3-yl) -6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propanamide
Figure PCTCN2019104558-APPB-000051
Preparation of (S) -2- ((7-cyclopropyl-2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propionamide reference is made to example 1.
MS m/z(ESI):447.1[M+H] +.
Example 6
Preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyl oxazolidin-3-yl) -7- (oxetan-3-yl) -6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propanamide
Figure PCTCN2019104558-APPB-000052
Preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyl oxazolidin-3-yl) -7- (oxetan-3-yl) -6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propionamide method reference is made to example 1.
MS m/z(ESI):463.1[M+H] +.
Example 7
Preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepin-9-yl) amino) propanamide
Figure PCTCN2019104558-APPB-000053
The first step is as follows: preparation of 2- (5-bromo-2-fluorophenyl) -1H-imidazole
Figure PCTCN2019104558-APPB-000054
5-bromo-2-fluorobenzaldehyde (5.0g, 24.6mmol) was dissolved in isopropanol/water (25mL/25mL) at room temperature, ammonium acetate (17.6g, 221.7mmol) was added, glyoxal (4.5mL, 221.7mmol) was added dropwise, and the mixture was stirred overnight. Isopropanol was added to dilute the reaction mixture, the reaction mixture was filtered and concentrated under reduced pressure, the concentrate was separated from dichloromethane and water, the organic phases were combined, and then the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound 2- (5-bromo-2-fluorophenyl) -1H-imidazole (3.3g, yield: 56%).
1H NMR(400MHz，DMSO-d6)δ8.16-8.10(m,1H),7.60-7.56(m,1H),7.38-7.33(m,1H),7.27-7.18(m,2H).
MS m/z(ESI):241.0[M+H] +.
The second step is that: preparation of 9-bromo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine
Figure PCTCN2019104558-APPB-000055
2- (5-bromo-2-fluorophenyl) -1H-imidazole (2.0g, 8.4mmol) was dissolved in N, N-dimethylformamide (10mL), and sodium hydride (442mg, 9.2mmol) was added to the reaction under cooling in an ice-water bath, stirred for 10 minutes, added to thiirane ring (612mg, 10.2mmol), warmed to 95 ℃ and stirred for 6 hours. After cooling to room temperature, a saturated aqueous ammonium chloride solution was added to the reaction flask, followed by extraction with dichloromethane three times. The organic phases were combined, and then the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound 9-bromo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine (1.0g, yield: 43%).
MS m/z(ESI):281.0[M+H] +.
The third step is the preparation of 9-bromo-2, 3-diiodo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine
Figure PCTCN2019104558-APPB-000056
To a solution of 9-bromo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine (980mg, 3.5mmol) in DMF (20mL) at room temperature was added NIS (2.4g, 10.5mmol) in portions, followed by stirring at 60 ℃ overnight. Cooling, adding water, and separating out solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1M aqueous NaOH solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 9-bromo-2, 3-diiodo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine (1.6g, yield: 86%).
MS m/z(ESI):532.8[M+H] +.
The fourth step is the preparation of 9-bromo-2-iodo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine
Figure PCTCN2019104558-APPB-000057
EtMgBr (1.0M THF solution, 3.3mL,3.3mmol) was added slowly and dropwise to a solution of 9-bromo-2, 3-diiodo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine (1.6g,3.0mmol) in THF (10mL) at-20 ℃. After the addition was complete, the mixture was stirred at-15 ℃ for 3 hours. Slowly warmed to room temperature, saturated aqueous ammonium chloride solution was added dropwise, stirred for 15 minutes, and extracted with ethyl acetate 3 times. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give the title compound 9-bromo-2-iodo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine (1.03g, yield: 85%).
MS m/z(ESI):406.9[M+H] +.
The fifth step is the preparation of (S) -3- (9-bromo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepin-2-yl) -4- (difluoromethyl) oxazolidin-2-one
Figure PCTCN2019104558-APPB-000058
9-bromo-2-iodo-5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Thiazapine (186.7mg, 0.46mmol), (S) -4- (difluoromethyl) oxazolidin-2-one (63mg,0.46mmol), (1R,2R) -N1,N 2-dimethylcyclohexane-1, 2-diamine (28.4mg,0.2mmol), cuprous iodide (19.0mg,0.1mmol), potassium carbonate (138mg,1.0mmol) were mixed in 1, 4-dioxane (4mL), reacted at 100 ℃ for 5 hours, cooled to room temperature, 14% ammonia was added, stirred for 5 minutes, extracted three times with EtOAc. The organic phases are combinedWashed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound (S) -3- (9-bromo-5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Thiazepin-2-yl) -4- (difluoromethyl) oxazolidin-2-one (124mg, yield: 65%).
MS m/z(ESI):416.0[M+H] +.
Sixth step preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepin-9-yl) amino) propanamide
Figure PCTCN2019104558-APPB-000059
(S) -3- (9-bromo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepin-2-yl) -4- (difluoromethyl) oxazolidin-2-one (49.8mg, 0.12mmol), L-alanine (21.4mg,0.24mmol), cuprous iodide (4.6mg,0.024mmol), potassium phosphate (51.5mg,0.24mmol), mixed in dimethylsulfoxide (2mL), reacted at 100 ℃ for 5 hours, cooled to room temperature, ammonium chloride (39mg, 0.72mmol), triethylamine (184mg, 1.8mmol), stirred for 5 minutes, 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (418mg, 1.1mmol), stirred at room temperature for 2 hours, filtered, saturated aqueous sodium bicarbonate solution was added, extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepin-9-yl) amino) propionamide (18mg, yield: 35%).
1H NMR(400MHz,CDCl 3)δ1.56(d,J＝7.0Hz,3H),3.44-3.52(m,2H),3.84-3.92(m,1H),4.12-4.21(m,2H),4.48-4.56(m,1H),4.68-4.74(m,1H),4.88-5.02(m,1H),5.36(s,1H),6.40(s,1H),6.45-6.77(m,2H),6.83-6.88(m,1H),7.33(s,1H),7.61(d,J＝8.4Hz,1H)；
MS m/z(ESI):424.1[M+H] +.
Biological test evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
Test example 1 assay for inhibitory Effect of the Compound of the present invention on PI 3K. alpha. kinase Activity
Purpose of the experiment: the purpose of this test example was to test the activity of the example compounds against inhibition of PI3K α/β/γ/δ kinase activity.
An experimental instrument: the centrifuge (5702R) is purchased from Eppendorf company, the pipettor is purchased from Eppendorf or Rainin company, and the microplate reader is purchased from BioTek company in the United states and is a SynergyH1 full-function microplate reader.
The experimental method comprises the following steps: the experiment adopts an ADP-Glo lipid kinase measuring method (Promega # V9102) of Promega company, and lipid kinase PI3K alpha/beta/gamma/delta is measured in a substrate PIP 2: catalyzing reaction in the presence of 3PS and ATP, generating ADP from ATP, characterizing the activity of lipid kinase by measuring the content of ADP in the reaction, and obtaining the half inhibition concentration IC of the compound on the inhibition of the activity of PI3K alpha/beta/gamma/delta kinase50。
The specific experimental operations were as follows:
the kinase reaction was performed in white 384-well plates (Perkin Elmer #6007299) with 2. mu.L of ddH containing 1% DMSO per well2O diluted Compounds at various concentrations, positive control wells were added 2. mu.L ddH containing 1% DMSO2O, then 2. mu.L of 5 Xkinase buffer (HEPES 250mM, MgCl) was added to each well215mM NaCl 250mM BSA 0.05%) diluted 0.1-2nM PI3K kinase solution, 2. mu.L of 5 Xkinase buffer was added to the negative control wells, 4. mu.L of 10 Xdilution buffer and ddH were added to all wells2O formulated 50 μ M substrate PIP 2: 3PS (Promega # V1701), adding 2. mu.L of 50-100. mu.M ATP solution diluted with water to start the reaction, reacting at room temperature for 90-120 minutes, and adding 10. mu.L ADP-Glo Reagent (containing 10mM MgCl) to each well2) The reaction was carried out at room temperature for 60 minutes to remove excess ATP, 20. mu.L of Kinase Detection Reagent was added to each well, and after reaction at room temperature for 20 minutes in the dark, the chemiluminescence value was measured using a BioTek Synergy H1 microplate reader.
Enzyme name Goods number Concentration of enzyme reaction Time of enzyme reaction ATP concentration
PI3Kα Promega#V1721 0.1nM 120min 50μM
PI3Kβ Carna#11-102 0.4nM 90min 100μM
PI3Kγ Thermofisher#PV4786 0.4nM 120min 50μM
PI3Kδ Carna#11-103 0.1nM 90min 100μM
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition 100- [ (test compound value-negative control value) for wells treated with compound was calculated by counting the percent inhibition data for wells treated with compound over positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate]V (positive control value-negative control value) × 100 }. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a four parameter nonlinear logistic formula50The value is obtained.
And (4) experimental conclusion:
it follows from the above protocol that the compounds of the examples shown in the present invention show biological activities in the PI3K α/β/γ/δ kinase activity assay as shown in table 1 below.
TABLE 1
Figure PCTCN2019104558-APPB-000060
The data show that the compound of the embodiment shown in the invention has good activity and selectivity in the aspect of PI3K alpha/beta/gamma/delta kinase activity, and is superior to the positive compound GDC-007.
Test example 2 measurement of proliferation inhibitory Effect of the Compound of the present invention on PI3K alpha mutant cancer cells
Purpose of the experiment: the purpose of this test example was to test the proliferation inhibitory activity of the compounds of the examples on PI3K mutant cancer cells HCC1954(H1047R), HGC-27(E542K) and MKN1 (E545K).
An experimental instrument: the centrifuge (5702R) is purchased from Eppendorf, the carbon dioxide incubator is purchased from Thermo, the biosafety cabinet is purchased from Shanghai Bowen, the pipettor is purchased from Eppendorf or Rainin, and the microplate reader is purchased from American BioTek, and is a SynergyH1 full-function microplate reader.
The experimental method comprises the following steps: the proliferation inhibitory effects of the compounds of the examples on PI3K alpha mutant cancer Cell lines (HCC1954, HGC-27(E542K) and MKN1 were examined by Cell Titer-Glo method. The cell lines were cultured in RPMI1640 medium (Gibco #22400089) containing 10% FBS (Gibco #10091148) and 1% Glutamine (Gibco #25030081) at 37 ℃ with 5% CO2Culturing under the conditions of (1). Cells were harvested prior to the experiment, cell density was adjusted after cell counting, cells were seeded in a white 96-well plate (Corning #3610) at a density of 1000-2Adding prepared compound solutions with different concentrations after overnight culture in an incubator, setting corresponding solvent control, and continuously placing at 37 deg.C and 5% CO2After culturing in an incubator for 48-96 hours, balancing the Cell plate and the content thereof to room temperature, adding 20-100 μ L of Cell Titer-Glo solution (Promega # G7573) into each hole, shaking, uniformly mixing, incubating for 5-30 minutes in a dark place at room temperature, and detecting the chemiluminescence value by using a SynergyH1 enzyme-labeling instrument of BioTek.
The experimental data processing method comprises the following steps:
the percent inhibition data {% inhibition of wells treated with compound is 100- (test compound value/vehicle control value) × 100} calculated by vehicle control wells on the plate. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a four parameter nonlinear logistic formula50The value is obtained.
And (4) experimental conclusion:
the above scheme shows that the compounds of the examples of the present invention show the biological activities as shown in table 2 below in the activity test of proliferation inhibition of PI3K α mutant cancer cells HCC1954(H1047R), HGC-27(E542K) and MKN1 (E545K).
TABLE 2
Figure PCTCN2019104558-APPB-000061
The above data show that the example compounds of the present invention have good activity for inhibiting the proliferation of PI3K α mutant cancer cells HCC1954(H1047R), HGC-27(E542K) and MKN1(E545K), which is superior to the positive compound GDC-007.
Test example 3 pharmacokinetic PK experiment of the Compound of the example of the present invention on mice
The mouse pharmacokinetic experiments with the compounds of the preferred embodiment of the invention were performed using Balb/c male mice (Shanghai Jie laboratory animals Co., Ltd.).
■ administration mode: single administration by intragastric administration.
■ dosage: 5 mg/10 ml/kg (body weight).
■ formulation: 0.5% CMC-Na, ultrasonic dissolving, and making into clear solution or uniform suspension.
■ sample points: 0.5, 1,2, 4, 6, 8 and 24 hours after administration.
■ sample treatment:
1) 0.1mL of blood is collected in orbit and placed in K2-Centrifuging the plasma in an EDTA test tube at the room temperature of 1000-3000 Xg for 5-20 min, and storing the plasma at-80 ℃.
2) Adding 160uL acetonitrile into 40uL of the plasma sample for precipitation, and centrifuging for 5-20 minutes at 500-2000 Xg after mixing.
3) Taking 100uL of the treated supernatant solution to perform LC/MS/MS analysis on the concentration of the embodiment to be detected.
■ LC-MS/MS analysis:
● liquid phase conditions: shimadzu LC-20AD pump
● Mass Spectrometry conditions: AB Sciex API4000 mass spectrometer
● column chromatography: phenomenex Gemiu 5um C18 50×4.6mm
● mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile
● flow rate: 0.8mL/min
● elution time: gradient elution for 0-4 min
■ pharmacokinetics:
the main parameters were calculated using WinNonlin 6.1, and the results of the mouse pharmacokinetic experiments are shown in table 3 below:
TABLE 3
Figure PCTCN2019104558-APPB-000062
The results of the mouse pharmacokinetic experiments in the table show that the compounds of the examples shown in the invention have good metabolic properties, plasma exposure AUC and maximum blood concentration CmaxAll the performances are good and are superior to that of a positive compound GDC-007.
Test example 4 in vivo efficacy test of the Compound of the example of the present invention
4.1 purpose of the experiment
The compound with obvious drug effect and less toxic and side effect is screened out through in vivo drug effect experiments.
4.2 Main instruments and materials for the experiment
4.2.1 Instrument:
1. biological safety cabinet (BSC-1300II A2, Shanghai Bocheng industry Co., Ltd.)
2. Clean bench (CJ-2F, Suzhou city Von shi laboratory animal facilities Co., Ltd.)
3、CO 2Incubator (Thermo-311)
4. Centrifuge (Centrifuge 5702R, Eppendorf)
5. Full-automatic cell counter (Countess II, Life)
6. Pipettor (10-20 μ L, Eppendorf)
7. Microscope (TS2, Nikang)
8. Slide measure (CD-6' AX, Japan Sanfeng)
9. Cell culture bottle (T75/T225, Corning)
10. Electronic balance (CPA2202S Saedolisi)
4.2.2 reagents:
1. RPMI-1640 medium (22400-089, Gibco)
2. Fetal Bovine Serum (FBS) (10091-148, Gibco)
3. 0.25% trypsin (25200-056, Gibco)
4. Penicillin streptomycin double antibody (15140-122, Gibco)
5. Phosphate Buffered Saline (PBS) (10010-023, Gibco)
6. Matrigel Matrix (356234, Corning)
4.2.3 animals:
BALB/c nude mice, 6-8 weeks old, purchased from Shanghai Sphall-Biky laboratory animals, Inc. 4.3 Experimental procedures
4.3.1 cell culture and cell suspension preparation
a, taking an HCC1954 cell strain from a cell bank, using an RPMI-1640 culture medium (RPMI-1640+ 10% FBS + 1% SP) to recover the cell, placing the recovered cell in a cell culture flask (marking the cell type, date, name of cultured person and the like on the flask wall) and placing the cell in CO2Culturing in incubator (incubator temperature 37 deg.C, CO)2Concentration 5%).
b, after the cells are paved at 80-90% of the bottom of the culture flask, carrying out passage, and continuously placing the cells in CO after passage2Culturing in an incubator. This process is repeated until the number of cells meets the in vivo pharmacodynamic requirements.
c, collecting cultured cells, counting by using a full-automatic cell counting instrument, and re-suspending the cells by using PBS and matrigel according to the counting result to prepare cell suspension (the density is 5 multiplied by 10)7mL), and placing in an ice box for standby.
4.3.2 cell inoculation
a, marking the nude mice with disposable universal big and small mouse ear tags before inoculation
And b, uniformly mixing the cell suspension during inoculation, pumping 0.1-1 mL of the cell suspension by using a 1mL syringe, removing bubbles, and then placing the syringe on an ice bag for later use.
And c, holding the nude mouse with the left hand, disinfecting the position (inoculation position) close to the right shoulder of the right back of the nude mouse by using 75% alcohol, and starting inoculation 30 seconds later.
d, test nude mice were sequentially inoculated (0.1 mL cell suspension per mouse).
4.3.3 tumor-bearing mice for measuring, grouping and administering tumors
a, measuring tumors at 14-18 days after inoculation according to tumor growth conditions, and calculating the tumor size.
Calculating the tumor volume: tumor volume (mm)3) Length (mm) × width (mm)/2
And b, grouping by adopting a random grouping method according to the weight and the tumor size of the tumor-bearing mice.
And c, according to grouping results, the test drug administration is started (administration mode: oral administration; administration dose: 10 mg/kg; administration volume: 10 mL/kg; administration frequency: 1 time/day; administration period: 21 days; vehicle: 0.5% CMC/1% Tween 80).
d, tumor is measured and weighed twice a week after the test drug administration is started.
e, euthanizing the animals after the experiment is finished.
f, processing the data by software such as Excel and the like. Calculation of tumor inhibition rate TGI (%) of compound: when there was no regression of the tumor, TGI (%) [ (1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group))/(average tumor volume at the end of treatment of the solvent control group-average tumor volume at the start of treatment of the solvent control group) ] × 100%. When there was regression of the tumor, TGI (%) [1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group)/average tumor volume at the start of administration of the treatment group ] × 100%.
4.4 test data:
grouping Number of animals (only) Days of administration (Tian) Tumor inhibition rate
Example 1 5 21 122％
Example 7 5 21 147％
4.5 results of the experiment
As can be seen from the above results, the above compounds of the present invention have better tumor inhibition rate than that of the positive compound GDC-007.
Test example 5 repeated gavage 7-day toxicity test in SD rats
5.1 purpose of the experiment
The objective of this study was to examine the possible toxicity of GDC-0077 and example 7 after 7 days of repeated gavage administration to SD rats, and to compare the difference in toxicity between GDC-0077 and example 7.
5.2 Experimental materials and instruments
5.2.1 test article
Test article 1: GDC-0077
Sample 2: example 7
5.2.2 vehicle
Name: 20% aqueous SBE-beta-CD (Captisol)
5.2.3 animal information
Species & strain: Sprague-Dawley (SD) rats
Animal grade: SPF stage
Animal number and sex: 112 rats, male and female halves.
5.2.4 instruments
Figure PCTCN2019104558-APPB-000063
The serial full-automatic blood analyzer is used for blood cell counting;
the SYSMEX CA-500 coagulometer is used for detecting a coagulation function index;
the TBA-120FR full-automatic biochemical analyzer is used for detecting biochemical indexes of blood;
the easy lyte electrolyte analyzer is used for electrolyte detection;
the liquid phase mass spectrum detector model API4000, the electrospray ionization source (ESI) positive ion mode and the chromatographic column model Agilent ZORBAX XDB-C18(3.5 mu m,2.1 multiplied by 50mm) are used for bioanalytical detection of a plasma sample;
5.3 Experimental methods
1) In the test, 112 rats (56 rats/sex) were classified into 14 groups according to the sex, 70 rats were used for toxicological studies (1-7 groups, 5 rats/sex/group) and 42 rats were used for toxicological studies (8-14 groups, 3 rats/sex/group);
2) group 1 and 8 animals were gavaged with a 20% aqueous solution of SBE-. beta. -CD (Captisol) as a vehicle control;
3) the animals in groups 2 and 9, 3 and 10, and 4 and 11 were gavaged with 10, 30, 60mg/kg GDC-0077 respectively;
4) animals in groups 5 and 12, 6 and 13, 7 and 14 were gavaged with 10, 30, 60mg/kg of example 51, respectively.
5) Animals were dosed 1 time a day for 7 consecutive days (6 consecutive days in groups 7, 14).
6) The dose volumes were 10 mL/kg.
7) During the test period, clinical observation, body weight, food intake, clinical pathological indexes (blood cell count, blood coagulation function, blood biochemistry), pharmacokinetics and other items are examined.
8) All animals were euthanized at d8 (animals in groups 7 and 14 were euthanized after d6 drug).
9) Gross anatomical observations were made during the trial in groups 1-7, 14 and dead animals (including surrogate study animals), and histopathological examination was made of abnormal tissue, gastrointestinal tissue (e.g., colon, caecum) and immune tissue (e.g., thymus). The test results show that the compound C of the inventionmaxAnd AUC(0-24h)Is obviously higher than GDC-0077 and better than GDC-0077 in tolerance.

Claims (26)

  1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2019104558-APPB-100001
    wherein:
    q, Y and Z are each independently selected from N or-CRaa；
    Ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
    m is selected from-S-or-NRaa-；
    R 1Selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, - (CH)2) n1R bb、-(CH 2) n1OR bb、-NR aaC(O)(CH 2) n1OR bb、-NR aaC(S)(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, and heteroaryl are optionally further substituted with a substituent selected from deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylA halogenated alkyl group, a halogen group, a substituted or unsubstituted cycloalkylamino group, an oxo group, a thio group, a nitro group, a cyano group, a hydroxyl group, a substituted or unsubstituted cycloalkylalkenyl group, a substituted or unsubstituted cycloalkylalkynyl group, a substituted or unsubstituted cycloalkylalkoxy group, a substituted or unsubstituted cycloalkylhaloalkoxy group, a substituted or unsubstituted cycloalkylhydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a- (CH) group2) n1R dd、-(CH 2) n1OR dd、-(CH 2) n1SR dd、-(CH 2) n1C(O)R dd、-(CH 2) n1C(O)OR dd、-(CH 2) n1S(O) m1R dd、-(CH 2) n1NR ddR ee、-(CH 2) n1C(O)NR ddR ee、-(CH 2) n1C(O)NHR dd、-(CH 2) n1NR ddC(O)R eeAnd- (CH)2) n1NR ddS(O) m1R eeIs substituted with one or more substituents of (1);
    R xand RyEach independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylhaloalkyl, halogen, substituted or unsubstituted cycloalkylamino, mercapto, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted cycloalkylhaloalkoxy, substituted or unsubstituted cycloalkylhydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH, or C2) n1R dd、-(CH 2) n1OR dd、-(CH 2) n1SR dd、-(CH 2) n1C(O)R dd、-(CH 2) n1C(O)OR dd、-(CH 2) n1S(O) m1R dd、-(CH 2) n1NR ddR ee、-(CH 2) n1C(O)NR ddR ee、-(CH 2) n1C(O)NHR dd、-(CH 2) n1NR ddC(O)R eeAnd- (CH)2) n1NR ddS(O) m1R eeIs substituted with one or more substituents of (1);
    or, any two adjacent or non-adjacent RxLinked to form a cycloalkyl, heteroalkyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccIs substituted with one or more substituents of (1);
    or, any two adjacent or non-adjacent RyLinked to form a cycloalkyl, heteroalkyl, aryl and heteroaryl groupAryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccIs substituted with one or more substituents of (1);
    R aaselected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, are optionally further substituted with a substituent selected from the group consisting of deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, and heteroarylSubstituted with one or more substituents selected from the group consisting of cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
    R bb、R cc、R ddand ReeEach independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
    n is 0, 1,2 or 3;
    p is 0, 1,2, 3, 4, 5 or 6;
    q is 0, 1,2, 3, 4, 5 or 6;
    m 1is 0, 1 or 2; and is
    n 1Is 0, 1,2, 3, 4 or 5.
  2. The compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, according to claim 1, wherein R isxIs- (CH)2) n1NR bbC(R ffR gg)C(O)R cc；
    R ffAnd RggEach independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, preferably hydrogen or C1-3Alkyl, more preferably hydrogen, methyl, ethyl or propyl;
    n 1，R bbor RccAs claimed in claim 1.
  3. The compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 1, further represented by formula (II):
    Figure PCTCN2019104558-APPB-100002
    wherein:
    w is selected from oxygen or sulfur, preferably oxygen;
    R 9and R10Each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1R dd、-(CH 2) n1OR dd、-(CH 2) n1SR dd、-(CH 2) n1C(O)R dd、-(CH 2) n1C(O)OR dd、-(CH 2) n1S(O) m1R dd、-(CH 2) n1NR ddR ee、-(CH 2) n1C(O)NR ddR ee、-(CH 2) n1C(O)NHR dd、-(CH 2) n1NR ddC(O)R eeAnd- (CH) 2) n1NR ddS(O) m1R eeIs substituted with one or more substituents of (1);
    or, R9And R10The linkage may form a heterocyclic group or a heteroaryl group, wherein said heterocyclic group and heteroaryl group are optionally further substituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH) or (C-H)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccIs substituted with one or more substituents of (1);
    A、Q、Y、Z、M、R bb、R cc、R dd、R ee、R x、R y、n、p、q、m 1and n1As claimed in claim 1.
  4. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof according to claim 1, further represented by formula (II-a) and (II-B):
    Figure PCTCN2019104558-APPB-100003
    wherein:
    g is selected from oxygen or sulfur;
    l is selected from nitrogen, oxygen, sulfur or-CRaa；
    Ring B is selected from heterocyclyl or heteroaryl, preferably thiaheterocyclyl or oxoheterocyclyl;
    R zselected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyanoHydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl- (CH)2) n1R dd、-(CH 2) n1OR dd、-(CH 2) n1SR dd、-(CH 2) n1C(O)R dd、-(CH 2) n1C(O)OR dd、-(CH 2) n1S(O) m1R dd、-(CH 2) n1NR ddR ee、-(CH 2) n1C(O)NR ddR ee、-(CH 2) n1C(O)NHR dd、-(CH 2) n1NR ddC(O)R eeAnd- (CH)2) n1NR ddS(O) m1R eeIs substituted with one or more substituents of (1);
    or, any two adjacent or non-adjacent RzThe groups linked may form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccAnd- (CH)2) n1NR bbS(O) m1R ccIs substituted with one or more substituents of (1);
    R 2in the presence or absence of L as a nitrogen atom or-CRaaWhen R is2Selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R cc；
    R 3And R4Each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, and mixtures thereof,Haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1R dd、-(CH 2) n1OR dd、-(CH 2) n1SR dd、-(CH 2) n1C(O)R dd、 -(CH 2) n1C(O)OR dd、-(CH 2) n1S(O) m1R dd、-(CH 2) n1NR ddR ee、-(CH 2) n1C(O)NR ddR ee、-(CH 2) n1C(O)NHR dd、-(CH 2) n1NR ddC(O)R eeAnd- (CH)2) n1NR ddS(O) m1R eeIs substituted with one or more substituents of (1);
    or, the group R2、R 3、R 4And RaaAny two of which are linked to form a cycloalkyl, heteroalkyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccIs substituted with one or more substituents of (1);
    m is 0, 1,2, 3, 4, 5 or 6;
    t is 0, 1,2, 3, 4, 5 or 6;
    q is 0, 1,2, 3, 4, 5 or 6;
    Q、Y、Z、M、R bb、R cc、R dd、R ee、R x、R y、n、p、q、m 1and n1As claimed in claim 1.
  5. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, further represented by formula (III):
    Figure PCTCN2019104558-APPB-100004
    wherein:
    R 5、R 6and R14Each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
    or, R5And R6Linked to form a cycloalkyl, heteroalkyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccAnd- (CH)2) n1NR bbS(O) m1R ccIs substituted with one or more substituents of (1);
    Q、Y、Z、M、R bb、R cc、R 1、R y、n、p、q、m 1and n1As claimed in claim 1; r2、G、m、R 3And R4As claimed in claim 4.
  6. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, further represented by formula (IV):
    Figure PCTCN2019104558-APPB-100005
    wherein:
    R 13selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with a substituent selected from the group consisting of deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl; preferably halogen, amino, nitro, cyano, alkyl, haloalkyl or cycloalkyl;
    ring B, Q, Z, G, M, R2～R 4、R y、R zM, n, q and t are as defined in claim 4.
  7. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof according to claim 1, further represented by formula (III-a) or (IIIV-B):
    Figure PCTCN2019104558-APPB-100006
    wherein:
    R 7、R 8、R 11and R12Each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R ccAnd- (CH)2) n1NR bbS(O) m1R ccWherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, mercapto, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
    or, the group R7、R 8、R 11And R12Any two of which may be linked to form a cycloalkyl, heteroalkyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further definedSubstituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
    R 9and R10As claimed in claim 3;
    Q、Z、G、M、R 2～R 6、R 14、R bb、R cc、R y、m、n、q、m 1and n1As claimed in claim 3;
    R 5、R 6or R14As claimed in claim 5.
  8. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, further represented by formula (V):
    Figure PCTCN2019104558-APPB-100007
    wherein:
    ring B as set forth in claim 4;
    Q、Z、G、M、L、R 2～R 8、R 11、R 12、R 14、R zm and t are as defined in claim 7.
  9. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, further represented by formula (VI):
    Figure PCTCN2019104558-APPB-100008
    wherein:
    ring B as set forth in claim 4;
    Q、Z、G、M、L、R 2～R 6、R 14、R y、R zq, m and t are as defined in claim 7.
  10. The compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, according to any of claims 3, 5, 7 or 8, wherein:
    ring B is selected from the following groups:
    Figure PCTCN2019104558-APPB-100009
  11. the compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, further represented by formula (VII):
    Figure PCTCN2019104558-APPB-100010
    wherein:
    R aaselected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
    L、M、R 2～R 8、R 11、R 12、R 14and m is as defined in claim 7.
  12. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof according to claim 11, wherein said compound is selected from the group consisting of
    M is selected from-S-or-NRaa-；
    L is selected from N;
    R aaselected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, aryl and heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-5Cycloalkyl, 3-5 membered heterocyclyl, aryl and heteroaryl, more preferably hydrogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C3-5Cycloalkyl, 3-5 membered heterocyclyl, halogen, hydroxy or amino, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane, cyclopentane, epoxypropyl or epoxybutyl;
    R 2～R 8、R 11、R 12or R14Independently selected from hydrogen, C1-6Alkyl, halogen, cyano, nitro, hydroxy or amino, preferably hydrogen, C1-3Alkyl or halogen, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine, further preferably hydrogen; m is as defined in claim 11.
  13. The compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 1, further represented by formula (VIII-a):
    Figure PCTCN2019104558-APPB-100011
    wherein:
    m is selected from-S-or-NRaa-；
    Ring B is selected from the following groups:
    Figure PCTCN2019104558-APPB-100012
    R aaselected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, aryl and heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-5Cycloalkyl, 3-5 membered heterocyclyl, aryl and heteroaryl, more preferably hydrogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C3-5Cycloalkyl, 3-5 membered heterocyclyl, halogen, hydroxy or amino, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane, cyclopentane, epoxypropyl or epoxybutyl;
    R 2～R 6or R14Independently selected from hydrogen, C1-6Alkyl, halogen, cyano, nitro, hydroxyOr amino, preferably hydrogen, C1-3Alkyl or halogen, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine, further preferably hydrogen;
    R zselected from hydrogen, C1-6Alkyl or C1-6Haloalkyl, preferably hydrogen, C1-3Alkyl or C1-3Haloalkyl, more preferably hydrogen, C1-3Alkyl or C containing 1-2 halogen atoms1-3Haloalkyl, more preferably hydrogen, methyl, ethyl, propyl, isopropyl, -CH2F、-CHF 2、-CHFCH 3、-CF 2CH 3、-CHFCH 2F、-CH 2Cl、-CHCl 2、-CHClCH 3、-CCl 2CH 3or-CHClCH2Cl；
    t is 0, 1,2 or 3.
  14. The compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 1, further represented by formula (VIII):
    Figure PCTCN2019104558-APPB-100013
    wherein:
    ring B, M, R3、R 5、R 6、R 14、R ZAnd t is as defined in claim 8;
    R aaas claimed in claim 11.
  15. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof according to claim 14, wherein ring B is selected from
    Figure PCTCN2019104558-APPB-100014
    R 3Selected from hydrogen, C1-6Alkyl radical, C1-6Alkoxy or alkyl substituted C1-6Alkoxy, preferably hydrogen, C1-3Alkyl radical, C1-3Alkoxy or C1-3Alkoxy-substituted C1-3Alkyl, more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, CH3OCH 2-or CH3CH 2OCH 2-；
    R 5、R 6Or R14Each independently selected from hydrogen or halogen, preferably hydrogen;
    R zselected from hydrogen, C1-6Alkyl or C1-6Haloalkyl, preferably hydrogen, C1-3Alkyl or C1-3Haloalkyl, more preferably hydrogen, C1-3Alkyl or C containing 1-2 halogen atoms1-3Haloalkyl, more preferably hydrogen, methyl, ethyl, propyl, isopropyl, -CH2F、-CHF 2、-CHFCH 3、-CF 2CH 3、-CHFCH 2F、-CH 2Cl、-CHCl 2、-CHClCH 3、-CCl 2CH 3or-CHClCH2Cl；
    t is as defined in claim 1.
  16. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, according to claim 1, further represented by formula (IX):
    Figure PCTCN2019104558-APPB-100015
    wherein:
    m is selected from-S-or-NRaa-；
    R aaSelected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, aryl and heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-5Cycloalkyl, 3-5 membered heterocyclyl, aryl and heteroaryl, more preferably hydrogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C3-5Cycloalkyl, 3-5 membered heterocyclyl, halogen, hydroxy or amino, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane, cyclopentane, epoxypropyl or epoxybutyl;
    R 2～R 4、R 6or R14Selected from hydrogen, C1-6Alkyl, halogen, cyano, nitro, hydroxy or amino, preferably hydrogen, C1-3Alkyl or halogen, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine, further preferably hydrogen or methyl;
    R 15or R16Each independently selected from hydrogen and C1-6Alkyl or C1-6Haloalkyl, preferably hydrogen, C1-3Alkyl or C1-3Haloalkyl, more preferably hydrogen, C1-3Alkyl or C containing 1-2 halogen atoms1-3Haloalkyl, more preferably hydrogen, methyl, ethyl, propyl, isopropyl, -CH2F、-CHF 2、-CHFCH 3、-CF 2CH 3、-CHFCH 2F、-CH 2Cl、-CHCl 2、-CHClCH 3、-CCl 2CH 3or-CHClCH2Cl。
  17. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof according to claim 1, further represented by formula (X):
    Figure PCTCN2019104558-APPB-100016
    wherein:
    m is selected from-S-or-NRaa-；
    R aaSelected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, aryl and heteroaryl, preferably hydrogen, deuterium, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C3-5Cycloalkyl, 3-5 membered heterocyclyl, aryl and heteroaryl, more preferably hydrogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C3-5Cycloalkyl, 3-5 membered heterocyclyl, halogen, hydroxy or amino, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane, cyclopentane, epoxypropyl or epoxybutyl;
    R 2～R 4、R 6or R14Selected from hydrogen, C1-6Alkyl, halogen, cyano, nitro, hydroxy or amino, preferably hydrogen, C1-3Alkyl or halogen, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine, further preferably hydrogen or methyl;
    R 15or R16Each independently selected from hydrogen and C1-6Alkyl or C1-6Haloalkyl, preferably hydrogen, C1-3Alkyl or C1-3Haloalkyl, more preferably hydrogen, C1-3Alkyl or C containing 1-2 halogen atoms1-3Haloalkyl, more preferably hydrogen, methyl, ethyl, propyl, isopropyl, -CH2F、-CHF 2、-CHFCH 3、-CF 2CH 3、-CHFCH 2F、-CH 2Cl、-CHCl 2、-CHClCH 3、-CCl 2CH 3or-CHClCH2Cl。
  18. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof according to claim 1, wherein said compound is selected from the group consisting of
    M is selected from-S-or-NRaa-
    Q, Y and Z are each independently selected from N or-CRaa；
    Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably C3-6Cycloalkyl, 3-6 membered heterocyclyl, aryl or heteroaryl containing 1-3 heteroatoms, more preferably C5-6Cycloalkyl, 5-6 membered heterocyclyl, aryl or heteroaryl containing 1-3N, O, S heteroatoms, further preferably cyclopentyl, cyclohexyl, pyrrolyl, pyridinyl, phenyl, tetrahydropyrrolyl or piperidinyl;
    R 1selected from substituted or unsubstituted oxoheterocyclic group or substituted or unsubstituted thioheterocyclic group, preferably substituted or unsubstituted 5-6-membered oxoheterocyclic group or substituted or unsubstituted 5-6-membered thioheterocyclic group, morePreferred is a substituted or unsubstituted 5-6-membered oxoheterocyclic group containing 1 to 2 heteroatoms of N, O, S or a substituted or unsubstituted 5-6-membered thioheterocyclic group containing 1 to 2 heteroatoms of N, O, S, and further preferred is
    Figure PCTCN2019104558-APPB-100017
    Figure PCTCN2019104558-APPB-100018
    R xAnd RyEach independently selected from hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, aryl, 3-6 membered heteroaryl, - (CH)2) n1-、-(CH 2) n1R bb、-(CH 2) n1OR bb、-(CH 2) n1SR bb、-(CH 2) n1C(O)R bb、-(CH 2) n1C(O)OR bb、-(CH 2) n1S(O) m1R bb、-(CH 2) n1NR bbR cc、-(CH 2) n1C(O)NR bbR cc、-(CH 2) n1NR bbC(O)R cc、-(CH 2) n1NR bbC(R ffR gg)C(O)R ccOr- (CH)2) n1NR bbS(O) m1R ccPreferably hydrogen, C1-3Alkyl, aryl, heteroaryl, and heteroaryl,C 1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, halogen, amino, C5-6Cycloalkyl, 5-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl or- (CH)2) n1NR bbC(R ffR gg)C(O)R ccMore preferably hydrogen, amino or- (CH)2) n1NR bbC(R ffR gg)C(O)R ccFurther, hydrogen or- (CH) is preferable2) n1NR bbC(R ffR gg)C(O)R cc；
    R aa、R bb、R cc、R dd、R ee、R ffOr RggSelected from hydrogen, deuterium, alkyl, cycloalkyl or heterocyclyl, preferably hydrogen, C1-6Alkyl radical, C3-6Cycloalkyl or 3-6 membered heterocyclyl, more preferably hydrogen, C1-3Alkyl radical, C3-5Cycloalkyl or 3-5 membered heterocyclyl, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane, cyclopentane, epoxypropyl or epoxybutyl;
    n, p, q, y, n1 or m1 are as described in claim 1.
  19. The compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 4, 7, or 9,
    R 2in the presence or absence, selected from hydrogen, methoxy, C1-6Alkyl or C1-6A haloalkyl group;
    or, R2And R3Or R2And R4Linked to form a 3-8 membered heterocyclic group, preferably pyrrolidinyl or azetidinyl;
    R 3and R4Each independently selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or 3-8 membered heterocyclyl;
    or R3And R4Link formation C3-8Cycloalkyl or 3-8 membered heterocyclyl, preferably oxetanyl;
    R 5and R6Each independently selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy or C1-6A haloalkyl group;
    or R5And R6Are linked to form a C3-8Cycloalkyl or 3-8 membered heterocyclyl, preferably cyclobutylalkyl, cyclopentylalkyl and 1, 3-dioxolanyl;
    R 14selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C3-8A cycloalkyl group;
    R yselected from hydrogen, C1-6Alkyl, halogen, C1-6Alkoxy radical, C1-6Haloalkyl and- (CH)2) n1-; preferably a hydrogen atom, C1-3Alkyl radical, C1-3A haloalkyl group; more preferably a hydrogen atom, a methyl group or- (CH)2) n1-；
    R aaSelected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl.
  20. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof according to any of claims 4, 6, 8, 9, 13 or 14, wherein R iszSelected from hydrogen, halogen, oxo, thioxo, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl and- (CH)2) n1-, wherein said C1-6Alkyl radical, C1-6Alkoxy and C1-6Haloalkyl optionally further substituted by hydrogen atom, halogen, oxo, thio, C1-6Alkyl radical, C1-6Alkoxy and C1-6Substituted by one or more substituents of haloalkyl, preferably halogen, C1-6Alkyl radical, C1-6Haloalkyl or oxo, more preferably halogen, C1-3Alkyl radical, C1-3Haloalkyl or oxo.
  21. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, according to any of claims 1 to 9 or 11 to 18, selected from the following compounds:
    Figure PCTCN2019104558-APPB-100019
    Figure PCTCN2019104558-APPB-100020
  22. a process for preparing a compound of the general formula (IV) or its stereoisomers and pharmaceutically acceptable salts thereof, as claimed in claim 6, which comprises the steps of,
    Figure PCTCN2019104558-APPB-100021
    reacting the general formula (IV-1) with the general formula (IV-2) to obtain a compound shown in the general formula (IV) or a stereoisomer and pharmaceutically acceptable salts thereof;
    wherein:
    x is selected from halogen;
    ring B, Q, Z, G, M, L, R2～R 4、R y、R zQ, m, n and t are as defined in claim 8.
  23. A process for the preparation of a compound of formula (VI) according to claim 9 or a stereoisomer thereof and pharmaceutically acceptable salts thereof, comprising the steps of,
    Figure PCTCN2019104558-APPB-100022
    reacting the general formula (VI-1) with the general formula (IV-2) to obtain a compound shown in the general formula (VI) or a stereoisomer and a pharmaceutically acceptable salt thereof;
    wherein:
    x is selected from halogen;
    ring B and t are as defined in claim 6;
    Q、Z、G、M、L、R 2～R 6、R 14、R y、R zq, m and n are as defined in claim 7.
  24. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 23, in association with one or more pharmaceutically acceptable carriers, diluents or excipients.
  25. The compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, or the pharmaceutical composition of claim 24 for use in the preparation of a PI3K inhibitor medicament, preferably in the preparation of a PI3K α inhibitor medicament.
  26. Use of a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, or a pharmaceutical composition according to claim 24, for the preparation of a medicament for the treatment of cancer, bone disorders, inflammatory diseases, immune diseases, neurological diseases, metabolic diseases, respiratory diseases and cardiac diseases; wherein the cancer is selected from breast cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, kidney cancer, myelodysplastic syndrome, acute myeloid leukemia, or colorectal cancer.
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