CN112789279B - Inhibitor containing tricyclic derivatives, preparation method and application thereof - Google Patents

Inhibitor containing tricyclic derivatives, preparation method and application thereof Download PDF

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CN112789279B
CN112789279B CN201980006386.8A CN201980006386A CN112789279B CN 112789279 B CN112789279 B CN 112789279B CN 201980006386 A CN201980006386 A CN 201980006386A CN 112789279 B CN112789279 B CN 112789279B
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substituted
alkyl
unsubstituted
cancer
hydrogen
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CN112789279A (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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Shanghai Hansoh Biomedical Co Ltd
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    • A—HUMAN NECESSITIES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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 an inhibitor containing tricyclic derivatives, a preparation method and application thereof. In particular, it relates to compounds of general formula (I), methods for their preparation and pharmaceutical compositions containing them, and their use as phosphoinositide 3 kinase (PI 3K) inhibitors in the treatment of cancer and diseases or conditions mediated or dependent on PI3K dysregulation.

Description

Inhibitor containing tricyclic derivatives, 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 (PI 3K) protein family is divided into four major classes I, II, III and IV, and is involved in the regulation of various cellular functions such as cell growth, proliferation, differentiation, survival and glucose metabolism. The four types of PI3K proteins have different structures and functions, wherein the most widely studied type I PI3K is divided into four subtypes of PI3K alpha, PI3K beta, PI3K delta and PI3K gamma, and the PI3K alpha is subjected to activation mutation and amplification in various tumors and is closely related to the occurrence and development of the tumors. PI3kβ has been reported to activate platelets and to play an important role in the development of diseases such as thrombosis. Pi3kδ and pi3kγ are mainly expressed in the blood system, are closely related to the immune system and the occurrence of inflammation, and pi3kγ is closely related to blood pressure stabilization and smooth muscle contraction.
PI3K alpha is a driving factor for the development of tumorigenesis by activating mutations and amplifications in a variety of tumors. PI3kα is a heterodimer consisting of a p110 catalytic subunit and a p85 regulatory subunit. PI3kα is activated by Receptor Tyrosine Kinases (RTKs) and G protein-coupled receptors (GPCRs), which upon activation catalyze the production of phosphatidylinositol 3 phosphate (PIP 3) from phosphatidylinositol 2 phosphate (PIP 2), PIP3 further activates protein kinase B (PKB, also known as AKT) and its downstream signaling pathway. 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 activate PI3K alpha, thereby activating the downstream proliferation signaling pathway of cells, and abnormal activation of PI3K alpha can lead to rapid proliferation of cells to cause tumorigenesis.
PI3kα has been an important target for development of tumor drugs, but most of the compounds are broad-spectrum inhibitors of PI3Ks, so that clinical research has a large side effect, and development of PI3Ks inhibitors is severely limited. Current studies have determined that most of the side effects of broad-spectrum inhibitors of PI3Ks are due to inhibition of PI3kβ, PI3kδ and PI3kγ subtypes. Wherein PI3K beta plays an important role in the mechanism of thrombocytopenia and thrombotic side effects; pi3kδ inhibition can lead to immune system abnormalities; autoimmune and infectious toxicities such as pneumonia, hepatitis and diarrhea/enteritis are closely associated with pi3kδ target inhibition; PI3K gamma is closely related to blood pressure stabilization and smooth muscle contraction, and is a main target for causing hypertension side effects. 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 eliminate various serious side effects such as inflammation, thrombocytopenia, hypertension and the like caused by other subtype inhibition.
Pi3K alpha selective inhibitor BYL-719 developed by Nohua is currently in clinical phase III research, pi3K alpha selective inhibitor MLN1117 developed by Wuta-tsu enters phase II clinical research, and selective inhibitor GDC-0077 developed by Gentec is also in clinical phase I research.
International applications WO2010029082A1 and WO2011022439A1 report compounds related to PI3K alpha selective inhibitors, but later studies indicate that the cell activity of the compounds is not high, and the clinical anti-tumor effect is affected. Therefore, 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 activating mutation or amplification, and has great clinical application value.
According to 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 drug effect model and higher safety.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
wherein:
Q, Y and Z are each independently selected from N or-CR aa ；
M is selected from-S-or-NR aa -；
Ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 1 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxo-heterocyclyl, thioheterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-NR aa C(O)(CH 2 ) n1 OR bb 、-NR aa C(S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc Or- (CH) 2 ) n1 NR bb S(O) m1 R cc Wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, halogenSubstituted alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxo-heterocyclyl, thioheterocyclyl, aryl and heteroaryl, optionally further substituted with a moiety selected from deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylhaloalkyl, halogen, substituted or unsubstituted cycloalkylamino, oxo, thioyl, 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) 2 ) n1 R dd 、-(CH 2 ) n1 OR dd 、-(CH 2 ) n1 SR dd 、-(CH 2 ) n1 C(O)R dd 、-(CH 2 ) n1 C(O)OR dd 、-(CH 2 ) n1 S(O) m1 R dd 、-(CH 2 ) n1 NR dd R ee 、-(CH 2 ) n1 C(O)NR dd R ee 、-(CH 2 ) n1 C(O)NHR dd 、-(CH 2 ) n1 NR dd C(O)R ee And- (CH) 2 ) n1 NR dd S(O) m1 R ee Is substituted by one or more substituents;
R x and R is y Each independently selected 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 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc Or- (CH) 2 ) n1 NR bb S(O) m1 R cc Wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with a moiety selected from 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, - 2 ) n1 R dd 、-(CH 2 ) n1 OR dd 、-(CH 2 ) n1 SR dd 、-(CH 2 ) n1 C(O)R dd 、-(CH 2 ) n1 C(O)OR dd 、-(CH 2 ) n1 S(O) m1 R dd 、-(CH 2 ) n1 NR dd R ee 、-(CH 2 ) n1 C(O)NR dd R ee 、-(CH 2 ) n1 C(O)NHR dd 、-(CH 2 ) n1 NR dd C(O)R ee And- (CH) 2 ) n1 NR dd S(O) m1 R ee Is substituted by one or more substituents;
Alternatively, any two adjacent or non-adjacent R x Linking to form a cycloalkyl, heteroalkyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally further substituted with a moiety 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 haloSubstituted alkoxy, 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 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc Or- (CH) 2 ) n1 NR bb S(O) m1 R cc Is substituted by one or more substituents;
alternatively, any two adjacent or non-adjacent R y And a cycloalkyl, a heteroaryl, an aryl and a heteroaryl group, wherein the cycloalkyl, the heterocyclyl, the aryl and the heteroaryl group are optionally further substituted with a substituent selected from deuterium, a substituted or unsubstituted alkyl group, a substituted or unsubstituted haloalkyl group, halogen, a substituted or unsubstituted amino group, oxo group, nitro group, cyano group, hydroxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted haloalkoxy group, a substituted or unsubstituted hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, - (CH) 2 ) n1 -、-(CH 2 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc Or- (CH) 2 ) n1 NR bb S(O) m1 R cc Is substituted by one or more substituents;
R aa selected from the group consisting of hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuteroalkyl, 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;
R bb 、R cc 、R dd and R is ee Each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuteroalkyl, 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 1 0, 1 or 2; and is also provided with
n 1 0, 1, 2, 3, 4 or 5.
The preferable scheme is as follows: r is R x Is- (CH) 2 ) n1 NR bb C(R ff R gg )C(O)R cc ；
R ff And R is gg Each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is 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 C 1-3 Alkyl, more preferably hydrogen, methyl, ethyl or propyl;
n 1 ，R bb Or R is cc As described by the general formula (I). In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (II):
wherein:
w is selected from oxygen or sulfur; preferably oxygen;
R 9 and R is 10 Each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyGroup, cyano, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc Or- (CH) 2 ) n1 NR bb S(O) m1 R cc Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with a moiety 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 ) n1 R dd 、-(CH 2 ) n1 OR dd 、-(CH 2 ) n1 SR dd 、-(CH 2 ) n1 C(O)R dd 、-(CH 2 ) n1 C(O)OR dd 、-(CH 2 ) n1 S(O) m1 R dd 、-(CH 2 ) n1 NR dd R ee 、-(CH 2 ) n1 C(O)NR dd R ee 、-(CH 2 ) n1 C(O)NHR dd 、-(CH 2 ) n1 NR dd C(O)R ee And- (CH) 2 ) n1 NR dd S(O) m1 R ee Is substituted by one or more substituents;
alternatively, R 9 And R is 10 The linking may form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are optionally further substituted with a member selected from 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 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc Or- (CH) 2 ) n1 NR bb S(O) m1 R cc Is substituted by one or more substituents;
A、Q、Y、Z、M、R bb 、R cc 、R dd 、R ee 、R x 、R y 、n、p、q、m 1 and n 1
As described by the general formula (I).
In a preferred embodiment of the present invention, the compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by the general formulae (II-A) and (II-B):
wherein:
g is selected from oxygen or sulfur;
l is selected from nitrogen, oxygen, sulfur or-CR aa ；
Ring B is selected from heterocyclyl or heteroaryl, preferably a thioheterocyclyl or an oxo-heterocyclyl;
R z selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, arylHeteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc Or- (CH) 2 ) n1 NR bb S(O) m1 R cc Wherein said alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with a moiety 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 ) n1 R dd 、-(CH 2 ) n1 OR dd 、-(CH 2 ) n1 SR dd 、-(CH 2 ) n1 C(O)R dd 、-(CH 2 ) n1 C(O)OR dd 、-(CH 2 ) n1 S(O) m1 R dd 、-(CH 2 ) n1 NR dd R ee 、-(CH 2 ) n1 C(O)NR dd R ee 、-(CH 2 ) n1 C(O)NHR dd 、-(CH 2 ) n1 NR dd C(O)R ee And- (CH) 2 ) n1 NR dd S(O) m1 R ee Is substituted by one or more substituents;
alternatively, any two adjacent or non-adjacent R z The groups may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally further substituted with a member selected from 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 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc And- (CH) 2 ) n1 NR bb S(O) m1 R cc Is substituted by one or more substituents;
R 2 in the presence or absence of, when L is a nitrogen atom or-CR aa When R is 2 Selected 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 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc Or- (CH) 2 ) n1 NR bb S(O) m1 R cc ；
R 3 And R is 4 Each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, and,Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc Or- (CH) 2 ) n1 NR bb S(O) m1 R cc Wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with a moiety 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 ) n1 R dd 、-(CH 2 ) n1 OR dd 、-(CH 2 ) n1 SR dd 、-(CH 2 ) n1 C(O)R dd 、-(CH 2 ) n1 C(O)OR dd 、-(CH 2 ) n1 S(O) m1 R dd 、-(CH 2 ) n1 NR dd R ee 、-(CH 2 ) n1 C(O)NR dd R ee 、-(CH 2 ) n1 C(O)NHR dd 、-(CH 2 ) n1 NR dd C(O)R ee And- (CH) 2 ) n1 NR dd S(O) m1 R ee Is substituted by one or more substituents;
alternatively, a group R 2 、R 3 、R 4 And R is aa Any two of which are linked to form a cycloalkyl, heteroalkyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl andheteroaryl, optionally further substituted with a substituent selected from 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 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc Or- (CH) 2 ) n1 NR bb S(O) m1 R cc Is substituted by one or more substituents;
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 1 and n 1 As described by the general formula (I).
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (III):
wherein:
R 5 、R 6 and R is 14 Each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyCyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc Or- (CH) 2 ) n1 NR bb S(O) m1 R cc Wherein 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;
alternatively, R 5 And R is 6 Linking to form a cycloalkyl, heteroalkyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally further substituted with a moiety selected from 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 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc And- (CH) 2 ) n1 NR bb S(O) m1 R cc Is substituted by one or more substituents;
Q、Y、Z、M、R bb 、R cc 、R 1 、R y 、n、p、q、m 1 and n 1 As described by the general formula (I).
R 2 、G、m、R 3 And R is 4 As described by the general formula (II-A).
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (IV):
wherein:
R 13 selected 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 is optionally further 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, R 2 ～R 4 、R y 、R z M, n, q and t are as described in formula (III).
In a preferred embodiment of the present invention, the compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by formulae (III-a) and (III-B):
wherein:
R 7 、R 8 、R 11 and R is 12 Each independently selected 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 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc And- (CH) 2 ) n1 NR bb S(O) m1 R cc Wherein 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;
alternatively, a group R 7 、R 8 、R 11 And R is 12 Can form a cycloalkyl, heteroalkyl, aryl, and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl group is 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 9 and R is 10 As described by the general formula (II).
Q、Z、G、M、R 2 ～R 6 、R 14 、R bb 、R cc 、R y 、m、n、q、m 1 And n 1 As described in general formula (III).
R 5 、R 6 Or R is 14 As described by the general formula (III-A).
In a preferred embodiment of the present invention, the compound of formula (III-a), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (V):
Wherein:
ring B is as described in formula (II-A);
Q、Z、G、M、L、R 2 ～R 8 、R 11 、R 12 、R 14 、R z m and t are as described in formula (III-A).
In a preferred embodiment of the present invention, the compound of formula (III-a), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (VI):
wherein:
ring B is as described in formula (II-A);
Q、Z、G、M、L、R 2 ～R 6 、R 14 ry, rz, q, m and t are as described in general formula (III-A).
In a preferred embodiment of the present invention, a compound of formula (II-A), (II-B), (IV), (V) or (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is any of those shown in the formula (II-A), (II-B), (IV), (V) or (VI), wherein
Ring B is selected from the following groups:
in a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (VII):
wherein:
R aa selected from the group consisting of hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from 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 14 And m is as described in formula (V).
Preferably, M is selected from the group consisting of-S-or-NR aa -；
L is selected from N;
R aa selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, aryl and heteroaryl, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C 3-5 Cycloalkyl, 3-5 membered heterocyclyl, aryl and heteroaryl, more preferably hydrogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 3-5 Cycloalkyl, 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 12 or R is 14 Selected from hydrogen, C 1-6 Alkyl, halogen, cyano, nitro, hydroxy or amino, preferably hydrogen, C 1-3 Alkyl or halogen, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine, still more preferably hydrogen;
m is as shown in the general formula (VII). In a preferred embodiment of the present invention, the compound of formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (VIII-a):
Wherein:
m is selected from-S-or-NR aa -；
Ring B is selected from the following groups:
R aa selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, aryl and heteroaryl, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C 3-5 Cycloalkyl, 3-5 membered heterocyclyl, aryl and heteroaryl, more preferably hydrogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 3-5 Cycloalkyl, 3-5 membered heterocyclylHalogen, hydroxy or amino, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane, cyclopentane, epoxypropyl or epoxybutyl;
R 2 ～R 6 or R is 14 Selected from hydrogen, C 1-6 Alkyl, halogen, cyano, nitro, hydroxy or amino, preferably hydrogen, C 1-3 Alkyl or halogen, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine, still more preferably hydrogen;
R z selected from hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably hydrogen, C 1-3 Alkyl or C 1-3 Haloalkyl, more preferably hydrogen, C 1-3 Alkyl or C containing 1-2 halogen atoms 1-3 Haloalkyl, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, -CH 2 F、-CHF 2 、-CHFCH 3 、-CF 2 CH 3 、-CHFCH 2 F、-CH 2 Cl、-CHCl 2 、-CHClCH 3 、-CCl 2 CH 3 or-CHClCH 2 Cl；
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):
wherein: ring B, M, R 3 、R 5 、R 6 、R 14 、R Z And t is as defined in formula (V).
R aa As described in general formula (VII). Preferably, the ring B is selected from
R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy or alkyl substituted C 1-6 Alkoxy, preferably hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkoxy substituted C 1-3 Alkyl, more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, CH 3 OCH 2 -or CH 3 CH 2 OCH 2 -；
R 5 、R 6 Or R is 14 Each independently selected from hydrogen or halogen, preferably hydrogen;
R z selected from hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably hydrogen, C 1-3 Alkyl or C 1-3 Haloalkyl, more preferably hydrogen, C 1-3 Alkyl or C containing 1-2 halogen atoms 1-3 Haloalkyl, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, -CH 2 F、-CHF 2 、-CHFCH 3 、-CF 2 CH 3 、-CHFCH 2 F、-CH 2 Cl、-CHCl 2 、-CHClCH 3 、-CCl 2 CH 3 or-CHClCH 2 Cl；
t is as shown in the general formula (I).
In a preferred embodiment of the present invention, any of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are further represented by formula (IX):
wherein:
m is selected from-S-or-NR aa -；
R aa Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, aryl and heteroaryl, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C 3-5 Cycloalkyl, 3-5 membered heterocyclyl, aryl and heteroaryl, more preferably hydrogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 3-5 Cycloalkyl, 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 6 or R is 14 Selected from hydrogen, C 1-6 Alkyl, halogen, cyano, nitro, hydroxy or amino, preferably hydrogen, C 1-3 Alkyl or halogen, more preferably hydrogen, methyl, ethyl, propyl, fluoro, chloro or bromo, still more preferably hydrogen or methyl;
R 15 or R is 16 Each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably hydrogen, C 1-3 Alkyl or C 1-3 Haloalkyl, more preferably hydrogen, C 1-3 Alkyl or C containing 1-2 halogen atoms 1-3 Haloalkyl, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, -CH 2 F、-CHF 2 、-CHFCH 3 、-CF 2 CH 3 、-CHFCH 2 F、-CH 2 Cl、-CHCl 2 、-CHClCH 3 、-CCl 2 CH 3 or-CHClCH 2 Cl。
In another preferred embodiment of the present invention, any of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are further represented by formula (X):
wherein:
m is selected from-S-or-NR aa -；
R aa Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy compoundsGroup, halogen, cyano, nitro, hydroxy, amino, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, aryl and heteroaryl, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C 3-5 Cycloalkyl, 3-5 membered heterocyclyl, aryl and heteroaryl, more preferably hydrogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 3-5 Cycloalkyl, 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 6 or R is 14 Selected from hydrogen, C 1-6 Alkyl, halogen, cyano, nitro, hydroxy or amino, preferably hydrogen, C 1-3 Alkyl or halogen, more preferably hydrogen, methyl, ethyl, propyl, fluoro, chloro or bromo, still more preferably hydrogen or methyl;
R 15 Or R is 16 Each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably hydrogen, C 1-3 Alkyl or C 1-3 Haloalkyl, more preferably hydrogen, C 1-3 Alkyl or C containing 1-2 halogen atoms 1-3 Haloalkyl, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, -CH 2 F、-CHF 2 、-CHFCH 3 、-CF 2 CH 3 、-CHFCH 2 F、-CH 2 Cl、-CHCl 2 、-CHClCH 3 、-CCl 2 CH 3 or-CHClCH 2 Cl。
In another preferred embodiment of the present invention, any of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein
M is selected from-S-or-NR aa -
Q, Y and Z are each independently selected from N or-CR aa ；
Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably C 3-6 Cycloalkyl, 3-6 membered heterogeniesA cyclic group, an aryl group or a heteroaryl group containing 1 to 3 hetero atoms, more preferably C 5-6 Cycloalkyl, 5-6 membered heterocyclyl, aryl or heteroaryl containing 1-3 heteroatoms N, O, S, further preferably cyclopentyl, cyclohexyl, pyrrolyl, pyridinyl, phenyl, tetrahydropyrrolyl or piperidinyl;
R 1 selected from a substituted or unsubstituted oxo-heterocyclic group or a substituted or unsubstituted thio-heterocyclic group, preferably a substituted or unsubstituted 5-6 membered oxo-heterocyclic group or a substituted or unsubstituted 5-6 membered thio-heterocyclic group, more preferably a substituted or unsubstituted 5-6 membered oxo-heterocyclic group containing 1 to 2N, O, S heteroatoms or a substituted or unsubstituted 5-6 membered thio-heterocyclic group containing 1 to 2N, O, S heteroatoms, still more preferably />
R x And R is y Each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, aryl, 3-6 membered heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R bb 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR bb 、-(CH 2 ) n1 C(O)R bb 、-(CH 2 ) n1 C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R bb 、-(CH 2 ) n1 NR bb R cc 、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 NR bb C(O)R cc 、-(CH 2 ) n1 NR bb C(R ff R gg )C(O)R cc Or- (CH) 2 ) n1 NR bb S(O) m1 R cc Preferably hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, halogen, amino, C 5-6 Cycloalkyl, 5-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl or- (CH) 2 ) n1 NR bb C(R ff R gg )C(O)R cc More preferably hydrogen, amino or- (CH) 2 ) n1 NR bb C(R ff R gg )C(O)R cc Further preferred is hydrogen or- (CH) 2 ) n1 NR bb C(R ff R gg )C(O)R cc ；
R aa 、R bb 、R cc 、R dd 、R ee 、R ff Or R is gg Selected from hydrogen, deuterium, alkyl, cycloalkyl or heterocyclyl, preferably hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, more preferably hydrogen, C 1-3 Alkyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl, further preferably hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane, cyclopentane, epoxypropyl or epoxybutyl;
n, p, q, y, n1 or m1 is as described in general formula (I). In a preferred embodiment of the present invention, any of the compounds of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein,
R 2 is present or absent, where present is selected from hydrogen, methoxy, C 1-6 Alkyl or C 1-6 A haloalkyl group;
alternatively, R 2 And R is R 3 Or R is 2 And R is R 4 Linking to form a 3-8 membered heterocyclic group, preferably pyrrolidinyl or azetidinyl;
R 3 and R is 4 Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or 3-8 membered heterocyclyl;
or R is 3 And R is 4 Linking to form C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, preferably oxetanyl;
R 5 and R is 6 Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 A haloalkyl group;
or R is 5 And R is 6 Linking to form a C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, preferably cyclobutyl, cyclopentyl and 1, 3-dioxolanyl;
R 14 selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl;
R y selected from hydrogen, C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkyl group and- (CH) 2 ) n1 -; preferably hydrogen atom, C 1-3 Alkyl, C 1-3 A haloalkyl group; more preferably a hydrogen atom, methyl group or- (CH) 2 ) n1 -；
R aa Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl.
In a preferred embodiment of the invention, any of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein R z Selected from hydrogen, halogen, oxo, thioxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl group and- (CH) 2 ) n1 -, wherein said C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl, optionally further substituted with hydrogen, halogen, oxo, thio, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituted by one or more substituents of haloalkyl, preferably halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or oxo, more preferably halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or oxo.
In a preferred embodiment of the invention, the structure of the compound is as follows:
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,
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 a pharmaceutically acceptable salt thereof;
wherein:
x is selected from halogen;
ring B, Q, Z, G, M, L, R 2 ～R 4 、R y 、R z Q, m, n and t are as defined in 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,
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;
the rings B and t are as described in the general formula (IV);
Q、Z、G、M、L、R 2 ～R 6 、R 14 、R y 、R z q, m and n are as defined in 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,
wherein:
x is selected from halogen;
ring B, Q, Z, G, M, L, R 2 ～R 6 、R y 、R z Q, m, n and t are as defined in 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,
wherein:
X 1 and X 2 Selected from halogen;
ring B, Q, Z, G, M, L, R 2 ～R 6 、R y 、R z Q, m, n and t are as defined in formula (VI).
The invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds of formula (I), stereoisomers or pharmaceutically acceptable salts thereof, as shown in any of the formulae shown herein, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to the application of any compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of PI3K modulator medicaments, preferably in the preparation of PI3K alpha inhibitor medicaments.
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 heart disease, wherein the cancer is selected from breast cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, renal cancer, myelodysplastic syndrome (MDS), acute Myelogenous Leukemia (AML) and colorectal cancer.
The invention further relates to methods of treating cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disease, respiratory disease and heart disease using the compounds of formula (I), stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
The present invention also relates to a method for the therapeutic prophylaxis and/or treatment of a pre-prepared treatment of cancer, which comprises administering to a patient a therapeutically effective dose of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The invention also provides methods of treating disease conditions, including but not limited to conditions associated with pi3kα, pi3kβ, pi3kδ and pi3kγ kinase dysfunctions, using the compounds or pharmaceutical compositions of the invention.
The 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 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 heart 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 carcinoma, 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 cancers. In some embodiments, the methods involve treatment of non-cancerous hyperproliferative disorders 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 invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Diseases associated with dysfunction of one or more types of ERKs include, but are not limited to, acute Disseminated Encephalomyelitis (ADEM), additivity 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 Myoclonus Syndrome (OMS), optic neuritis, ald's thyroiditis (Ord's thyroiditis), pemphigus (oemphigus), polyarthritis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, leptospir syndrome, high-safety arteritis, temporal arteritis (also known as "giant cell arteritis"), warm autoimmune hemolytic anemia (wa-rm a utoimm une hemoly ticanemia), wegener's granulomatosis, chalcone syndrome, chebyshesis, atherosclerosis, dysfunctional uterine fibrotic ulcer, orthodropsy, dysfunctional uterine fibrotic diseases, dysfunctional uterine fibroids, orthoses, dysfunctional uterine fibroids, dysestes, dysfunctional uterine fibroids, and dysfunctional uterine fibroids. Other conditions include bone resorption disorders and thrombosis (thrombobsis).
Detailed description of the invention
Unless stated to the contrary, the 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 from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 8 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, and most preferably an alkyl group containing from 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, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and 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, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following 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, with methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred.
The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means-CH 2 - "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, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups 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, more preferably cyclopropyl.
The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
spirocycloalkyl groups also containing a spiro atom common to both the monocyclocycloalkyl and heterocycloalkyl groups, non-limiting examples include:
the term "fused ring alkyl" refers to a 5 to 20 membered, all carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the 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 fully conjugated pi electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused ring alkyl groups include:
The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
the cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, 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, carboxyl, or carboxylate groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; most preferably containing 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 heterocyclyl groups include spiro, fused and bridged heterocyclic groups; the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring mode.
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having 3 to 20 membered monocyclic rings sharing one atom (referred to as the spiro atom) wherein one or more ring atoms are selected from nitrogen,Oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably 3-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:
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 the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 3-membered/5-membered, 4-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
The term "bridged heterocyclyl" refers to 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 has a fully conjugated pi electron system in which one or more ring atoms are selected fromNitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:
etc.
The heterocyclic group may be optionally 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, oxo, carboxyl, or carboxylate groups.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing 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:
aryl groups 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, carboxyl, or carboxylate groups.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 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, furanyl, 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 attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
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, hydroxy, 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, cyclopentoxy, cyclohexyloxy. The 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, carboxyl, or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, where 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 groups, also known as alkenyl groups, wherein the alkenyl groups may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"alkynyl" refers to (CH≡C-), wherein the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"carboxy" means-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 2 O "refers to 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 "means tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1,1' -bis-diphenylphosphino ferrocene.
"HATU" refers to 2- (7-oxo-benzotriazol) -N, N' -tetramethylurea hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bis (trimethylsilylamide).
"MeLi" refers to lithium-based.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc) 3 "means sodium triacetoxyborohydride.
"DCM" refers to dichloromethane.
The terms "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", etc. all express the same meaning, that is, X may be any one or several of A, B, C.
The hydrogen atoms of the invention can be replaced by the isotope deuterium thereof, and any hydrogen atom in the compound of the embodiment of the invention can be replaced by deuterium atoms.
"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 group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, 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 substituents are only in their possible chemical positions, and that the 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 when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
Detailed Description
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
Examples
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18X 4.6mm column).
The thin layer chromatography silica gel plate uses a smoke table 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. Column chromatography generally uses yellow sea silica gel with 200-300 meshes as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized according to methods known in the art.
All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific explanation.
Intermediate 1
(S) -4- (difluoromethyl) oxazolidin-2-one
The first step: preparation of (R) -3-benzyl-4- (hydroxymethyl) oxazolidin-2-one
(R) -Oxopropan-2-ylmethanol (3.7 g,50.0 mmol) and (isocyanatomethyl) benzene (6.66 g,50.0 mmol) were mixed in DCM (50 mL) and warmed to 45℃under nitrogen and stirred overnight. 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, and concentrated under reduced pressure, followed by column chromatography to give the title compound (R) -3-benzyl-4- (hydroxymethyl) oxazolidin-2-one (4.14 g, yield: 40%).
MS m/z(ESI)：208.2[M+H] + .
And a second step of: preparation of (S) -3-benzyl-4- (dihydroxymethyl) oxazolidin-2-one
(R) -3-benzyl-4- (hydroxymethyl) oxazolidin-2-one (4.14 g,20.0 mmol), IBX (16.8 g,60.0 mmol) were mixed in EA (100 mL) and stirred at 85deg.C for 3h under nitrogen. After cooling, filtration and concentration under reduced pressure gave 4.46g of crude (S) -3-benzyl-4- (dihydroxymethyl) oxazolidin-2-one, which was used directly in the next reaction.
MS m/z(ESI)：224.2[M+H] + .
And a third step of: preparation of (S) -3-benzyl-4- (difluoromethyl) oxazolidin-2-one
(S) -3-benzyl-4- (dimethylol) oxazolidin-2-one (4.46 g,20.0 mmol) was dissolved in DCM (100 mL), ice-bath and DAST (6.45 g,40.0 mmol) was added dropwise to the reaction solution under nitrogen protection, and the reaction was carried out at room temperature for 3h. The reaction solution was slowly added dropwise to a pre-cooled saturated aqueous sodium bicarbonate solution. DCM (200 ml×2) was extracted and the combined organic phases concentrated under reduced pressure and then column chromatographed to give the title compound (S) -3-benzyl-4- (difluoromethyl) oxazolidin-2-one (1.82 g, 40% yield in two steps).
MS m/z(ESI)：228.2[M+H] + .
Fourth step: preparation of (S) -4- (difluoromethyl) oxazolidin-2-one
(S) -3-benzyl-4- (difluoromethyl) oxazolidin-2-one (1.82 g,8 mmol) was dissolved in ethanol (100 mL) and Pd (OH) was added 2 C (300 mg) under hydrogen atmosphere, stirring overnight at 70 ℃. Cooling, filtering, concentrating the filtrate under reduced pressure to give the title compound (S) -4- (difluoromethyl) oxazolidin-2-one (0.88 g, yield: 8)0％)。
1 H 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] diazepin-9-yl) amino) propanamide
The first step: preparation of 5-bromo-2- (1H-imidazol-2-yl) aniline
To a methanol solution (50 mL) of 2-amino-4-bromobenzene (methylaldehyde) (4.9 g,24.6 mmol) was added an aqueous glyoxal solution (40 wt.%,18g,124 mmol), and then aqueous ammonia (28 wt.%,24g,172 mmol) was slowly added dropwise with stirring in a water bath for 30 minutes, with the reaction solution temperature controlled to be not more than 40 ℃. The mixture was then stirred overnight at 35℃and cooled, after which the title compound was obtained by column chromatography (3.5 g, yield: 60%) of 5-bromo-2- (1H-imidazol-2-yl) aniline.
MS m/z(ESI)：238.0[M+H] + .
And a second step of: preparation of 10-bromo-5, 6,7, 8-tetrahydrobenzo [ c ] imidazo [1,2-a ] [1,5] diazepine Xin Yin
5-bromo-2- (1H-imidazol-2-yl) aniline (3.3 g,14 mmol), 1, 2-dibromoethane (1.38 mL,15.9 mmol), cesium carbonate (10.4 g,31.8 mmol) were mixed in N, N-dimethylformamide (50 mL), 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, and concentrated under reduced pressure, followed by column chromatography to give the title compound 10-bromo-5, 6,7, 8-tetrahydrobenzo [ c ] imidazo [1,2-a ] [1,5] diazocine (1.55 g, yield: 40%).
MS m/z(ESI)：278.0[M+H] + .
And a third step of: preparation of 9-bromo-2, 3-diiodo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepine
NIS (3.8 g,16.8 mmol) was added in portions to a solution of 10-bromo-5, 6,7, 8-tetrahydrobenzo [ c ] imidazo [1,2-a ] [1,5] diazocine (1.55 g,5.6 mmol) in DMF (30 mL) at room temperature, followed by stirring overnight at 60 ℃. Cooling, adding water, and separating out solid. After filtration, the solid was dissolved in ethyl acetate, washed with 1M aqueous NaOH and saturated brine in this order, 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 (2.6 g, yield: 90.2%).
MS m/z(ESI)：515.8[M+H] + .
Fourth step: preparation of 9-bromo-2-iodo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepine
EtMgBr (1.0M in THF, 10mL,10 mmol) was slowly added dropwise to a solution of 9-bromo-2, 3-diiodo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepine (2.52 g,4.9 mmol) in THF (20 mL) at-20deg.C. After the completion of the dropwise addition, the mixture was stirred at-15℃for 3 hours. Slowly heating to room temperature, dropwise adding saturated ammonium chloride aqueous solution, stirring for 15 min, and extracting with ethyl acetate for 3 times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and then column-chromatographed to give the title compound 9-bromo-2-iodo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepine (1.52 g, yield: 80%).
MS m/z(ESI)：389.9[M+H] + .
Fifth step: preparation of (S) -3- (9-bromo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepin-2-yl) -4- (difluoromethyl) oxazolidin-2-one
9-bromo-2-iodo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepine (178 mg,0.46 mmol), (S) -4- (difluoromethyl) oxazolidin-2-one (63 mg,0.46 mmol), (1R, 2R) -N1, N2-dimethylcyclohexane-1, 2-diamine (28.4 mg,0.2 mmol), cuprous iodide (19.0 mg,0.1 mmol) and potassium carbonate (138 mg,1.0 mmol) were mixed in 1, 4-dioxane (4 mL), heated to 100deg.C for 5 hours, cooled to room temperature, 14% aqueous ammonia was added, stirred for 5 minutes, and extracted three times with EtOAc. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatographed to give the title compound (S) -3- (9-bromo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepin-2-yl) -4- (difluoromethyl) oxazolidin-2-one (111 mg, yield: 60%).
MS m/z(ESI)：399.1[M+H] + 。
Sixth step: preparation of (S) -3- (9-bromo-7-methyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepin-2-yl) -4- (difluoromethyl) oxazolidin-2-one
(S) -3- (9-bromo-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepin-2-yl) -4- (difluoromethyl) oxazolidin-2-one (111 mg,0.28 mmol) was dissolved in methanol (5 mL), catalytic amounts of acetic acid and aqueous formaldehyde (37% in water, 50mg,0.62 mmol) were added, stirred at room temperature for 30 min, sodium cyanoborohydride (39 mg,0.62 mmol) was added, the reaction was stopped at room temperature for 3 hours, and the reaction was quenched with saturated aqueous ammonium chloride solution and extracted three times with EtOAc. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatographed to give the title compound (S) -3- (9-bromo-7-methyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepin-2-yl) -4- (difluoromethyl) oxazolidin-2-one (81 mg, yield: 70%).
MS m/z(ESI)：413.1[M+H] + .
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] diazepin-9-yl) amino) propanamide
(S) -3- (9-bromo-7-methyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepin-2-yl) -4- (difluoromethyl) oxazolidin-2-one (49.4 mg,0.12 mmol), L-alanine (21.4 mg,0.24 mmol), cuprous iodide (4.6 mg,0.024 mmol) and potassium phosphate (51.5 mg,0.24 mmol) were mixed in dimethyl sulfoxide (2 mL), reacted at 100℃for 5 hours, cooled to room temperature, ammonium chloride (39 mg,0.72 mmol), triethylamine (184 mg,1.8 mmol) was added, stirring was performed for 5 minutes, 2- (7-benzotriazol-oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (418 mg,1.1 mmol) was added, stirring was performed at room temperature for 2 hours, filtration, saturated aqueous sodium bicarbonate was added, and ethyl acetate was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, followed by 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] diazepin-9-yl) amino) propanamide (20 mg, yield: 40%).
1 H NMR(400MHz，CD 3 OD)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] diazepin-9-yl) amino) propanamide
The preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepin-9-yl) amino) propanamide is described in example 1.
1 H NMR(400MHz，CD 3 OD)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-carbonyl oxazolidin-3-yl) -7-ethyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propanamide
The 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 is described in example 1.
MS m/z(ESI)：435.1[M+H] + .
Example 4
Preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyl oxazolidin-3-yl) -7-isopropyl-6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazoheptin-9-yl) amino) propanamide
The 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] diazepin-9-yl) amino) propanamide is described in example 1.
MS m/z(ESI)：449.1[M+H] + .
Example 5
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] diazepin-9-yl) amino) propanamide
The 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] diazepin-9-yl) amino) propanamide is described in 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] diazo heptin-9-yl) amino) propanamide
Preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyloxazolidin-3-yl) -7- (oxetan-3-yl) -6, 7-dihydro-5H-benzo [ f ] imidazo [1,2-d ] [1,4] diazepin-9-yl) amino) propanamide 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-carbonyl oxazolidin-3-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepin-9-yl) amino) propanamide
The first step: preparation of 2- (5-bromo-2-fluorophenyl) -1H-imidazole
5-bromo-2-fluorobenzaldehyde (5.0 g,24.6 mmol) was dissolved in isopropanol/water (25 mL/25 mL) at room temperature, ammonium acetate (17.6 g,221.7 mmol) was added, glyoxal (4.5 mL,221.7 mmol) was added dropwise, and stirring was continued overnight. Isopropanol was added for dilution, the reaction solution was filtered, then concentrated under reduced pressure, the concentrated solution was concentrated with methylene chloride and water, the organic phases were combined, then dried over anhydrous sodium sulfate, and after concentration under reduced pressure, column chromatography gave the title compound 2- (5-bromo-2-fluorophenyl) -1H-imidazole (3.3 g, yield: 56%).
1 H 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] + .
And a second step of: preparation of 9-bromo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine
2- (5-bromo-2-fluorophenyl) -1H-imidazole (2.0 g,8.4 mmol) was dissolved in N, N-dimethylformamide (10 mL), sodium hydride (442 mg,9.2 mmol) was added to the reaction under ice-water bath cooling, stirring was performed for 10 minutes, thiirane (612 mg,10.2 mmol) was added, and stirring was performed for 6 hours at 95 ℃. Cooled to room temperature, saturated aqueous ammonium chloride solution was added to the reaction flask, and the mixture was extracted three times with methylene chloride. The organic phases were combined, then the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatographed to give the title compound 9-bromo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine (1.0 g, yield: 43%).
MS m/z(ESI)：281.0[M+H] + .
And a third step of: preparation of 9-bromo-2, 3-diiodo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine
NIS (2.4 g,10.5 mmol) was added in portions to a DMF solution (20 mL) of 9-bromo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine (480 mg,3.5 mmol) at room temperature, followed by stirring overnight at 60 ℃. Cooling, adding water, and separating out solid. After filtration, the solid was dissolved in ethyl acetate, washed with 1M aqueous NaOH and saturated brine in this order, 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 (1.6 g, yield: 86%).
MS m/z(ESI)：532.8[M+H] + .
Fourth step: preparation of 9-bromo-2-iodo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine
EtMgBr (1.0M in THF, 3.3mL,3.3 mmol) was slowly added dropwise to a solution of 9-bromo-2, 3-diiodo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine (1.6 g,3.0 mmol) in THF (10 mL) at-20deg.C. After the completion of the dropwise addition, the mixture was stirred at-15℃for 3 hours. Slowly heating to room temperature, dropwise adding saturated ammonium chloride aqueous solution, stirring for 15 min, and extracting with ethyl acetate for 3 times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and then column-chromatographed to give the title compound 9-bromo-2-iodo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepine (1.03 g, yield: 85%).
MS m/z(ESI)：406.9[M+H] + .
Fifth step: preparation of (S) -3- (9-bromo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepin-2-yl) -4- (difluoromethyl) oxazolidin-2-one
9-bromo-2-iodo-5, 6-dihydrobenzo [ f]Imidazo [1,2-d][1，4]Thiazepine (186.7 mg,0.46 mmol), (S) -4- (difluoromethyl) oxazolidin-2-one (63 mg,0.46 mmol), (1R, 2R) -N 1 ，N 2 Dimethylcyclohexane-1, 2-diamine (28.4 mg,0.2 mmol), cuprous iodide (19.0 mg,0.1 mmol), potassium carbonate (138 mg,1.0 mmol), and mixed in 1, 4-dioxane (4 mL), reacted at 100℃for 5 hours, cooled to room temperature, added with 14% ammonia water, stirred for 5 minutes, and extracted three times with EtOAc. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatographed to give the title compound (S) -3- (9-bromo-5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d][1，4]Thiazepin-2-yl) -4- (difluoromethyl) oxazolidin-2-one (124 mg, yield: 65%).
MS m/z(ESI)：416.0[M+H] + .
Sixth step: preparation of (S) -2- ((2- ((S) -4- (difluoromethyl) -2-carbonyl oxazolidin-3-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepin-9-yl) amino) propanamide
(S) -3- (9-bromo-5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazepin-2-yl) -4- (difluoromethyl) oxazolidin-2-one (49.8 mg,0.12 mmol), L-alanine (21.4 mg,0.24 mmol), cuprous iodide (4.6 mg,0.024 mmol), potassium phosphate (51.5 mg,0.24 mmol), mixed in dimethyl sulfoxide (2 mL), reacted for 5 hours at 100 ℃, cooled to room temperature, ammonium chloride (39 mg,0.72 mmol), triethylamine (184 mg,1.8 mmol) were added, stirred for 5 minutes, 2- (7-benzotriazol-oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (418 mg,1.1 mmol) was added, stirred for 2 hours at room temperature, filtered, saturated aqueous sodium bicarbonate was added, and ethyl acetate was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, followed by 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) propanamide (18 mg, yield: 35%).
1 H 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 invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
Test example 1 measurement of inhibition of PI3K alpha kinase Activity by Compounds of the invention
The purpose of the experiment is as follows: the purpose of this test example was to test the activity of the example compounds against inhibition of pi3kα/β/γ/δ kinase activity.
Experimental instrument: the centrifuge (5702R) was purchased from Eppendorf corporation, the pipettor from Eppendorf or Rainin corporation, and the microplate reader from BioTek corporation, USA under the model SynergyH1 full function microplate reader.
The experimental method comprises the following steps: the experiment uses ADP-Glo lipid kinase assay method (Promega#V9102) from Promega company, lipid kinase PI3K alpha/beta/gamma/delta on substrate PIP2: catalytic reaction of 3PS with ATP to generate ADP, characterization of lipid kinase activity by measuring ADP content in the reaction, and obtaining half inhibition concentration IC of compound to inhibition of PI3K alpha/beta/gamma/delta kinase activity 50 。
The specific experimental operation is as follows:
the kinase reaction was performed in a white 384 well plate (Perkin Elmer # 6007299) with 2. Mu.L of ddH in 1% DMSO per well 2 O diluted compounds at different concentrations, positive control wells were added with 2. Mu.L ddH containing 1% DMSO 2 O, then 2. Mu.L of 5 Xkinase buffer (HEPES 250mM, mgCl) was added to each well 2 15mM,NaCl 250mM,BSA0.05%) diluted 0.1-2nM PI3K kinase solution, negative control wells were added with 2. Mu.L of 5 Xkinase buffer, and all wells were added with 4. Mu.L of 10 Xdilution buffer and ddH 2 O formulated 50 μm substrate PIP2:3PS (Promega#V1701), and finally adding 2. Mu.L of 50-100. Mu.M ATP solution diluted with water to start the reaction, and after 90-120 minutes at room temperature, adding 10. Mu.L of ADP-Glo Reagent (containing 10mM MgCl) per well 2 ) After reaction at room temperature for 60 minutes to remove excess ATP, 20. Mu. L Kinase Detection Reagent was added to each well, and after reaction at room temperature for 20 minutes in the dark, the chemiluminescent value was measured using a BioTek Synergy H1 microplate reader.
Enzyme name Goods number Concentration of enzyme reaction Enzyme reaction time 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 were calculated by positive control wells (DMSO control wells) and negative control wells (no kinase added) on plates]/(positive control value-negative control value) ×100}. IC is calculated by using GraphPad prism to fit different concentration and corresponding percent inhibition rate data to a four-parameter nonlinear logic formula 50 Values.
Conclusion of experiment:
from the above schemes, it was concluded that the example compounds according to the invention show the biological activity in the PI3K alpha/beta/gamma/delta kinase activity assay as shown in table 1 below.
TABLE 1
According to the data, the compounds of the examples shown in the invention have good activity and selectivity in terms of PI3K alpha/beta/gamma/delta kinase activity, and are superior to the positive compound GDC-007.
Test example 2 determination of proliferation inhibition of PI3K alpha mutant cancer cells by Compounds of the invention
The purpose of the experiment is as follows: the purpose of this test example was to test the proliferation inhibitory activity of the example compounds against PI3K mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K) and MKN1 (E545K).
Experimental instrument: the centrifuge (5702R) is purchased from Eppendorf company, the carbon dioxide incubator is purchased from Thermo company, the biosafety cabinet is purchased from Shanghai Bo Hirship company, the pipettor is purchased from Eppendorf or Rainin Hirship, and the microplate reader is purchased from BioTek Corp. In America, and the model number is SynergyH1 full-function microplate reader.
The experimental method comprises the following steps: proliferation inhibition of PI3K alpha mutant cancer Cell lines (HCC 1954, HGC-27 (E542K) and MKN 1) by the example compounds was examined by the method of Cell Titer-Glo Cell lines were cultured in RPMI1640 medium (Gibco # 22400089) containing 10% FBS (Gibco # 10091148) and 1% Glutamine (Gibco # 25030081) at 37℃with 5% CO 2 Is cultured under the condition of (2). Collecting cells before experiment, regulating cell density after cell count, seeding cells at 1000-10000 cells/well in white 96-well plate (Corning # 3610), placing into 37deg.C, 5% CO 2 After the culture in the incubator overnight, compound solutions with different concentrations are prepared, corresponding solvent controls are arranged, and the incubator is continuously put into 37 ℃ and 5% CO 2 After 48-96 hours of culture in an incubator, the Cell plate and its contents are equilibrated to room temperature, 20-100. Mu.L of Cell Titer-Glo solution (Promega#G7573) is added to each well, the mixture is shaken and mixed uniformly, incubated at room temperature for 5-30 minutes in the absence of light, and the chemiluminescent value is detected by a BioTek's synergy H1 microplate reader.
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition = 100- (test compound value/vehicle control value) ×100} for wells treated with compound were calculated from vehicle control wells on the plate. Fitting different concentrations and corresponding percent inhibition data to four parameters using GraphPad prismIC is calculated to number nonlinear logic formula 50 Values.
Conclusion of experiment:
the activity test of the compounds of the examples shown in the present invention against proliferation inhibition of PI3kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K) and MKN1 (E545K) was derived from the above protocol, and showed the biological activity as shown in table 2 below.
TABLE 2
The above data shows that the compounds of the examples of the present invention have good activity against the proliferation inhibition activity of PI3kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K) and MKN1 (E545K), better than the positive compound GDC-007.
Test example 3 pharmacokinetic PK experiments of Compounds of the examples of the invention on mice
The pharmacokinetic experiments in mice of the compounds of the preferred embodiments of the present invention were performed using Balb/c male mice (Shanghai Jieshijie laboratory animals Co., ltd.).
■ The administration mode is as follows: single gastric lavage administration.
■ Dosage of administration: 5 mg/10 ml/kg (body weight).
■ Formulation recipe: 0.5% CMC-Na, dissolved ultrasonically, formulated as a clear solution or homogeneous suspension.
■ Sampling points: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.
■ Sample treatment:
1) The orbit is sampled by 0.1mL and placed in K 2 In EDTA test tube, the plasma is separated by centrifugation at 1000-3000 Xg for 5-20 min and stored at-80 deg.C.
2) The plasma sample 40uL was precipitated by adding 160uL acetonitrile, and after mixing, it was centrifuged at 500 to 2000 Xg for 5 to 20 minutes.
3) 100uL of the treated supernatant was subjected to LC/MS/MS analysis for the concentration of the test example.
■ LC-MS/MS analysis:
● Liquid phase conditions: shimadzu LC-20AD pump
● Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer
● Chromatographic column: phenomenex Gemiu 5um C 18 50×4.6mm
● Mobile phase: solution A is 0.1% formic acid water solution, solution B is acetonitrile
● Flow rate: 0.8mL/min
● Elution time: gradient elution for 0-4 min
■ Pharmacokinetics:
the main parameters were calculated with WinNonlin 6.1 and the results of the mouse drug substitution experiments are shown in table 3 below:
TABLE 3 Table 3
The results of the mouse-over experiments in the table show that the compounds of the examples shown in the invention show good metabolic properties, plasma exposure AUC and maximum blood concentration C max All performed well over the positive compound GDC-007.
Test example 4 in vivo efficacy test of the Compounds of the examples of the invention
4.1 purpose of experiment
The compounds with obvious efficacy and small toxic and side effects are screened out through in vivo efficacy experiments.
4.2 Experimental major instruments and materials
4.2.1 instruments:
1. biological safety cabinet (BSC-1300 II A2, shanghai Bo Xie medical equipment factory)
2. Ultra clean bench (CJ-2F, von Willebrand laboratory animal Co., ltd.)
3、CO 2 Incubator (Thermo-311)
4. Centrifuge (Centrifuge 5702R, eppendorf)
5. Full-automatic cell counter (Countess II, life)
6. Pipettor (10-20. Mu.L, eppendorf)
7. Microscope (TS 2, nikang)
8. Vernier caliper (CD-6' AX, sanfeng Japan)
9. Cell culture bottle (T75/T225, corning)
10. Electronic balance (CPA 2202S, sidoris)
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. Green 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, male, purchased from Shanghai Sipule-BiKai laboratory animal Co.
4.3 Experimental procedures
4.3.1 cell culture and preparation of cell suspension
a, taking out HCC1954 cells from cell bank, recovering cells with RPMI-1640 culture medium (RPMI-1640+10% FBS+1% SP), placing the recovered cells in cell culture flask (with labeled cell type, date, cultured person name, etc.) and placing in CO 2 Culturing in incubator (temperature of incubator is 37deg.C, CO) 2 Concentration 5%).
b, after the cells are spread at 80-90% of the bottom of the culture flask, passaging, and placing the cells in CO continuously after passaging 2 Culturing in an incubator. This process is repeated until the number of cells meets the in vivo pharmacodynamic requirements.
c, collecting cultured cells, counting with a fully automatic cell counter, and re-suspending cells with PBS and matrigel according to the counting result to obtain cell suspension (density 5×10) 7 /mL), placed in an ice bin for use.
4.3.2 cell seeding
a, marking nude mice with disposable universal ear tags for large and small mice before inoculation
b, mixing the cell suspension during inoculation, extracting 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 standby.
c, the left hand is kept to be a nude mouse, the right shoulder position (inoculation position) of the right back of the nude mouse is sterilized by 75% alcohol, and the inoculation is started after 30 seconds.
d, the test nude mice were inoculated sequentially (0.1 mL cell suspension was inoculated per mouse).
4.3.3 tumor-bearing mice were metered, grouped and dosed
a, tumor is measured on the 14 th to 18 th days after inoculation according to the growth condition of the tumor, and the tumor size is calculated.
Tumor volume calculation: tumor volume (mm) 3 ) =length (mm) ×width (mm)/2
And b, grouping according to the weight of the tumor-bearing mice and the size of the tumors by adopting a random grouping method.
c, according to the grouping result, starting to administer the test medicine (administration mode: oral administration; administration dosage: 10mg/kg; administration volume: 10mL/kg; administration frequency: 1 time/day; administration period: 21 days; vehicle: 0.5% CMC/1% Tween 80).
d, tumor twice weekly after starting to administer test drug, and weighing.
e, euthanized animals after the end of the experiment.
f, processing the data by Excel and other software. Calculation of compound tumor inhibition rate TGI (%): when there was no tumor regression, TGI (%) = [ (1- (mean tumor volume at the end of the treatment group-mean tumor volume at the beginning of the treatment group))/(mean tumor volume at the end of the treatment with the solvent control group-mean tumor volume at the beginning of the treatment with the solvent control group) ]%100%. When there was regression of the tumor, TGI (%) = [1- (mean tumor volume at the end of dosing of a treatment group-mean tumor volume at the beginning of dosing of the treatment group)/mean tumor volume at the beginning of dosing 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 experimental results
From the results, the compound of the patent has better tumor inhibition rate and is better than the positive compound GDC-007.
Test example 5, SD rat repeated gavage 7 days toxicity test
5.1 purpose of experiment
The purpose of this study was to examine the possible toxic response of GDC-0077 and example 7 after repeated gavage administration to SD rats for 7 days and to compare the toxicity differences of GDC-0077 and example 7.
5.2 Experimental materials and instruments
5.2.1 test pieces
Test article 1: GDC-0077
Test article 2: example 7
5.2.2 solvent
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
A series of fully automatic hematology analyzers for blood cell count;
the SYSMEX CA-500 coagulometer is used for detecting coagulation function indexes;
the TBA-120FR full-automatic biochemical analyzer is used for detecting biochemical indexes of blood;
the easy electrolyte analyzer is used for electrolyte detection;
liquid phase Mass Spectrometry Detector model API4000, electrospray Source (ESI) positive ion model and chromatographic column model AgilentZORBAX XDB-C18 (3.5 μm, 2.1X150 mm) for bioanalytical detection of plasma samples;
5.3 Experimental methods
1) In the test, 112 rats (56/sex) were divided into 14 groups according to body weight, 70 rats were used as toxicological study (1-7 groups, 5/sex/group) and 42 rats were used as toxicological study (8-14 groups, 3/sex/group);
2) Animals of groups 1 and 8 were gavaged with 20% aqueous SBE-beta-CD (Captisol) as vehicle control;
3) Groups 2 and 9, 3 and 10, 4 and 11 animals were given 10, 30, 60mg/kg GDC-0077 by gavage, respectively;
4) Animals of groups 5 and 12, 6 and 13, 7 and 14 were given 10, 30, 60mg/kg of example 51, respectively, by gavage.
5) Animals were dosed 1 time a day for 7 consecutive days (animals in groups 7, 14 were dosed for 6 consecutive days).
6) The administration volume was 10mL/kg.
7) During the test, the items of clinical observation, weight, food intake, clinical pathological indexes (blood cell count, blood coagulation function, blood biochemistry), toxicology and the like are examined.
8) All animals were euthanized at d8 (animals of groups 7, 14 were euthanized after d 6).
9) During the test period, group 1-7 animals, group 14 animals and dead animals (including toxin study animals) were all observed in a gross anatomical manner, and histopathological examination was performed on abnormal tissues, gastrointestinal tissues (e.g., colon, cecum) and immune tissues (e.g., thymus). The test results show that the compound C of the invention max And AUC (0-24h) Is significantly higher than GDC-0077 and has better tolerance than GDC-0077.

Claims (6)

1. A compound of the general formula (VIII-a) or a pharmaceutically acceptable salt thereof:
wherein:
m is selected from-S-or-NR aa -；
Ring B is selected from the following groups:
R aa selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane or epoxybutyl;
R 2 ～R 6 or R is 14 Independently selected from hydrogen or methyl;
R z selected from hydrogen or-CHF 2 ；
t is 1 or 2.
2. The compound of formula (VIII-a) or a pharmaceutically acceptable salt thereof according to claim 1, which is further represented by formula (IX):
wherein:
m is selected from-S-or-NR aa -；
R aa Selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropane or epoxybutyl;
R 2 ～R 4 、R 6 or R is 14 Selected from hydrogen or methyl;
R 15 or R is 16 Each independently selected from hydrogen or-CHF 2 。
3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
4. a pharmaceutical composition comprising a therapeutically effective amount of a compound as set forth in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
5. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4, for the preparation of a PI3K alpha inhibitor drug.
6. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the treatment of cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disease, respiratory disease and heart disease; wherein the cancer is selected from breast cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, renal cancer, myelodysplastic syndrome, acute myelogenous leukemia, or colorectal cancer.
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