CN110467629A - Quinone derivatives, its pharmaceutical composition and application - Google Patents

Quinone derivatives, its pharmaceutical composition and application Download PDF

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CN110467629A
CN110467629A CN201910373807.2A CN201910373807A CN110467629A CN 110467629 A CN110467629 A CN 110467629A CN 201910373807 A CN201910373807 A CN 201910373807A CN 110467629 A CN110467629 A CN 110467629A
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alkyl
compound
base
pharmaceutically acceptable
stereoisomer
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CN110467629B (en
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赵志明
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Shanghai de Novo Pharmatech Co Ltd
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Shanghai de Novo Pharmatech Co Ltd
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    • 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
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Abstract

The invention discloses a kind of quinone derivatives, its pharmaceutical composition and applications.Quinone derivatives (I), its stereoisomer or pharmaceutically acceptable salt of the invention has the following structure.Quinone derivatives of the invention all have the good effect for inhibiting STAT3 level in vivo and in vitro, and further quinone derivatives of the invention can also effectively inhibit the balling-up ability of cancer cell.

Description

Quinone derivatives, its pharmaceutical composition and application
Technical field
The present invention relates to a kind of quinone derivatives, its pharmaceutical composition and applications.
Background technique
Signal transduction and (the signal transducers and activators of of transcriptional activators 3 Transcription 3, STAT3) it is the protein that molecular size range is about 89~92kD, by 750~795 amino acid residues Composition, and encoded by STAT3 gene, which includes 6 functional domains: N-terminal amino acid conserved sequence, helical region, DNA knot Close domain, bonding pad, SH2 structural domain and C-terminal transcription activating area.Wherein the effect of DNA binding domain and SH2 structural domain is mostly important. STAT3 phosphorylation site mainly has: Tyr phosphorylation site (Y705) and Ser-phosphorylation site (S727) (Sriuranpong V,et al.,Cancer Res,2003,63(11):2948-2956)。
In the case of ordinary circumstance, cell factor, growth factor etc. are in combination with the corresponding receptor to cell surface, to start Intracellular tyrosine tyrosine phosphorylation cascade reaction.In the effect of the kinases such as EGFR, JAK, c-Met, Src, MAPK or mTOR Under, the STAT3 in endochylema can occur dimerization and then be activated because of itself Y705 and S727 site phosphorylation, furthermore STAT3 can also be activated by invertibity acetylation.The STAT3 of activation is indexable to genomic DNA is incorporated into core, plays and turns Record regulating and controlling effect.This signal transduction and transcriptional activation of STAT3 maintains and regulates and controls a series of biologies of normal body Scholarship and moral conduct is, including embryonic development, apoptosis, organ generation, congenital immunity, adaptive immunity, cell growth etc., By this transcription, generate relevant to cell proliferation, survival, angiogenesis and immunologic escape various protein (Myc, Cyclin D1/D2, Bcl-xl, Mcl, survivin, VEGF, HIF-1, immunosuppressive factor etc.).And the exception of STAT3 Activation can lead to generation (Song L, the et al., Oncogene 2003 of a variety of diseases；22(27):4150-4165；Levy et Al., Nat.Rev.Mol.Cell Biol., 2002,3) is the study found that immunity disease (inflammatory disease, autoimmune disease Disease, asthma, infection), proliferative disorder (psoriasis, myelodysplastic syndrome, polycythemia vera), CNS disease The pathophysiological processes such as generation, the development of (Alzheimer's disease, multiple sclerosis etc.) and tumour (solid tumor, neoplastic hematologic disorder) In, STAT3 activity high-frequency abnormal activation occurs, play it is vital effect (Morikawa T, et al., Clin Cancer Res 2011；17(6):1452-1462；Lovato,P.,et al.,J Biol Chem,2003,278 (19):16777-81；Krause,A.,J Immunol,2002,169(11):6610-6；Pfitzner,E.,et al.,Curr Pharm Des,2004,10(23):2839-50).
STAT3 can adjust the biological behaviour of immunocyte by the extracellular signal of transmitting inflammation medium, be inflammation shape At key molecules (Yu H, et al., Nat Rev Cancer 2009 indispensable in the process；9(11):798-809). STAT3 can be activated by cytokine profiles, with inflammation and the relationship of tumor immunity very close (Tianzhu Z, et al.,inflammation 2015；38:1529-1536), the study found that activity RA patient peripheral blood and knuckle synovia Monocyte in discovery STAT3mRNA level rise (Sambursky R, et al., JAMA Ophthalmol, 2013,13 (1):24-28).STAT3 is not only an activating transcription factor and an oncogene, regulate and control to grow in normal cell, A series of physiological activities such as proliferation, differentiation and apoptosis, and more and more evidences show the STAT3 quilt in kinds cancer in recent years Sustained activation plays an important role in the occurrence and development of tumour.STAT3 not only in the proliferation of cancer cell, enter to invade, migrate In work, can also change gene expression by epigenetic modification, to promote cancer development, including in induction cancer cell Epithelial-mesenchymal converts phenotype (EMT), adjusts tumor microenvironment, promotes cancer stem cell self-renewing and differentiation.
STAT3 participates in many aspects of tumor microenvironment and is provided with force environment for the development of cancer, mainly includes following several A aspect: the generation of humoral factor interacts with fibroblast, fat cell and macrophage, promotes immunosupress, will Inflammation is connected with cancer and tumor vessel occurs.STAT3 is in terms of promoting immunosupress not only by the tune of IL-6, IL-10 family Control, can also be overexpressed in a variety of solid tumors by the regulation of other cell factors such as IL-23, IL-23, be to lead to colon cancer Gastric cancer poor prognosis relevant with pylori major reason (Liu, C., et al., Cancer Cell Int, 2014.14 (1):104；Grivennikov,S.I.,et al.,Nature,2012,491(7423):254-8).STAT3 and solid tumor and The development of hematological system tumor has close ties, and interleukin class, growth factor class and certain cancer proteins etc. can cause STAT3's Phosphorylation, STATS excessive activation then show oncogene effect, participate in proliferation, the differentiation, invasion, transfer, blood of tumour cell Pipe is formed and anti-apoptotic.STAT3 plays a driving role in Several Kinds of Malignancy process, such as the cancer of the esophagus, lung cancer, breast cancer, ovary Cancer, cancer of pancreas, melanoma, prostate cancer, clear-cell carcinoma, cervical carcinoma, carcinoma of endometrium, gastric cancer, leukaemia, lymthoma etc. (Watson,C.J.,etc,Br JCancer,1995,71(4):840-4；Song,L.,et al.,Oncogene,2003,22 (27):4150-65；Toyonaga,T.,et al.,Cancer let,2003,201(1):107-16；Corvinus,F.M., et al.,Neoplasia,2005.7(6):545-55；Buettner,R.,et al.,ClinCancer Res,2002,8 (4):945-54；Spiekermann,K.,et al.,EurJ Haematol,2001,67(2):63-71；Kanda,N.,et al.,Oncogene,2004,23(28):4921-9)。
Cancer stem cell (CSC, cancer stem cells, or hypermalignant cancer cells) is more It is found and separates in kind tumour patient, lead to since CSC is overexpressed multi-efflux pumps, can activate anti-apoptotic and promotees survival signaling Road and the repair ability that damaged dna can be promoted, so that CSC all has inherent tolerance to conventional chemotherapy and radiotherapy, often Rule chemotherapy is also enriched with to CSC while killing common cancer cell.The malignancy of CSC and cancer, transfer, recurrence and Prognosis is closely related.The design of previous anti-CSC drug is concentrated mainly on design can be with selectively targeted CSC surface specific mark The drug of object.But Youzhi Li, et al. provide a kind of new approaches for inhibiting CSC, are handled by gene silencing and have found work For supporting driven factor-transcription factor STAT3 of cancer cell " stemness maintenance ".STAT3 is that one of CSC maintenance stemness is important Transcription factor, and according to this theory discovery compound BBI608 can effectively inhibit STAT3 mediate genetic transcription and CSC, the expression for inhibiting stemness gene.The transplanted tumor in nude mice system in human pancreas cancer (PaCa-2) xenograft tumor mouse model and spleen System (colon cancer HT29) in discovery BBI608 can effectively prevent cancer recurrence and transfer (Youzhi Li, et al., PANS, 2015,112(6):1839-44)。
Currently, the x-ray crystal structure of STAT3 has been reported, and there are more there is STAT3 and cancer stem cell The compound structure of inhibitory activity is disclosed, such as: WO2011/116398, WO2009/036059, WO2015/151490.Mesh Preceding to list not yet for the micromolecular inhibitor of STAT3 and CSC, quinone derivatives of the invention are to inhibit STAT3 and CSC Research and development provide new thinking.
Summary of the invention
Technical problem to be solved by the present invention lies in, provide a kind of new benzoquinone derivative, its pharmaceutical composition and Using.Quinone derivatives of the invention have good STAT3 and cancer stem cell (CSC) inhibiting effect, can effectively treat And/or alleviate and STAT3 and its extremely relevant various diseases of signal path, such as cancer.
The present invention provides a kind of quinone derivatives (I), its stereoisomer or pharmaceutically acceptable salts；
Wherein,
A ring is phenyl ring or 5-10 member hetero-aromatic ring；The 5-10 unit's heteroaryl is monocycle or condensed ring group, and includes 1 ~4 selected from N,O、S、S(O)2, C (O) hetero atom or group；
X is connecting key ,-C (O)-,-C (O) NR4-、-C(O)NR4S(O)2-、-C(O)NR4S(O)2NR4a-、-NR4S(O)2NR4a-、-NR4S(O)2-、-NR4S(O)2NR4aC(O)-、-NR4C(O)NR4a-、-NR4C(O)-、-NR4-、-S(O)2-、-S(O) (NR4a)-、-S(O)2NR4-、-S(O)2NR4C (O)-or-S (O)2NR4C(O)NR4a-；
Y is connecting key or-C (R5R5a)n-；The integer that n is 1~6；
Z is O, S or NR6；
R is alkyl, naphthenic base, Heterocyclylalkyl, alkenyl, alkynyl, aryl or heteroaryl, and the R is unsubstituted, alternatively, selecting Selecting property is by one or more RAGroup replaces at an arbitrary position；RAFor-CN ,-ORa、-C(O)N(Rb)2、-OC(O)Ra、-OC(O) ORa、-OC(O)N(Rb)2、-C(O)ORa、-C(O)Ra、-N(Rb)2、-NRaC(O)Ra、-NRaC(O)ORa、-NRaC(O)N(Rb)2、- NRaS(O)2Ra、-NRaS(O)2N(Ra)2、-S(O)0-2Rb、-S(O)2N(Rb)2, halogen, alkyl, aryl, naphthenic base, Heterocyclylalkyl, Heteroaryl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl or heteroaryl alkyl；RAIn, the alkyl, aryl, heteroaryl Base, naphthenic base, Heterocyclylalkyl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl, heteroaryl alkyl are unsubstituted, Huo Zhexuan Selecting property is by 1~3 RBGroup replaces at an arbitrary position；RBFor-OH ,-NH2、-CN、-C(O)Ra、-C(O)ORa、-S(O)2Ra、-S (O)2N(Rb)2, oxo base, halogen, C1-6Alkyl, C1-6Alkoxy or C1-6Alkylamino；RBIn, the C1-6Alkyl, C1-6Alcoxyl Base, C1-6Alkylamino is unsubstituted, or is further selected from-OH ,-NH by 1~32, halogen, C1-4Alkoxy and C1-4Alkylamino Substituent group replace at an arbitrary position；
R1、R2And R3Separately it is selected from Ra1、-CN、-N(Rb1)2、-NHC(O)Rb1、-NHS(O)2Rb1、-ORa1、-OC (O)Rb1、-S(O)0-2Rb1、-C(O)Rb1、-C(O)ORa1、-C(O)N(Rb1)2Or halogen；
R4And R4aSeparately it is selected from H, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl or miscellaneous Cycloalkyl-alkyl；
R5And R5aSeparately it is selected from H ,-ORa2、-N(Rb2)2、-SRa2, halogen, alkyl, naphthenic base, Heterocyclylalkyl, virtue Base, heteroaryl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl, heteroaryl alkyl；Alternatively, R5And R5aWith their common chains The C atom connect is formed together C3-8Naphthenic base or 3-8 membered heterocycloalkyl, the C3-8Naphthenic base or 3-8 membered heterocycloalkyl are not take Generation, alternatively, selectivity is by 1~3 RcGroup replaces at an arbitrary position, RcFor-OH ,-CN ,-NH2、C1-4Alkyl, C1-4Alkoxy, Or C1-4Alkylamino；RcIn, the C1-4Alkyl, C1-4Alkoxy, C1-4Alkylamino is unsubstituted, or is further selected by 1~3 From-OH ,-NH2, halogen, C1-4Alkoxy and C1-4The substituent group of alkylamino replaces at an arbitrary position；
R6For H ,-C (O) N (Rb3)2、-C(O)Rb3、-C(O)ORa3、-S(O)2N(Rb3)2、-S(O)2Rb3、C1-6Alkyl, C2-6 Alkenyl, C2-6Alkynyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, phenyl, 5-6 unit's heteroaryl；The C1-6Alkyl, C2-6Alkenyl, C2-6 Alkynyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, phenyl or 5-6 unit's heteroaryl are unsubstituted, or selectivity is by 1~3 choosing From :-SH ,-NH2,-CN ,-OH, halogen, C1-4Alkyl, C1-4Alkoxy, C1-4Alkylamino, halogenated C1-4Alkoxy, halogenated C1-4Alkane Base ,-C (O) NH2、-C(O)OH、-C(O)NH(C1-6Alkyl) ,-C (O) N (C1-6Alkyl)2、-NH(CO)-C1-6Alkyl ,-C (O) O- C1-6Alkyl ,-C (O)-C1-6Alkyl ,-S (O)0-2-C1-6Alkyl, C3-8The substituent group of naphthenic base or 3-8 membered heterocycloalkyl is substituted in Any position；
R4And R6For independent substitution or R4And R6It is interconnected to form 5~10 membered heterocycloalkyls；5~10 circle heterocyclic ring Alkyl is unsubstituted, or selectivity is by 1~3-OH ,-NH2、C1-4Alkyl, C1-4Alkoxy, C1-4Alkylamino, halogenated C1-4Alkane Base or halogenated C1-4The substituent group of alkoxy replaces at an arbitrary position；
Each Ra、Ra1、Ra2And Ra3It independently is H, alkyl, alkenyl, alkynyl, aryl, naphthenic base, Heterocyclylalkyl, heteroaryl Base, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl or heteroaryl alkyl；Ra、Ra1、Ra2Or Ra3In, the alkyl, alkene Base, alkynyl, aryl, naphthenic base, Heterocyclylalkyl, heteroaryl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl or heteroaryl Alkyl be it is unsubstituted, or selectivity by 1~3 be selected from-OH ,-NH2,-CN, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6 Alkylamino ,-C1-6Alkylidene-OH ,-C1-6Alkylidene-NH2, halogenated C1-6Alkyl, halogenated C1-6The substituent group of alkoxy replaces in office Meaning position；
Each Rb、Rb1、Rb2And Rb3Independently be H, alkyl, alkenyl, alkynyl, alkoxy, aryloxy group, aryl, naphthenic base, Heterocyclylalkyl, heteroaryl, cycloalkyl-alkyl, hetercycloalkylalkyl, aryl alkyl or heteroaryl alkyl；Rb、Rb1、Rb2Or Rb3 In, it is the alkyl, alkenyl, alkynyl, alkoxy, aryloxy group, aryl, naphthenic base, Heterocyclylalkyl, heteroaryl, cycloalkyl-alkyl, miscellaneous Cycloalkyl-alkyl, aryl alkyl or heteroaryl alkyl be it is unsubstituted, or selectivity by 1~3 be selected from-OH ,-NH2、- CN, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkylamino ,-C1-6Alkylidene-OH ,-C1-6Alkylidene-NH2, halogenated C1-6Alkyl, Halogenated C1-6The substituent group of alkoxy replaces at an arbitrary position；
Following situations is not included in the range of the compound as shown in formula (I):
1) when A is phenyl ring, X be connecting key；
2) when A is phenyl ring, X is-NR4C (O)-, R4For H, R C1-6Alkyl；
3) when A is phenyl ring, X is-NR4, R4For H or C3-8Naphthenic base, R C1-6Alkyl；
4) A is 5-6 member hetero-aromatic ring, and X is connecting key, and Y is connecting key, R C1-6Alkyl, substituted or unsubstituted aryl or Substituted or unsubstituted heteroaryl；With
5) A is 5-6 member hetero-aromatic ring, and X is connecting key, and Y is-C (R5R5a)n, R5And R5aIt is independently H or C1-6Alkane Base, R C1-6Alkyl.
In the present invention:
The A ring is preferably following A-1~A-15 any structure:
In the A ring, the R1、R2Or R3It is preferred that are as follows: Ra1、-CN、-N(Rb1)2、-NHC(O)Rb1、-NHS(O)2Rb1、- ORa1、-OC(O)Rb1、-S(O)0-2Rb1、-C(O)Rb1、-C(O)ORa1、-C(O)N(Rb1)2,F,Cl,Br；Ra1And Rb1Definition such as It is preceding described.
R1、R2Or R3In, the Ra1Preferably H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, phenyl, C3-8Naphthenic base, 3-8 member Heterocyclylalkyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3-8 membered heterocycloalkyl C1-4Alkyl, phenyl C1-4Alkyl or 5-6 Unit's heteroaryl C1-4Alkyl；The Ra1Be unsubstituted, or selectivity by 1~3 be selected from-OH ,-NH2,-CN, halogen, C1-6 Alkyl, C1-6Alkoxy, C1-6Alkylamino ,-C1-6Alkylidene-OH ,-C1-6Alkylidene-NH2, halogenated C1-6Alkyl, halogenated C1-6Alcoxyl The substituent group of base replaces at an arbitrary position.
R1、R2Or R3In, the Rb1Preferably H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, 1-8 member alkoxy, 5-6 member virtue Oxygroup, phenyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3-8 membered heterocycloalkyl C1-4Alkyl, phenyl C1-4Alkyl or 5-6 unit's heteroaryl C1-4Alkyl；The Rb1Be unsubstituted, or selectivity by 1~3 Selected from-OH ,-NH2,-CN, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkylamino ,-C1-6Alkylidene-OH ,-C1-6Alkylidene- NH2, halogenated C1-6Alkyl, halogenated C1-6The substituent group of alkoxy replaces at an arbitrary position.
The X is preferably-C (O)-,-C (O) NR4-、-S(O)2-、-S(O)(NR4a)-or-S (O)2NR4-；R4And R4a's It is defined as described above.
The X is preferably-C (O)-,-C (O) NR4Or-S (O)2NR4-；R4And R4aIt is defined as described above.
In the X, the R4Preferably H, C1-6Alkyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, phenyl, 5-6 member heteroaryl Base, 3-8 member naphthenic base C1-4Alkyl or 3-8 membered heterocycloalkyl C1-6Alkyl.
In the X, the R4aPreferably H, C1-6Alkyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, phenyl, 5-6 member heteroaryl Base, 3-8 member naphthenic base C1-4Alkyl or 3-8 membered heterocycloalkyl C1-6Alkyl.
The Y is preferably-C (R5R5a)n-；N is preferably 1~4 integer；Wherein, R5And R5aIt is defined as described above.
In the Y, the R5Preferably H ,-ORa2、-N(Rb2)2、-SRa2, halogen, C1-6Alkyl, C3-8Naphthenic base, 3-8 member Heterocyclylalkyl, phenyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3-8 membered heterocycloalkyl C1-6Alkyl, phenyl C1-6Alkyl, Or 5-6 unit's heteroaryl C1-6Alkyl；Wherein, Ra2And Rb2It is defined as described above.
In the Y, the R5aPreferably H ,-ORa2、-N(Rb2)2、-SRa2, halogen, C1-6Alkyl, C3-8Naphthenic base, 3-8 member Heterocyclylalkyl, phenyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3-8 membered heterocycloalkyl C1-6Alkyl, phenyl C1-6Alkyl, Or 5-6 unit's heteroaryl C1-6Alkyl；Wherein, Ra2And Rb2It is defined as described above.
In the Y, R5Or R5aIn, the Ra2Preferably H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, phenyl, C3-8Cycloalkanes Base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3-8 membered heterocycloalkyl C1-4Alkyl, phenyl C1-4Alkane Base or 5-6 unit's heteroaryl C1-4Alkyl；The Ra2Be unsubstituted, or selectivity by 1~3 be selected from-OH ,-NH2、-CN、 Halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkylamino ,-C1-6Alkylidene-OH ,-C1-6Alkylidene-NH2, halogenated C1-6Alkyl, halogen For C1-6The substituent group of alkoxy replaces at an arbitrary position.
In the Y, R5Or R5aIn, the Rb2It is preferred that H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, 1-8 member alkoxy, 5-6 First aryloxy group, phenyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3-8 circle heterocyclic ring Alkyl C1-4Alkyl, phenyl C1-4Alkyl or 5-6 unit's heteroaryl C1-4Alkyl；The Rb2Be unsubstituted, or selectivity by 1~ 3 are selected from-OH ,-NH2,-CN, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkylamino ,-C1-6Alkylidene-OH ,-C1-6Alkylene Base-NH2, halogenated C1-6Alkyl, halogenated C1-6The substituent group of alkoxy replaces at an arbitrary position.
In the Y, the R5Or R5aFor independent substitution or R5And R5aIt is formed together with the C atom that they connect jointly C3-8Naphthenic base or 3-8 membered heterocycloalkyl, the C3-8Naphthenic base or 3-8 membered heterocycloalkyl are unsubstituted, alternatively, selectivity is by 1 ~3 RcGroup replaces at an arbitrary position, RcFor-OH ,-CN ,-NH2、C1-4Alkyl, C1-4Alkoxy or C1-4Alkylamino；RcIn, The C1-4Alkyl, C1-4Alkoxy or C1-4Alkylamino is unsubstituted, or is further selected from-OH ,-NH by 1~32, halogen Element, C1-4Alkoxy and C1-4The substituent group of alkylamino replaces at an arbitrary position.
In the Y, the R5Or R5aFor independent substitution or R5And R5aIt is formed together with the C atom that they connect jointly C3-6Naphthenic base.
The Y is more preferably-CH2-、-CH2CH2-、-CH(CH3)-、-C(CH3)2Or
The Z is preferably O.
The Z is preferably S.
The Z is preferably NR6；R6It is defined as described above.
The Z is NR6When；The R6Preferably H ,-C (O) N (Rb3)2、-C(O)Rb3、-C(O)ORa3、-S(O)2N (Rb3)2、-S(O)2Rb3、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, phenyl, 5-6 member heteroaryl Base；The C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, phenyl or 5-6 unit's heteroaryl are not Replace, or selectivity is selected from by 1~3 :-SH ,-NH2,-CN ,-OH, halogen, C1-4Alkyl, C1-4Alkoxy, C1-4Alkane ammonia Base, halogenated C1-4Alkoxy, halogenated C1-4Alkyl ,-C (O) NH2、-C(O)OH、-C(O)NH(C1-6Alkyl) ,-C (O) N (C1-6Alkane Base)2、-NH(CO)-C1-6Alkyl ,-C (O) O-C1-6Alkyl ,-C (O)-C1-6Alkyl ,-S (O)0-2-C1-6Alkyl, C3-8Naphthenic base, Or the substituent group of 3-8 membered heterocycloalkyl replaces at an arbitrary position；Wherein, Ra3Preferably H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, Phenyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3-8 membered heterocycloalkyl C1-4Alkane Base, phenyl C1-4Alkyl or 5-6 unit's heteroaryl C1-4Alkyl；The Ra3Be unsubstituted, or selectivity by 1~3 selected from- OH、-NH2,-CN, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkylamino ,-C1-6Alkylidene-OH ,-C1-6Alkylidene-NH2, it is halogenated C1-6Alkyl, halogenated C1-6The substituent group of alkoxy replaces at an arbitrary position；Rb3Preferably H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes Base, 1-8 member alkoxy, 5-6 member aryloxy group, phenyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3-8 membered heterocycloalkyl C1-4Alkyl, phenyl C1-4Alkyl or 5-6 unit's heteroaryl C1-4Alkyl；The Rb3To be unsubstituted, Or selectivity by 1~3 be selected from-OH ,-NH2,-CN, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkylamino ,-C1-6It is sub- Alkyl-OH ,-C1-6Alkylidene-NH2, halogenated C1-6Alkyl or halogenated C1-6The substituent group of alkoxy replaces at an arbitrary position.
When the X is-C (O) NR4-、-C(O)NR4S(O)2-、-C(O)NR4S(O)2NR4a-、-NR4S(O)2NR4a-、-NR4S (O)2-、-NR4S(O)2NR4aC(O)-、-NR4C(O)NR4a-、-NR4C(O)-、-NR4-、-S(O)2NR4-、-S(O)2NR4C(O)-、 Or-S (O)2NR4C(O)NR4a, the Z is NR6When；The R4And R6It can be independent substitution or R4And R6It is connected with each other shape At 5~8 membered heterocycloalkyls；5~8 membered heterocycloalkyl is unsubstituted, or selectivity is by 1~3-OH ,-NH2、C1-4Alkane Base, C1-4Alkoxy, C1-4Alkylamino, halogenated C1-4Alkyl or halogenated C1-4The substituent group of alkoxy replaces at an arbitrary position.
The R is preferably C1-6Alkyl, C3-10Naphthenic base, 3-10 membered heterocycloalkyl, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl Or 5-10 unit's heteroaryl, the R is unsubstituted, alternatively, selectivity is by one or more RAGroup replaces at an arbitrary position；It is preferred that By 1~4 RAGroup replaces at an arbitrary position；More preferably by 1~3 RAGroup replaces at an arbitrary position；RAInstitute as defined above It states.
In the R, the C6-10Aryl is preferably phenyl.
In the R, the 5-10 unit's heteroaryl is preferably pyridyl group, pyrazinyl, thienyl, thiazolyl or pyrimidine radicals.
In the R, the 3-10 membered heterocycloalkyl be preferably piperazinyl, pyrrolidinyl, morpholine base, piperidyl,
In the R, when the R is substituted, the substituent RAPreferably-CN ,-ORa、-OC(O)Ra、-OC(O)ORa、- OC(O)N(Rb)2、-C(O)ORa、-C(O)Ra、-C(O)N(Rb)2、-N(Rb)2、-NRaC(O)Ra、-NRaC(O)ORa、-NRaC(O)N (Rb)2、-NRaS(O)2Ra、-NRaS(O)2N(Ra)2、-S(O)0-2Rb、-S(O)2N(Rb)2, halogen, C1-6Alkyl, phenyl, C3-8Ring Alkyl, 3-10 membered heterocycloalkyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3-8 membered heterocycloalkyl C1-4Alkyl, phenyl C1-4 Alkyl or 5-6 unit's heteroaryl C1-4Alkyl.
In the R, the RAIn, the alkyl, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, cycloalkyl-alkyl, heterocycle Alkyl-alkyl, aryl alkyl or heteroaryl alkyl are unsubstituted, or selectivity is by 1~3 RBGroup replaces at an arbitrary position； Wherein, RBIt is defined as described above.
In the R, the RAIn, the 3-10 membered heterocycloalkyl is preferably piperazinyl, piperidyl, pyrrolidinyl, morphine Quinoline base or high piperazine base.
In the R, the RAIn, the RaPreferably H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, phenyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3-8 membered heterocycloalkyl C1-4Alkyl, phenyl C1-4Alkyl or 5-6 unit's heteroaryl C1-4Alkyl；The RaBe unsubstituted, or selectivity by 1~3 be selected from-OH ,-NH2,-CN, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkylamino ,-C1-6Alkylidene-OH ,-C1-6Alkylidene-NH2, halogenated C1-6Alkyl or halogenated C1-6 The substituent group of alkoxy replaces at an arbitrary position.
In the R, the RAIn, the RbIt is preferred that H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, 1-8 member alkoxy, 5-6 member Aryloxy group, phenyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3-8 circle heterocyclic ring alkane Base C1-4Alkyl, phenyl C1-4Alkyl or 5-6 unit's heteroaryl C1-4Alkyl；The RbBe unsubstituted, or selectivity by 1~3 It is a to be selected from-OH ,-NH2,-CN, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkylamino ,-C1-6Alkylidene-OH ,-C1-6Alkylidene- NH2, halogenated C1-6Alkyl or halogenated C1-6The substituent group of alkoxy replaces at an arbitrary position.
In the R, the RAIn, the RBIn, the RaPreferably H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, phenyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3-8 membered heterocycloalkyl C1-4Alkyl, benzene Base C1-4Alkyl or 5-6 unit's heteroaryl C1-4Alkyl；The RaBe unsubstituted, or selectivity by 1~3 selected from-OH ,- NH2,-CN, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkylamino ,-C1-6Alkylidene-OH ,-C1-6Alkylidene-NH2, halogenated C1-6 Alkyl or halogenated C1-6The substituent group of alkoxy replaces at an arbitrary position.
In the R, the RAIn, the RBIn, the RbIt is preferred that H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, 1-8 member alkane Oxygroup, 5-6 member aryloxy group, phenyl, C3-8Naphthenic base, 3-8 membered heterocycloalkyl, 5-6 unit's heteroaryl, C3-8Naphthenic base C1-4Alkyl, 3- 8 membered heterocycloalkyl C1-4Alkyl, phenyl C1-4Alkyl or 5-6 unit's heteroaryl C1-4Alkyl；The RbIt is unsubstituted, or selectivity By 1~3 be selected from-OH ,-NH2,-CN, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Alkylamino ,-C1-6Alkylidene-OH ,- C1-6Alkylidene-NH2, halogenated C1-6Alkyl or halogenated C1-6The substituent group of alkoxy replaces at an arbitrary position.
In the R, the RAMore preferably: F, Cl, hydroxyl, amino, cyano, methyl, ethyl, isopropyl, methoxyl group, second Oxygroup, trifluoromethoxy, difluoro-methoxy, trifluoromethyl, piperazinyl, morpholine base, pyrrolidinyl,
In some embodiments, in the quinone derivatives (I), its stereoisomer or pharmaceutically acceptable salt The definition of certain groups can be as described below, and the group not described can be as above described in either a program:
A ring is
X is-C (O)-or-C (O) NR4-；
Y is connecting key or-C (R5R5a)n-；The integer that n is 1~6；
Z is O or S；
R is phenyl or 5-10 unit's heteroaryl, and the R is unsubstituted, alternatively, selectivity is by one or more RAGroup replaces At an arbitrary position；RAFor-CN ,-ORa、-C(O)N(Rb)2、-OC(O)Ra、-OC(O)ORa、-OC(O)N(Rb)2、-C(O)ORa、-C (O)Ra、-N(Rb)2、-NRaC(O)Ra、-NRaC(O)ORa、-NRaC(O)N(Rb)2、-NRaS(O)2Ra、-NRaS(O)2N(Ra)2、-S (O)0-2Rb、-S(O)2N(Rb)2, halogen, C1-6Alkyl, C3-8Naphthenic base or 3-10 membered heterocycloalkyl；RAIn, the C1-6Alkyl, C3-8Naphthenic base or 3-10 membered heterocycloalkyl are unsubstituted, or selectivity is by 1~3 RBGroup replaces at an arbitrary position；RBFor- OH、-NH2、-CN、-C(O)Ra、-C(O)ORa、-S(O)2Ra、-S(O)2N(Rb)2, oxo base, halogen, C1-6Alkyl, C1-6Alcoxyl Base or C1-6Alkylamino；RBIn, the C1-6Alkyl, C1-6Alkoxy or C1-6Alkylamino is unsubstituted, or further by 1~3 It is a to be selected from-OH ,-NH2, halogen, C1-4Alkoxy and C1-4The substituent group of alkylamino replaces at an arbitrary position；
R1、R2And R3Separately it is selected from Ra1、-CN、-N(Rb1)2、-NHC(O)Rb1、-NHS(O)2Rb1、-ORa1、-OC (O)Rb1、-S(O)0-2Rb1、-C(O)Rb1、-C(O)ORa1、-C(O)N(Rb1)2Or halogen；
R4For H or C1-6Alkyl；
R5And R5aIt is separately H or C1-6Alkyl；Alternatively, R5And R5aIt is formed together with the C atom that they connect jointly C3-8Naphthenic base；
Each Ra、Ra1、Ra2And Ra3It independently is H or C1-6Alkyl；The C1-6Alkyl is unsubstituted or selectivity is by 1~3 A halogen replaces at an arbitrary position；
Each Rb、Rb1、Rb2And Rb3It independently is H or C1-6Alkyl.
In some embodiments, in the quinone derivatives (I), its stereoisomer or pharmaceutically acceptable salt The definition of certain groups can be as described below, and the group not described can be as above described in either a program:
A ring is
X is-C (O) NR4-；
Y is-CH2-、-CH2CH2-、-CH(CH3)-、-C(CH3)2Or
Z is S；
R is phenyl, pyridyl group, pyrazinyl, thienyl, thiazolyl or pyrimidine radicals, and the R is unsubstituted, alternatively, selectively By one or more RAGroup replaces at an arbitrary position；RAFor F, Cl, hydroxyl, amino, cyano, methyl, ethyl, isopropyl, methoxy Base, ethyoxyl, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, piperazinyl, morpholine base, pyrrolidinyl,
R1、R2And R3Separately it is selected from H, F, Cl or methyl；
R4For H or methyl.
In some embodiments, the quinone derivatives (I), its stereoisomer or pharmaceutically acceptable salt are Following any structure:
The present invention also provides the preparations of the quinone derivatives (I), its stereoisomer or pharmaceutically acceptable salt Method, the method is as follows:
Method one: in solvent, in the presence of alkali, compound 1-1 and compound X-1 is subjected to condensation reaction；
Wherein, R4For H；A ring, R, R1、R2And R3It is as defined above.
In the method as shown in reaction equation 1, the condition and step of the condensation reaction can be anti-for the condensation of this field routine The condition and step answered, following reaction condition specifically preferred according to the invention: the preferred methylene chloride of the solvent or N, N- dimethyl Formamide；The dosage of the solvent preferably 5~20mL/mmol compound 1-1；The preferred N of the alkali, N- diisopropylethylamine or Triethylamine；Preferred 1:1~the 5:1 of molar ratio of the alkali and compound 1-1；It, can also be to reactant to accelerate reaction speed The 4-dimethylaminopyridine of catalytic amount is added in system, the 4-dimethylaminopyridine and the molar ratio of compound 1-1 are preferred 0.05:1~0.2:1.Preferably 0~40 DEG C of the temperature of the reaction；The reaction can be detected by TLC, generally with Terminal when compound 1-1 disappears as reaction, preferably 0.5~24 hour；It is described after reaction, can also pass through post-processing Product is further purified, preferably includes following steps: after reaction system is quenched with water, being diluted with solvent, separates organic phase, has Machine is mutually dried, and is removed under reduced pressure organic solvent, residue general purification means, for example, silica gel column chromatography, Flash column chromatography or Prep-HPLC purifying.The step of silica gel column chromatography, Flash column chromatography or the prep-HPLC is purified and condition can be ability In domain the step of general purification and condition.
Method two: in solvent, compound 2-1 and compound X-1 is subjected to amine ester exchange reaction；
Wherein, Pg is methyl or ethyl；A ring, R, R1、R2、R3And R4It is as defined above.
In the method as shown in reaction equation 2, the condition and step of the amine ester exchange reaction can be the amine of this field routine The condition and step of ester exchange reaction, following reaction condition specifically preferred according to the invention:
Condition 1: the solvent is preferably toluene, the dosage of the solvent preferably 5~20mL/mmol compound 2-1；Three Preferred 2:1~the 3:1 of molar ratio of aluminium methyl and compound X-1.Preferred 1:1~3 of the molar ratio of compound X-1 and compound 2-1: 1；Preferred room temperature~the solvent refluxing of the temperature of the reaction；More preferable 90~110 DEG C of the temperature of the reaction；Described is anti- Should can be detected by TLC, generally using compound I-a disappear when as reaction terminal, preferably 1~24 hour；Described After reaction, also product can be further purified by post-processing, the purification process includes silica gel column chromatography, Flash column layer Analysis or prep-HPLC purifying.The step of silica gel column chromatography, Flash column chromatography or the prep-HPLC is purified and condition can be In this field the step of general purification and condition.
Condition 2: the solvent is preferably acetonitrile, the dosage of the solvent preferably 5~20mL/mmol compound 2-1；Change Close the preferred 1:1~3:1 of molar ratio of object X-1 and compound 2-1；Preferred room temperature~the solvent refluxing of the temperature of the reaction；Institute More preferable 90~110 DEG C of the temperature for the reaction stated；The preferred microwave of heating condition；The reaction can be examined by TLC Survey, generally using compound 2-1 disappear when as reaction terminal, preferably 1~24 hour；It is described after reaction, can also lead to Later product is further purified in processing, and the purification process includes silica gel column chromatography, Flash column chromatography or prep-HPLC purifying. The step of silica gel column chromatography, Flash column chromatography or the prep-HPLC is purified and condition can be general purification in this field Step and condition.
Method three: in solvent, compound 3-1 and compound X-2 (Grignard Reagent) is subjected to addition reaction；
Wherein, Pg is methyl or ethyl；R is aromatic ring or hetero-aromatic ring, A ring, R1、R2And R3It is as defined above.
In the method as shown in reaction equation 3, the condition and step of the addition reaction can be tried for the format of this field routine The condition and step of agent addition reaction, following reaction condition specifically preferred according to the invention: reaction preferably carries out under nitrogen atmosphere, described The preferred tetrahydrofuran of solvent (anhydrous)；The dosage of the solvent preferably 5~20mL/mmol compound 3-1；The X-2 with Preferred 1:1~the 3.5:1 of the molar ratio of compound 3-1；.Preferably 0~30 DEG C of the temperature of the reaction；The reaction can pass through TLC is detected, generally using compound 1-1 disappear when as reaction terminal, preferably 0.5~6 hour；The reaction terminates Afterwards, also product can be further purified by post-processing, preferably includes following steps: after reaction system is quenched with hydrochloric acid (1M), It being diluted with solvent, separates organic phase, organic phase is dry, it is removed under reduced pressure organic solvent, residue general purification means, for example, Silica gel column chromatography, Flash column chromatography or prep-HPLC purifying.Silica gel column chromatography, Flash column chromatography or the prep-HPLC The step of the step of purifying and condition can be general purification in this field and condition.
The pharmaceutically acceptable salt of the quinone derivatives (I) can be chemically synthesized by general.
Under normal circumstances, the preparation of salt can by free alkali or acid and equal chemical equivalents or excess acid (inorganic acid or Organic acid) or alkali (inorganic base or organic base) reacted in suitable solvent or solvent compositions be made.
The present invention also provides a kind of pharmaceutical compositions comprising the active component of therapeutically effective amount and can pharmaceutically connect The auxiliary material received；The active component includes one of quinone derivatives (I), its stereoisomer or pharmaceutically acceptable salt Or it is a variety of.
In described pharmaceutical composition, the active component may also include other therapeutic agents of cancer.
In described pharmaceutical composition, the pharmaceutically acceptable auxiliary material may include pharmaceutically acceptable carrier, dilution Agent and/or excipient.
According to therapeutic purposes, pharmaceutical composition can be made to various types of administration unit dosage forms, such as tablet, pill, powder Agent, liquid, suspension, lotion, granule, capsule, suppository and injection (solution and suspension) etc., preferred liquid, suspension, cream Liquid, suppository and injection (solution and suspension) etc..
In order to shape the pharmaceutical composition of tablet form, it can be used this field any known and widely used figuration Agent.For example, carrier, such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, avicel cellulose and silicon Acid etc.；Adhesive, such as water, ethyl alcohol, propyl alcohol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose Element, lac, methylcellulose and potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, such as dried starch, mosanom, agar powder and sea Band powder, sodium bicarbonate, calcium carbonate, the aliphatic ester of polyethylene sorbitan, lauryl sodium sulfate, stearic acid monoglycerides, Starch and lactose etc.；Disintegration inhibitor, such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil and fat；Adsorption enhancer, such as season Amine base and lauryl sodium sulfate etc.；Wetting agent, such as glycerol, starch；Adsorbent, such as starch, lactose, kaolin, bentonite With colloid silicic acid etc.；And lubricant, such as pure talcum, stearate, boric acid powder and polyethylene glycol etc..It can also be according to need Select common coated material be made sugar coated tablet, apply gelatin film tablet, enteric coated tablets, film coated tablets, duplicature tablet and Multilayer tablet.
In order to shape the pharmaceutical composition of pill, it can be used this field any of and widely used figuration Agent, for example, carrier, such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talcum powder etc.；Adhesive, such as Arabic tree Rubber powder, tragacanth gum powder, gelatin and ethyl alcohol etc.；Disintegrating agent, such as agar and Kelp Powder.
In order to shape the pharmaceutical composition of suppository form, it can be used this field any known and widely used inborn nature Agent, for example, polyethylene glycol, coconut oil, higher alcohol, the ester of higher alcohol, gelatin and semi-synthetic glyceride etc..
In order to prepare the pharmaceutical composition of injection form, (suitable chlorine can will be preferably added after solution or suspension liquid disinfectant Change sodium, glucose or glycerol etc.), it is made and the isotonic injection of blood.When preparing injection, it is possible to use in the art any Common carrier.For example, water, ethyl alcohol, propylene glycol, the isooctadecanol of ethoxylation, the isooctadecanol and polyethylene of polyoxy The aliphatic ester etc. of anhydro sorbitol.In addition, common lytic agent, buffer and analgesic etc. can also be added.
In the present invention, content of the composition in pharmaceutical composition, can be in a wide range without specifically limited It is selected, generally can be the 5~95% of mass percent, preferably mass percent 30~80%.
In the present invention, the medication of described pharmaceutical composition is not particularly limited.Can according to patient age, gender and its Its condition and symptom select the preparation of various dosage forms to be administered.For example, tablet, pill, solution, suspension, lotion, granule or Capsule oral administration；Injection can be administered alone, or mixed with injection conveying liquid (such as glucose solution and amino acid solution) Conjunction is injected intravenously；Suppository is to be administered into rectum.
The present invention also provides the quinone derivatives (I), its stereoisomer or pharmaceutically acceptable salts or described Pharmaceutical composition is preparing the application in STAT3 inhibitor.
The present invention also provides the quinone derivatives (I), its stereoisomer or pharmaceutically acceptable salts or described Pharmaceutical composition is preparing the application in cancer stem cell (CSC) inhibitor.
The present invention also provides the quinone derivatives (I), its stereoisomer or pharmaceutically acceptable salts or described Application of the pharmaceutical composition in preparation treatment, the drug of alleviation and/or prevention by the STAT3 related disease mediated.The benzene Quinones (I), its isomers, prodrug, solvate, hydrate, stable isotope derivatives or pharmaceutically acceptable Salt or described pharmaceutical composition for the therapeutic agent for the treatment of cancer and/or can also be controlled with one or more other types Treatment method combines the related disease for treating, alleviating and/or prevent to be mediated by STAT3.
The present invention also provides the quinone derivatives (I), its stereoisomer or pharmaceutically acceptable salts or described Pharmaceutical composition is in preparation for inhibiting the application in cancer stem cell drug.The benzoquinone compound (I), its isomers, Prodrug, solvate, hydrate, stable isotope derivatives or pharmaceutically acceptable salt or described pharmaceutical composition are also It can combine with the therapeutic agent and/or treatment method for treating cancer of one or more other types for inhibiting cancer dry Cell.
The therapeutic agent for treating cancer and/or inhibition cancer stem cell of other types can be with the benzoquinones Derivative (I) is made into the therapeutic dosage forms of single administration, or is taken up in order of priority the therapeutic dosage forms of administration.
The therapeutic agent and/or treatment method for treating cancer of other types may include but be not limited to: DNA damage Agent (alkylating agent, DNA intercalator and topological enzyme I/II inhibitor), antimitotic agent, antimetabolitas, hormone therapy agent, One of targeted therapy, immunization therapy and radiotherapy are a variety of.
The alkylating agent may be selected from but not limited to: cis-platinum, carboplatin, oxaliplatin, Nedaplatin, mustargen, hydrochloric acid N- oxidation-nitrogen Mustard, ring butyric acid mustargen, uracil mastard, cyclophosphamide, ifosfamide, thiotepa, carboquone, triethyleneiminobenzoquinone, toluenesulfonic acid Improsulfan, mannosulfan, Treosulfan, busulfan, Nimustine, dibromannitol, melphalan, Dacarbazine, thunder Mo Siting, Carmustine, lomustine, streptozotocin, Temozolomide, procarbazine, ethylenimine derivatives, methane sulfonate One of class, nitrosourea, Triazenes are a variety of.
DNA intercalator may be selected from but not limited to: in proflavin, adriamycin, daunorubicin, actinomycin D and Thalidomide It is one or more.
The topological enzyme I/II inhibitor may be selected from but not limited to: Doxorubicin, daunorubicin, epirubicin, according to up to than Star, topotecan, Rubitecan, Belotecan, Etoposide, mentions Buddhist nun's pool glycosides, adriamycin and dexrazoxane, happiness at Irinotecan Set one of alkali or a variety of.
The antimitotic agent includes but is not limited to: taxol, Docetaxel, polyglutamic acid paclitaxel, different Changchun Alkali, vincristine, vincaleukoblastinum, eldisine, vinzolidine, Etoposide, Teniposide, Ipsapirone, La Luotasai, One of ortataxel, tesetaxel, tocosal and Yi Sipingsi or a variety of.
The antimetabolitas may be selected from but not limited to: antifol, pyrimidine analogue, purine analogue, adenosine Deaminase inhibitors, such as: methotrexate (MTX), 5 FU 5 fluorouracil, fluridine, cytarabine, Ismipur, 6- thioguanine, One of fludarabine phosphate, Pentostatin and gemcitabine are a variety of.
The hormone therapy agent may be selected from but not limited to: Fosfestrol, diethylstilbestrol, Chlorotrianisne, medroxyprogesterone acetate, vinegar Sour megestrol acetate, serine progesterone acetate, cyproterone acetate, danazol, Dienogest, Allylestrenol, gestrinone, promise U.S. are pregnant Ketone, Tadenan, mepartricin, Raloxifene, Ormeloxifene, Zuo Meiluo former times sweet smell, An Lu meter Te, Testolactone, anti-estrogens, LH-RH derivative, aromatase inhibitor, anti-androgens, adrenocortical hormone, androgen synthetic inhibitor, vitamin A acid With one of the drug of delay retinoic acid metabolism or a variety of.
The immunization therapy may be selected from but not limited to: anti-tumor vaccine (such as: synthetic peptide, DNA vaccination and recombinant virus), Oncolytic virus, novel adjuvant, cytokine therapy (such as: IL2 and GM-CSF), Chimeric antigen receptor T cell cure (CAR- T), one of immunomodulator, tumor microenvironment regulator and anti-angiogenesis or a variety of.The immunomodulator It may include but be not limited to: 1) inhibiting the active protein antagonist of T cell (such as: immunologic test point inhibitor): CTLA4 (such as: Ipilimumab and tremelimumab), PD-1 (such as: pembrolizumab and nivolumab), PD-L1 (such as: Durvalumab, avelumab and atezolizumab), one of LAG3 and TIM3 or a variety of；2) stimulation T cell is active Protein agonist: one of GITR, OX40, OX40L, 4-1BB (CD137), CD27 and CD40 or a variety of；3) TLR7 excitement One of agent, TLR8 agonist and TLR9 agonist are a variety of；4) IDO inhibitor, CD73 inhibitor, STING inhibitor.
The targeted therapy includes but is not limited to: BCR/ABL kinase inhibitor, epidermal growth factor receptor inhibitor, Her-2/neu acceptor inhibitor, AKT family kinase inhibitors, PI3K signal pathway inhibitor, cell cycle checkpoint inhibit Agent, VEGF/VEGFR signal pathway inhibitor, Src family kinase inhibitors, Src signal pathway inhibitor and the suppression of c-Fes kinases One of preparation is a variety of.
The cancer may include but be not limited to: cancer eye, osteocarcinoma, lung cancer, gastric cancer, cancer of pancreas, breast cancer, prostate cancer, The cancer of the brain (including glioblastoma, medulloblastoma), oophoroma, bladder cancer, cervix cancer, carcinoma of testis, kidney (including gland Cancer and kidney mother cell cancer), carcinoma of mouth (including squamous cell carcinoma), tongue cancer, laryngocarcinoma, nasopharyngeal carcinoma, head and neck cancer, colon cancer, carcinoma of small intestine, The carcinoma of the rectum, parathyroid carcinoma, thyroid cancer, the cancer of the esophagus, gallbladder cancer, cholangiocarcinoma, cervical carcinoma, liver cancer, lung cancer, sarcoma, cutaneum carcinoma, Lymphatic leukemia (including acute lymphoblastic leukemia, lymthoma, myeloma, chronic lymphocytic leukemia, Huo Qijin leaching Bar tumor, non-Hodgkin lymphoma, T cell chronic lymphatic leukemia, B cell chronic lymphatic leukemia), marrow it is relevant white Blood disease one of (including acute myeloid leukaemia, chronic myelogenous leukemia) and the relevant leukaemia of AIDs or a variety of.
The mammal, preferably people.
In the present invention, when with substituent group be bonded display in connection ring two atoms be bonded intersect when, then in this way The bonding any bonding annular atom on ring of substituent group.
Unless otherwise indicated, the following term occurred in description of the invention and claims has the meaning that
Term " alkyl " refers to saturated straight chain or branched hydrocarbyl comprising 1-20 carbon atom, preferably 1-10 carbon atom, More preferable 1-8,1-6,1-4 or 1-3 carbon atom, the representative example of alkyl includes but is not limited to: methyl, ethyl, n-propyl, Isopropyl, normal-butyl, sec-butyl, tert-butyl, isobutyl group, amyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4- dimethyl-penten Base, 2,2,4- tri-methyl-amyls, undecyl, dodecyl and their various isomers etc..Term " alkylidene " refers to can Alkyl to be keyed other two groups as connection, the alkylidene can be straight chain and be also possible to branched structure, example Including but not limited to-CH2-、-CH2CH2-、-CH2CH(CH3)-。
Term " naphthenic base " refers to the saturation comprising 3-20 carbon atom or part unsaturated (comprising 1 or 2 double bond) One or more cyclic groups." monocyclic cycloalkyl " preferably 3-10 unit monocycle alkyl, more preferable 3-8 unit monocycle alkyl, such as: cyclopropyl Base, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclodecyl, cyclo-dodecyl, cyclohexenyl group." polycyclic naphthene base " Including " bridged ring base ", " fused cycloalkyl " and " spiro cycloalkyl group ", the representative example of " bridged ring base " includes but is not limited to: borneol It is base, bicyclic [2.2.1] heptenyl, bicyclic [3.1.1] heptane base, bicyclic [2.2.1] heptane base, bicyclic [2.2.2] octyl, double Ring [3.2.2] nonyl, bicyclic [3.3.1] nonyl, bicyclic [4.2.1] nonyl and adamantyl etc.." fused cycloalkyl " Comprising the cycloalkyl ring being fused on phenyl, naphthenic base or heteroaryl, fused cycloalkyl includes but is not limited to: benzocyclobutene, 2,3- dihydro -1-H- indenes, 2,3- cyclopenta pyridine, 5,6- dihydro -4H- cyclopenta [B] thiophene, decahydronaphthalene etc..Monocycle cycloalkanes Base or polycyclic naphthene base can be connected on parent molecule by carbon atom chain arbitrary on ring.
Term " Heterocyclylalkyl " refers to by carbon atom and the saturation or part insatiable hunger that form selected from hetero atoms such as nitrogen, oxygen or sulphur The non-aromatic cyclic radical of (including 1 or 2 double bond), this cyclic group can be one or more cyclic groups, in the present invention, miscellaneous Hetero atom number preferably 1,2,3 or 4 in naphthenic base, nitrogen, carbon or sulphur atom in Heterocyclylalkyl are optionally oxidized.Nitrogen-atoms It can optionally further be replaced by other groups and form tertiary amine or quaternary ammonium salt." monocyclic heterocycloalkyl " preferably 3-10 unit monocycle heterocycle Alkyl, more preferable 3-8 unit monocycle Heterocyclylalkyl.Such as: '-aziridino, tetrahydrofuran -2- base, morpholine -4- base, thio morphine Quinoline -4- base, thiomorpholine-S-oxide -4- base, piperidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperazine -1- base etc.. " polycyclic Heterocyclylalkyl " includes " annelated heterocycles alkyl ", " spiro heterocyclic radical " and " bridge Heterocyclylalkyl "." annelated heterocycles alkyl " includes It is fused to the monocyclic heterocycloalkyl ring of phenyl, naphthenic base, Heterocyclylalkyl or heteroaryl, annelated heterocycles alkyl includes but is not limited to: 2,3- dihydro benzo furyl, 1,3- dihydroisobenzofuran base, indolinyl, 2,3- dihydrobenzo [b] thienyl, dihydro Benzo piperazine mutter base, 1,2,3,4- tetrahydric quinoline group, Deng.Monocyclic heterocycloalkyl and polycyclic miscellaneous Naphthenic base can be linked on parent molecule by annular atom arbitrary on ring.The carbon that above-mentioned annular atom refers in particular to composition ring skeleton is former Son and/or nitrogen-atoms.
Term " alkoxy " refers to has the carbon atom number purpose cyclic annular or acyclic alkyl groups by what oxygen bridge connected, Described in cyclic alkyl also can further include one or more hetero atoms, the alkoxy includes alkyl oxy, cycloalkyloxy group Base and Heterocyclylalkyl oxygroup." alkoxy " includes the definition of abovementioned alkyl, Heterocyclylalkyl and naphthenic base as a result,.
Term " aryl " refers to any stable 6-20 unit monocycle or Ppolynuclear aromatic group, such as: phenyl, naphthalene, four Hydrogen naphthalene, indanyl, xenyl or benzo [d] [1,3] dioxolanyl etc..
Term " heteroaryl " refers to that the carbon atom at least one ring is formed by the hetero atom displacement selected from nitrogen, oxygen or sulphur Aromatic group, can be 5-7 unit monocycle structure or 7-20 condensed ring structure, preferably 5-6 unit's heteroaryl.In the present invention, Hetero atom number preferably 1,2 or 3, comprising: pyridyl group, pyrimidine radicals, pyrazinyl, (2H) -one of pyridazine -3 base, furyl, thienyl, Thiazolyl, pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1, 3,4- oxadiazoles base, 1,3,4- thiadiazoles, 1,2,4- triazol radical, 1,2,3- triazol radical, tetrazole base, indazolyl, different Yin Oxazolyl, indyl, isoindolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinoline Quinoline base, isoquinolin ketone group, quinazolyl, 4- hydroxy thiophene simultaneously [3,2-c] pyridyl group, 4,5- dihydro -4- oxo furans [3,2] pyrrole Piperidinyl, 4- hydroxyl -5- azaindolyl, furans [2,3-c] and (6H) -one of pyridine -7 base, thiophene [2,3-c] and pyridine -7 (6H) -one base etc..
Term " halogen " indicates fluorine, chlorine, bromine or iodine.
Term " halogenated alkyl " refers to the alkyl arbitrarily replaced by halogen.As a result, " halogenated alkyl " include the above halogen and The definition of alkyl.
Term " halogenated alkoxy " refers to the alkoxy arbitrarily replaced by halogen.More than " halogenated alkoxy " include as a result, The definition of halogen and alkoxy.
Term " amino " refers to-NH2, term " alkylamino " refers to that at least one hydrogen atom is replaced alkyl on amino, Including but not limited to :-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH2CH3)2。
Term " cyano " refers to-CN.
Term " oxo base " refers to=O.
" room temperature " of the present invention refers to 15-35 DEG C.
" pharmaceutically acceptable salt " of the present invention is in Berge, et al., " Pharmaceutically Acceptable salts ", J.Pharm.Sci., 66,1-19 are discussed in (1977), and for Pharmaceutical Chemist be it is aobvious and Be clear to, the salt is substantially avirulent, and pharmacokinetic property needed for capable of providing, palatability, absorption, distribution, Metabolism or excretion etc..Compound of the present invention can have acidic-group, basic group or amphiprotic group, typically pharmaceutically Acceptable salt includes the salt that compound and acid reaction are prepared through the invention, such as: hydrochloride, hydrobromate, sulfuric acid Salt, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphoric acid Salt, pyrophosphate, nitrate, acetate, propionate, caprate, caprylate, formates, acrylates, isobutyrate, caproic acid Salt, enanthate, oxalates, malonate, succinate, suberate, benzoate, methyl benzoic acid salt, phthalic acid Salt, maleate, mesylate, tosilate, (D, L)-tartaric acid, citric acid, maleic acid, (D, L)-malic acid are rich Horse acid, succinic acid, succinate, lactate, fluoroform sulphonate, naphthalene -1- sulfonate, mandelate, acetonate, stearic acid Salt, ascorbate, salicylate.When the compounds of this invention contains acidic-group, pharmaceutically acceptable salt can be with It include: alkali metal salt, such as sodium or sylvite；Alkali salt, such as calcium or magnesium salts；Organic alkali salt, for example, with ammonia, alkyl ammonia The salt of the formation such as class, hydroxy alkyl Ammonia, amino acid (lysine, arginine), N-METHYL-ALPHA-L-GLUCOSAMINE.
" isomers " of the present invention refer to formula of the invention (I) compound can have asymmetric center and racemic modification, Racemic mixture and single diastereoisomer, all these isomers, including stereoisomer, geometric isomer include In the present invention.In the present invention, compound of formula I or its salt in the form of stereomeric (for example, its contain it is one or more not Symmetric carbon atom) in the presence of, individual stereoisomer (enantiomter and diastereoisomer) and their mixture It is included within the scope of the invention.The independent isomers of the compound or salt that are indicated the invention also includes Formulas I, and with wherein one The mixture of the isomers of a or multiple chiral centers reversion.Scope of the invention include that the mixture of stereoisomer, and The enantiomter or enantiomter of purifying/diastereoisomer enrichment mixture.The present invention includes all enantiomerisms The mixture of the stereoisomer of body and all possible various combination of non-corresponding isomers.The present invention includes institute defined above There are the whole combinations and subset of the stereoisomer of specific group.The invention also includes compound of formula I or the geometrical isomerisms of its salt Body, the geometric isomer include cis-trans-isomer.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably Example.
The reagents and materials used in the present invention are commercially available.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient The selection of product specification.
The structure of all compounds of the present invention can by nuclear magnetic resonance (1H NMR) and/or Mass Spectrometer Method (MS) identification.
1H nmr chemical is displaced (δ) with PPM record (10-6).NMR is carried out by Bruker AVANCE-400 spectrometer.It closes Suitable solvent is deuterated chloroform (CDCl3), deuterated methanol (MeOD-d4), deuterated dimethyl sulfoxide (DMSO-d6), tetramethylsilane is made For internal standard (TMS).
Low resolution mass spectrometry (MS) is measured by Agilent 1200HPLC/6120 mass spectrograph, using XBridge C18,4.6 × 50mm, 3.5 μm, elution requirement includes acid condition and alkaline condition.Wherein, acid condition: 80-5% solvent A1And 20- 95% solvent B1(1.8 minutes), then 95% solvent B1With 5% solvent A1(3 minutes or more), percentage are that a certain solvent Zhan is total The percentage by volume of solvent volume.Solvent A1: the aqueous solution of 0.01% trifluoroacetic acid (TFA)；Solvent B1: 0.01% trifluoroacetic acid Acetonitrile solution；Percentage is the percentage by volume that solute accounts for solution.Alkaline condition: 80-5% solvent A2With 20-95% solvent B2 (1.5 minutes), then 95% solvent B2With 5% solvent A2(2 minutes or more), percentage are that a certain solvent accounts for total solvent volume Percentage by volume.Solvent A2: the aqueous solution of the ammonium hydrogen carbonate of 10mM；Solvent B2: acetonitrile.
All compounds of the present invention can pass through high performance liquid chromatograph, silica gel column chromatography, thin layer silica gel plate, fast selector Separation.
Fast selector (Flash column chromatography) (flash system/CheetahTM) use Agela Technologies MP200, matching used splitter are Flash columm Silica-CS (80g), Cat No.CS140080-0。
High performance liquid chromatograph (prep-HPLC) uses Shimadzu LC-20 preparative liquid chromatography, Detection wavelength: 214nm& 254nm；Flow velocity: 9.0mL/ minutes.Chromatographic column are as follows: waters xbridge Pre C18,10um, 19mm × 260mm.Elute item Part (alkaline condition): solvent A: the aqueous solution of the ammonium hydrogen carbonate of 10mM；Solvent B: acetonitrile.
Thin layer silica gel plate is Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate.Column chromatography generally uses the Yantai Huanghai Sea 200-300 mesh silica gel is as carrier.
Embodiment 1:N- benzyl -4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- formamide (compound 1) synthesis
Step 1: at room temperature, being added into concentrated hydrochloric acid (200mL) solution of 5- isoquinolinol (10g, 68.8mmol) dense Nitric acid (30mL), reaction system stir 2 hours at 90 DEG C.Then reaction system is cooled to room temperature, water (200mL) is added to dilute, Ethyl acetate (200mL × 3) extraction, organic phase anhydrous sodium sulfate is dry, is concentrated under reduced pressure and removes solvent, residue is through flash column Analysis (petrol ether/ethyl acetate=85/15) purifying obtains 6,7- dichloro isoquinolin -5,8- diketone (2.23g, yield 15%) as Huang Color solid.m/z:[M+H]+228.0,230.0.
Step 2: at room temperature, to Isosorbide-5-Nitrae-dioxane of 6,7- dichloro isoquinolin -5,8- diketone (1g, 4.39mmol) Sodium bicarbonate (1.66g, 19.7mmol) and thio-oxamide ethyl ester are added in (15mL) and ethyl alcohol (15mL) mixed solution (880mg, 6.58mmol), reaction system stir 3 hours at 90 DEG C.Reaction system is cooled to room temperature, is concentrated under reduced pressure and removes Solvent, residue add ethyl acetate (150mL) to dilute, organic phase washed with water (50mL) and saturated salt solution (50mL) washing, Separation organic phase is simultaneously dry with anhydrous sodium sulfate, is concentrated under reduced pressure and removes solvent, residue is through rapid column chromatography (petroleum ether/acetic acid Ethyl ester=2/3) purifying obtain 4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- carboxylic acid, ethyl ester (200mg, produce Rate: 16%) being yellow solid.m/z:[M+H]+289.0.
Step 3: at room temperature, to 4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- carboxylic acid, ethyl ester Benzylamine (40mg, 0.34mmol) is added in acetonitrile (1mL) solution of (50mg, 0.17mmol), reaction system is under nitrogen protection It is placed at 100 DEG C microwave reaction 1~1.5 hour (TLC monitoring reaction terminates).Through prep-HPLC after reaction solution reduced pressure (NH4HCO3System) purifying obtain compound 1 (2.5mg, yield: 17%) be yellow solid.m/z:[M+H]+350.0,1H NMR (400MHz,CDCl3): δ 9.58 (s, 1H), 9.17 (d, J=4.0Hz, 1H), 8.06 (d, J=4.0Hz, 1H), 7.85-7.77 (m, 1H), 7.42-7.31 (m, 5H), 4.68 (d, J=4.0Hz, 2H)
Embodiment 2:N- (4- methoxy-benzyl) -4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- first The synthesis of amide trifluoroacetate salt (compound 2)
Using the synthetic method of compound 1, the benzylamine in step 3 is replaced with into 4- methoxybenzylamine and obtains compound 2 (prep-HPLC:TFA system) is yellow solid.m/z:[M+H]+380.0,1H NMR(400MHz,CD3OD):δ9.43(s, 1H), 9.10-9.11 (m, 1H), 8.08-8.11 (m, 1H), 7.33 (d, J=8.8Hz, 2H), 6.90 (d, J=8.8Hz, 2H), 4.54(s,2H),3.77(s,3H).
Embodiment 3:N- butyl -4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- formamide (compound 3) synthesis
Using the synthetic method of compound 1, the benzylamine in step 3 is replaced with into n-butylamine obtains compound 3 and consolidate for yellow Body.m/z:[M+H]+316.2,1H NMR(400MHz,CD3OD): δ 9.44 (s, 1H), 9.11 (d, J=4.0Hz, 1H), 8.11 (d, J=4.0Hz, 1H), 3.44 (t, J=8.0Hz, 2H), 1.66-1.61 (m, 2H), 1.00-0.90 (m, 5H)
Embodiment 4:N- (4- cyanobenzyls) -4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- formyl The synthesis of amine trifluoroacetate (compound 4)
Using the synthetic method of compound 1, the benzylamine in step 3 is replaced with into 4- cyano benzylamine and obtains compound 4 (prep-HPLC:TFA system) is yellow solid.m/z:[M+H]+375.0,1H NMR(400MHz,CD3OD):δ9.45(s, 1H), 9.12 (s, 1H), 8.05 (d, J=4.0Hz, 1H), 7.72 (d, J=8.0Hz, 2H), 7.58 (d, J=8.0Hz, 2H), 4.68(s,2H).
Embodiment 5:N- Benzyl-N-methyl -4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- formamide The synthesis of (compound 5)
Using the synthetic method of compound 1, the benzylamine in step 3 is replaced with into N- methylbenzylamine and obtains compound 5 as Huang Color solid.m/z:[M+H]+364.0,1H NMR(400MHz,CDCl3): δ 9.58-9.55 (d, J=12.0Hz, 1H), 9.15 (t, J=4.4Hz, 1H), 8.05 (t, J=4.8Hz, 1H), 7.38-7.28 (m, 5H), 5.44 (s, 1H), 4.80 (s, 1H), 3.60 (s,2H),3.14(s,1H).
Embodiment 6:2- (1,2,3,4- tetrahydroisoquinoline -2- carbonyl) thiazole simultaneously [5,4-g] isoquinolin -4,9- diketone trifluoro The synthesis of acetate (compound 6)
Using the synthetic method of compound 1, the benzylamine in step 3 is replaced with 1,2,3,4 ,-tetrahydroisoquinoline Closing object 6 (prep-HPLC:TFA system) is yellow solid.m/z:[M+H]+376.0,1H NMR(400MHz,CDCl3):δ9.39- 9.46(m,1H),9.11-9.13(m,1H),8.10-8.19(m,1H),7.21-7.23(m,3H),7.13-7.17(m,1H), 4.53-4.63 (m, 2H), 3.66-3.69 (m, 1H), 3.01-3.10 (m, 2H), 2.86 (t, J=6.0Hz, 1H)
The synthesis of embodiment 7:2- benzoyl thiazole simultaneously [5,4-g] isoquinolin -4,9- diketone (compound 7)
Step 1: under condition of ice bath, to nitrogen protection under methoxy amine hydrochlorate (92mg, 0.94mmol) two Trimethyl aluminium (hexane solution of 0.94mL, 1M) is added in chloromethanes (5.0mL) solution, it is small that reaction system stirs 1 at 0 DEG C When.It states then up and 4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- carboxylic acid, ethyl ester is added in reaction solution Methylene chloride (1mL) solution of (90mg, 0.31mmol), reaction system stir 4 hours at room temperature.It is quenched instead with hydrochloric acid (1M) It answers, obtained mixture is diluted with water (5mL), separates organic phase, and dried, filtered with anhydrous sodium sulfate, contract and remove, residue warp Prep-TLC (methylene chloride/methanol=20/1) purifying obtains N- methoxy-. N-methyl -4,9- dioxo -4,9- thiazoline And [5,4-g] isoquinolin -2- formamide (37mg, yield 39%) is yellow solid.m/z:[M+H]+304.0.
Step 2: under condition of ice bath, to nitrogen protection under N- methoxy-. N-methyl -4,9- dioxo -4,9- dihydro thiophene Simultaneously phenyl-magnesium-bromide is added in tetrahydrofuran (2mL) solution of [5,4-g] isoquinolin -2- formamide (37mg, 0.12mmol) in azoles (diethyl ether solution of 0.1mL, 3M), reaction system stir 3 hours at room temperature.With hydrochloric acid (1M) quenching reaction, reaction system water (2mL) dilution, ethyl acetate (5mL × 2) extraction, organic phase anhydrous sodium sulfate are dried, filtered, are concentrated, and residue is through prep- HPLC(NH4HCO3System) purifying obtain compound 7 (3mg, yield: 8%) be yellow solid.m/z:[M+H]+321.0,1H NMR(400MHz,CDCl3): δ 9.65 (s, 1H), 9.21 (s, 1H), 8.61 (d, J=8.0Hz, 2H), 8.09 (s, 1H), 7.73 (t, J=7.2Hz, 1H), 7.60 (t, J=7.6Hz, 2H)
- 4,9- dioxo -4,9- thiazoline is simultaneously [5,4-g] by embodiment 8:N- (4- (4- methylpiperazine-1-yl) benzyl) The synthesis of isoquinolin -2- formamide (compound 8)
Under nitrogen protection, into toluene (4mL) solution of 4- (4- methylpiperazine-1-yl) benzylamine (43mg, 0.21mmol) It is added trimethyl aluminium (hexane solution of 0.2mL, 1M), reaction system is stirred at room temperature 15 minutes, and 4,9- dioxo -4,9- is added Simultaneously [5,4-g] isoquinolin -2- carboxylic acid, ethyl ester (20mg, 0.07mmol), reaction system stir 5 hours thiazoline at 90 DEG C.Instead Through prep-HPLC (NH after answering liquid to be concentrated under reduced pressure4HCO3System) purifying obtain compound 8 (2mg, yield: 7%) be yellow solid. m/z:[M+H]+448.2,1H NMR(400MHz,CDCl3): δ 9.57 (s, 1H), 9.17 (d, J=4.0Hz, 1H), 8.05 (d, J =4.8Hz, 1H), 7.79-7.74 (m, 1H), 7.28 (d, J=8.0Hz, 2H), 6.91 (d, J=8.0Hz, 2H), 4.59 (d, J =4.8Hz, 2H), 3.50-3.44 (m, 4H), 3.06-2.97 (m, 4H), 2.65 (s, 3H)
Embodiment 9:4,9- dioxo-N- (2- phenylpropyl alcohol -2- base) -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- formyl The synthesis of amine (compound 9)
Using the synthetic method of compound 7,4- (4- methylpiperazine-1-yl) benzylamine is replaced with into 2- phenylpropyl alcohol -2- amine and is obtained Compound 9 is yellow solid.m/z:[M+H]+378.0,1H NMR(400MHz,CDCl3): δ 9.60 (s, 1H), 9.18 (d, J= 5.2Hz, 1H), 8.06 (d, J=5.2Hz, 1H), 7.79 (s, 1H), 7.46 (d, J=7.6Hz, 2H), 7.37 (t, J=8.0Hz, 2H), 7.29 (d, J=7.2Hz, 1H), 1.87 (s, 6H)
Embodiment 10:4,9- dioxo-N- phenyl -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- formamide (chemical combination Object 10) synthesis
Using the synthetic method of compound 7,4- (4- methylpiperazine-1-yl) benzylamine is replaced with into aniline and obtains compound 10 (prep-HPLC:TFA system) is yellow solid.m/z:[M+H]+336.0,1H NMR(400MHz,CDCl3):δ9.56(s, 1H), 9.10-9.16 (m, 1H), 8.03 (d, J=4.0Hz, 1H), 7.71 (d, J=8.0Hz, 2H), 7.39 (t, J=8.0Hz, 2H),7.16-7.18(m,1H).
Embodiment 11:2- (isoindoline -2- carbonyl) thiazole simultaneously [5,4-g] isoquinolin -4,9- diketone (compound 11) Synthesis
Using the synthetic method of compound 7,4- (4- methylpiperazine-1-yl) benzylamine is replaced with isoindoline and obtains chemical combination Object 11 (prep-HPLC:TFA system) is yellow solid.m/z:[M+H]+362.0,1H NMR(400MHz,CDCl3):δ9.55 (s, 1H), 9.11-9.12 (m, 1H), 8.03 (d, J=4.8Hz, 1H), 7.31-7.36 (m, 4H), 5.54 (s, 2H), 5.03 (s, 2H).
Simultaneously [5,4-g] isoquinolin 6- is aoxidized embodiment 12:2- (benzyl carbamyl) -4,9- dioxo -4,9- thiazoline The synthesis of object (compound 12)
Metachloroperbenzoic acid is added into methylene chloride (3mL) solution of compound 1 (13mg, 0.037mmol) (32mg, 0.18mmol), reaction system stir 20 hours in 45 DEG C.Through prep-HPLC (NH after reaction solution is concentrated under reduced pressure4HCO3 System) obtaining compound 12 after purification, (2.5mg, yield: 18%) being yellow solid.m/z:[M+H]+366.0,1H NMR (400MHz,CDCl3): δ 8.86 (d, J=1.6Hz, 1H), 8.44 (dd, J=6.8,1.6Hz, 1H), 8.09 (d, J=6.8Hz, 1H), 7.81-7.76 (m, 1H), 7.38-7.33 (m, 5H), 4.67 (d, J=6.0Hz, 2H)
Embodiment 13:N- (2- (4- (4- methylpiperazine-1-yl) phenyl) propyl- 2- yl) -4,9- dioxo -4,9- dihydro thiophene The synthesis of azoles simultaneously [5,4-g] isoquinolin -2- formamide (compound 13)
The synthesis of intermediate 1A:
Under nitrogen protection, to the anhydrous tetrahydro furan of 4- (4- methylpiperazine-1-yl) cyanophenyl (200mg, 1mmol) Methyl-magnesium-bromide (the 2- methyltetrahydrofuran solution of 3.3mL, 3M) is added in (2.0mL) solution, it is anti-that reaction system is placed in microwave It answers in device and stirs 10 minutes for 100 DEG C.Then reaction system is cooled to room temperature, into system be added methyl-magnesium-bromide (0.7mL, The 2- methyltetrahydrofuran solution of 3M), tetraisopropoxy titanium (570mg, 2.0mmol), reaction system is placed in microwave reactor 50 DEG C are stirred 30 minutes.It is cooled to room temperature, adds water quenching reaction, after ethyl acetate extraction, organic phase passes through quick after being concentrated under reduced pressure Column chromatography (methylene chloride/methanol=95/5) purifying obtain 2- (4- (4- methylpiperazine-1-yl) phenyl) propyl- 2- amine (1A, 50mg, yield 21%) it is brown solid.m/z:[M+H]+234.2.
Step 1: being added into the ethanol solution (10mL) of 6,7- dichloro isoquinolin -5,8- diketone (500mg, 2.19mmol) Ammonium hydroxide (310mg, 2.19mmol, 25%), reaction system stir 4 hours in 50 DEG C.Through flash column after reaction solution reduced pressure Analysis (petrol ether/ethyl acetate=7/3) purifying obtains 7- amino -6- chlorine isoquinolin -5,8- diketone, and (yield: 66%) 300mg is Red solid.m/z:[M+H]+209.0.
Step 2: sulphur being added into the aqueous solution (20mL) of 7- amino -6- chlorine isoquinolin -5,8- diketone (1g, 4.80mmol) Change sodium hydrate (6.25g, 48.0mmol, 60%), reaction system stirs 2 hours in 100 DEG C.Cooled to room temperature, Xiang Ti Glyoxylic acid ethyl ester (toluene solution of 2.95g, 14.4mmol, 50%) is added in system, reaction system is stirred at room temperature 1 hour, is added Hydrochloric acid (1M) regulation system pH to 3~4 is filtered, pure through rapid column chromatography (methylene chloride/methanol=65/35) after filtration cakes torrefaction Change obtains 4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- formic acid (285mg, yield: 23%) solid for brown Body.m/z:[M+H]+261.0.
Step 3: to 4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- formic acid (55.0mg, In n,N-Dimethylformamide (2.0mL) solution 0.21mmol) be added n,N-diisopropylethylamine (DIPEA) (55.0mg, 0.42mmol), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) (120.0mg, 0.32mmol), intermediate 1A (50mg, 0.21mmol), reaction system stir 3 hours at room temperature.Reaction system is diluted with water, second Acetoacetic ester extraction, through prep-HPLC (NH after organic phase reduced pressure4HCO3System) purifying obtain compound 13 (4.3mg, produce Rate: 4%) being grey black solid.m/z:[M+H]+476.2,1H NMR(400MHz,CDCl3):δ9.59(s,0.6H),9.51(s, 0.4H), 9.18 (t, J=5.2Hz, 1H), 8.13 (d, J=5.2Hz, 0.4H), 8.03 (d, J=5.2Hz, 0.6H), 7.72 (d, J=10.8Hz, 1H), 7.36 (d, J=8.7Hz, 2H), 6.90 (d, J=8.7Hz, 2H), 3.39-3.29 (m, 4H), 2.95- 2.77(m,4H),2.54(s,3H),1.84(s,6H).
Embodiment 14:N- (4- (4- methylpiperazine-1-yl) phenethyl) -4,9- dioxo -4,9- thiazoline simultaneously [5,4- G] isoquinolin -2- formamide (compound 14) synthesis
The synthesis of intermediate 2A:
Step 1: to the ethylene glycol dimethyl ether solution (10mL) to bromobenzylcyanide (500mg, 2.55mmol) under nitrogen protection Middle addition N methyl piperazine (310mg, 3.06mmol), 2- (di-t-butyl phosphine) biphenyl (115mg, 0.4mmol), palladium acetate (30mg, 3.82mmol), potassium carbonate (530mg, 3.82mmol), reaction system stir 20 hours in 85 DEG C.Reaction system adds water Dilution, methylene chloride extraction, organic phase separate after being concentrated under reduced pressure through rapid column chromatography (petrol ether/ethyl acetate=55/45) To 2- (4- (4- methylpiperazine-1-yl) phenyl) acetonitrile, (50mg, yield: 9%) being yellow solid.m/z:[M+H]+216.2.
Step 2: to the methanol solution of 2- (4- (4- methylpiperazine-1-yl) phenyl) acetonitrile (50mg, 0.23mmol) Raney's nickel (20mg) is added in (5.0mL), reaction system is stirred at room temperature 16 hours in hydrogen.Reaction system filtering, filtrate subtract It is yellow solid that pressure, which is concentrated to get 2- (4- (4- methylpiperazine-1-yl) phenyl) ethamine (2A, 43mg, yield 84%),.m/z:[M+ H]+220.2.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 2A and obtains compound 14 For grey black solid.m/z:[M+H]+462.2,1H NMR(400MHz,CDCl3):δ9.58(s,0.5H),9.51(s,0.5H), 9.18-9.16 (t, J=4.7Hz, 1H), 8.12 (d, J=5.2Hz, 0.5H), 8.04 (d, J=5.2Hz, 0.5H), 7.62- 7.52 (m, 1H), 7.14-7.12 (d, J=8.4Hz, 2H), 6.89-6.87 (d, J=8.5Hz, 2H), 3.74-3.69 (dd, J= 13.8,6.8Hz, 2H), 3.29-3.20 (m, 4H), 2.91-2.88 (t, J=7.2Hz, 2H), 2.72-2.62 (s, 4H), 2.42 (s,3H).
Embodiment 15:N- ((6- (4- methylpiperazine-1-yl) pyridin-3-yl) methyl) -4,9- dioxo -4,9- dihydro thiophene The synthesis of azoles simultaneously [5,4-g] isoquinolin -2- formamide (compound 15)
The synthesis of intermediate 3A:
Step 1: molten to the n,N-Dimethylformamide of the chloro- nicotinonitrile of 6- (200mg, 1.45mmol) under nitrogen protection N methyl piperazine (150mg, 1.45mmol), sodium carbonate (310mg, 2.9mmol) are added in liquid (10mL), reaction system is in 90 DEG C Stirring 5 hours.Reaction system is diluted with water, and ethyl acetate extraction, organic phase is concentrated under reduced pressure to give 6- (4- methylpiperazine-1-yl) (250mg, yield: 85%) being yellow solid to nicotinic acid nitrile.m/z:[M+H]+203.2.
Step 2: obtaining (6- (4- methylpiperazine-1-yl) pyridin-3-yl) methylamine by the synthetic method of intermediate 2A step 2 (3A) is yellow solid.m/z:[M+H]+207.2.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 3A and obtains compound 15 For grey black solid.m/z:[M+H]+449.2,1H NMR(400MHz,CDCl3):δ9.57(s,0.7H),9.51(s,0.3H), 9.17 (dd, J=5.2,3.2Hz, 1H), 8.19 (s, 1H), 8.12 (d, J=5.2Hz, 0.3H), 8.04 (d, J=5.2Hz, 0.7H), 7.78-7.71 (m, 1H), 7.54 (dd, J=8.4,2.4Hz, 1H), 6.66 (d, J=8.8Hz, 1H), 4.55 (d, J= 6.0Hz,2H),3.86–3.68(m,4H),2.86–2.70(m,4H),2.53(s,3H).
Embodiment 16:N- ((5- (4- methylpiperazine-1-yl) pyridine -2- base) methyl) -4,9- dioxo -4,9- dihydro thiophene The synthesis of azoles simultaneously [5,4-g] isoquinolin -2- formamide (compound 16)
The synthesis of intermediate 4A:
Step 1: under nitrogen protection, to the glycol dimethyl ether of 2- cyano -5- chloropyridine (200mg, 1.09mmol) N methyl piperazine (122mg, 1.2mmol), 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl (X- are added in (10mL) solution Phos, 53mg, 0.11mmol), tris(dibenzylideneacetone) dipalladium (Pd2(dba)3, 45mg, 0.05mmol), potassium phosphate (583mg, 2.73mmol), reaction system stir 20 hours in 100 DEG C.Reaction system is diluted with water, ethyl acetate extraction, organic 2- cyano -5- (4- methyl piperazine -1- is obtained through rapid column chromatography (petrol ether/ethyl acetate=3/2) purifying after being mutually concentrated under reduced pressure Base) (190mg, yield: 86%) being yellow solid to pyridine.m/z:[M+H]+203.2.
Step 2: obtaining (5- (4- methylpiperazine-1-yl) pyridine -2- base) methylamine by the synthetic method of intermediate 2A step 2 (4A) is yellow solid.m/z:[M+H]+207.2.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 4A and obtains compound 16 For grey black solid.m/z:[M+H]+449.2,1H NMR(400MHz,CDCl3):δ9.52(s,0.6H),9.45(s,0.4H), 9.17 (t, J=4.7Hz, 1H), 8.31-8.25 (m, 1H), 8.24-8.21 (m, 1H), 8.06 (d, J=4.9Hz, 0.4H), 7.97 (d, J=4.9Hz, 0.6H), 7.18-7.12 (m, 2H), 4.66-4.65 (d, J=5.5Hz, 2H), 3.40-3.29 (m, 4H),2.88–2.72(m,4H),2.49(s,3H).
Embodiment 17:N- (4- (4- cyclopropylpiperazin -1- base) benzyl) -4,9- dioxo -4,9- thiazoline simultaneously [5,4- G] isoquinolin -2- formamide (compound 17) synthesis
The synthesis of compound 5A:
Step 1:, will be to Brominal (5g, 27.5mmol), N-Boc piperazine (7.6g, 41.2mmol), Pd under nitrogen protection2 (dba)3(50mg, 0.05mmol), R- (+)-bis- diphenyl phosphines of 1,1'- dinaphthalene -2,2'- (BINAP, 103mg, 0.16mmol) and uncle Sodium butoxide (3.96g, 41.2mmol) is added in toluene (50mL), and reaction system stirs 16 hours at reflux.Then will Reaction solution saturated common salt water washing, separation organic phase, concentration, residue silica gel column chromatography (methylene chloride/methanol=95/ 5) purifying obtain N-Boc-4- (4- cyano-phenyl) piperazine (3.0g, yield: 38%) be white solid.
Step 2: under nitrogen protection, hydrochloric acid 1 is added in N-Boc-4- (4- cyano-phenyl) piperazine (1.0g, 3.48mmol), In 4- dioxane solution (20mL, 2M), reaction system is stirred at room temperature 16 hours.Then reaction solution is concentrated to dryness to obtain (780mg, yield: 86%) being white solid to 4- (4- cyano-phenyl) piperazine dihydrochloride.
Step 3: under nitrogen protection, by 4- (4- cyano-phenyl) piperazine dihydrochloride (280mg, 1.25mmol), cyclopropyl Boric acid (215mg, 2.50mmol), copper acetate (227mg, 1.25mmol), 2,2- bipyridyls (195mg, 1.25mmol) and carbonic acid Sodium (265mg, 2.50mmol) is added in 1,2- dichloroethanes (20mL), and reaction system stirs 16 hours at reflux.So Afterwards by reaction solution saturated common salt water washing, organic phase, concentration, residue silica gel column chromatography (petrol ether/ethyl acetate are separated =2/1) purifying obtain 4- (4- cyclopropylpiperazin -1- base) cyanophenyl (180mg, yield: 63%) be white solid.
Step 4: obtaining (4- (4- cyclopropylpiperazin -1- base) phenyl) methylamine by the synthetic method of intermediate 2A step 2 (5A, purification condition: methylene chloride/methanol=10/1) is white solid.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 5A and obtains compound 17 For grey black solid.m/z:[M+H]+474.2,1H NMR(400MHz,CD3OD):δ9.43(s,0.5H),9.38(s,0.5H), 9.10-9.12 (m, 1H), 8.09-8.15 (m, 1H), 7.31 (d, J=8.4Hz, 2H), 6.98 (d, J=8.8Hz, 2H), 4.52 (s,2H),3.05-3.25(m,8H),1.58-1.62(m,1H),1.25-1.26(m,2H),0.88-0.91(m,2H).
Embodiment 18:4- (4- ((4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- formamido) first Base) phenyl) piperazine -1- methyl formate (compound 18) synthesis
The synthesis of intermediate 6A:
Step 1: under nitrogen protection, by 4- (4- cyano-phenyl) piperazine dihydrochloride (300mg, 1.28mmol), chloro-carbonic acid Methyl esters (126mg, 1.28mmol) and triethylamine (650mg, 6.42mmol) are added in methylene chloride (10mL), and reaction system exists It stirs 1 hour at room temperature.Then by reaction solution saturated common salt water washing, organic phase, concentration, residue silica gel column layer are separated Analysis (methylene chloride/methanol=95/5) purifying obtains 4- (4- cyano-phenyl) piperazine -1- methyl formate (240mg, yield: 73%) For white solid.
Step 2: obtaining 4- (4- (amino methyl) phenyl) piperazine -1- formic acid first by the synthetic method of intermediate 2A step 2 Ester (6A, purification condition: methylene chloride/methanol=10/1) is white solid.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 6A and obtains compound 18 For grey black solid.m/z:[M+H]+492.2,1H NMR(400MHz,CDCl3):δ9.52(s,0.5H),9.45(s,0.5H), 9.10-9.12 (m, 1H), 7.98-8.06 (m, 1H), 7.71-7.74 (m, 1H), 7.26-7.34 (m, 3H), 4.57 (d, J= 6.0Hz,2H),3.73-3.83(m,4H),3.68(s,3H),3.15-3.19(m,4H).
Embodiment 19:N- (1- (4- (4- methylpiperazine-1-yl) phenyl) cyclopropyl) -4,9- dioxo -4,9- dihydro thiophene The synthesis of azoles simultaneously [5,4-g] isoquinolin -2- formamide (compound 19)
The synthesis of intermediate 7A:
Under nitrogen protection, by 4- (4- methylpiperazine-1-yl) cyanophenyl (500mg, 2.48mmol) and tetraisopropyl titanate (1.25mL, 4.22mmol) is added in ether (10mL), and ethylmagnesium bromide is added dropwise to reaction system under the conditions of -78 DEG C (diethyl ether solution of 1.82mL, 5.46mmol, 3M).The reaction system is stirred at room temperature 1.5 hours.Then by boron trifluoride second Ether (0.94mL, 7.45mmol) instills in reaction system, which is stirred at room temperature 1 hour.Reaction solution is quenched with water, Ethyl acetate extracts reaction solution, separates organic phase, is concentrated, and residue is pure with silica gel column chromatography (methylene chloride/methanol=95/5) Change obtains 1- (4- (4- methylpiperazine-1-yl) phenyl) cyclopropylamine, and (7A, 180mg, yield: 31%) being yellow oil.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 7A and obtains compound 19 (prep-HPLC:TFA system) is grey black solid.m/z:[M+H]+474.2,1H NMR(400MHz,CDCl3):δ9.53(s, 0.7H), 9.45 (s, 0.3H), 9.10-9.13 (m, 1H), 7.97-8.09 (m, 2H), 7.32 (d, J=8.4Hz, 2H), 6.83 (d, J=8.4Hz, 2H), 3.45-3.58 (m, 6H), 2.94-2.99 (m, 2H), 2.77 (d, J=4.0Hz, 3H), 1.31-1.32 (m,2H),1.26-1.28(m,2H).
Embodiment 20:N- ((5- (4- methylpiperazine-1-yl) thiophene -2- base) methyl) -4,9- dioxo -4,9- dihydro thiophene The synthesis of azoles simultaneously [5,4-g] isoquinolin -2- formamide (compound 20)
The synthesis of intermediate 8A:
Step 1: under nitrogen protection, by 2- cyano -5- bromothiophene (1g, 5.31mmol), N methyl piperazine (640mg, 6.38mmol), palladium acetate (116mg, 0.53mmol), BINAP (330mg, 0.53mmol) and cesium carbonate (2.6g, 8mmol) add Enter in toluene (10mL), reaction system stirs 16 hours at reflux.Then by reaction solution saturated common salt water washing, divide From organic phase, concentration, residue silica gel column chromatography (methylene chloride/methanol=10/1) purifying obtains 2- cyano -5- (4- methyl Piperazine -1- base) (440mg, yield: 40%) being brown solid to thiophene.
Step 2: under hydrogen atmosphere, by 2- cyano -5- (4- methylpiperazine-1-yl) thiophene (440mg, 2.12mmol), ammonia Methanol solution (2ml) and Raney's nickel (20mg) are added in methanol (10mL), and reaction system stirs 2 hours at 40 DEG C.Then will Reaction solution filtering and concentrating, residue silica gel column chromatography (methylene chloride/methanol=10/1) purifying obtain (5- (4- methyl piperazine- 1- yl) thiophene -2- base) (8A, 140mg, yield: 31%) being yellow oil to methylamine.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 8A and obtains compound 20 (prep-HPLC:TFA system) is grey black solid.m/z:[M+H]+454.2,1H NMR(400MHz,CDCl3):δ9.51(s, 0.6H), 9.45 (s, 0.4H), 9.10-9.12 (m, 1H), 7.97-8.06 (m, 1H), 7.69-7.72 (m, 1H), 6.68 (d, J= 3.6Hz, 1H), 5.93 (d, J=3.6Hz, 1H), 4.63 (d, J=6.0Hz, 2H), 3.24 (s, 4H), 2.72 (s, 4H), 2.43 (s,3H).
Embodiment 21:4,9- dioxo-N- (4- (piperazine -1- base) benzyl) -4,9- thiazoline simultaneously [5,4-g] isoquinoline The synthesis of quinoline -2- formamide (compound 21)
The synthesis of intermediate 9A:
Under hydrogen atmosphere, by N-Boc-4- (4- cyano-phenyl) piperazine (1g, 3.48mmol), ammonium hydroxide (1mL) and Raney's nickel (50mg) is added in methanol (10mL), and reaction system is stirred at room temperature 16 hours.Filtering, filtrate are concentrated to dryness to obtain 1-N- (9A, 1g, yield: 99%) being white solid to Boc-4- (4- (amino methyl) phenyl) piperazine.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 9A and obtains compound 21- 1 is grey black solid.
The reaction in hydrochloric acid Isosorbide-5-Nitrae-dioxane solution in (3mL, 7M) is added in compound 21-1 (20mg, 0.04mmol) System is stirred at room temperature 1 hour.Reaction solution is concentrated to dryness, methylene chloride (2mL) and triethylamine are added into residue (19mg, 0.2mmol), obtained mixture are stirred at room temperature 10 minutes, are concentrated under reduced pressure.Residue passes through prep-HPLC (NH4HCO3System) purifying obtain compound 21 (4.5mg, yield: 28%) be gray solid.m/z:[M+H]+434.2,1H NMR(400MHz,CDCl3):δ9.51(s,0.5H),9.45(s,0.5H),9.09-9.11(m,1H),7.97-8.05(m,1H), 7.67-7.70 (m, 1H), 7.20-7.24 (m, 2H), 6.86 (d, J=8.0Hz, 2H), 4.53 (d, J=6.0Hz, 2H), 3.74- 3.82(m,1H),3.14-3.25(m,7H).
Embodiment 22:N- (4- (4- Acetylpiperazine -1- base) benzyl) -4,9- dioxo -4,9- thiazoline simultaneously [5,4- G] isoquinolin -2- formamide (compound 22) synthesis
Under nitrogen protection, the methylene chloride of compound 21 (20mg, 0.037mmol) and triethylamine (37mg, 0.37mmol) Chloroacetic chloride (4.3mg, 0.055mmol) is added in (5mL) solution, which is stirred at room temperature 1 hour.It then will reaction Liquid is concentrated to dryness, and residue passes through prep-HPLC (NH4HCO3System) purifying obtains compound 22 (yield: 4%) 0.68mg is Red solid.m/z:[M+H]+476.0,1H NMR(400MHz,CDCl3):δ9.51(s,0.5H),9.45(s,0.5H),9.10- 9.11(m,1H),7.97-8.05(m,1H),7.67-7.71(m,1H),7.22-7.24(m,2H),6.89-6.91(m,2H), 4.54 (d, J=6.0Hz, 2H), 3.58-3.74 (m, 4H), 3.11-3.14 (m, 4H), 2.08 (s, 3H)
- 4,9- dioxo -4,9- thiazoline is simultaneously by embodiment 23:N- (the fluoro- 4- of 2- (4- methylpiperazine-1-yl) benzyl) The synthesis of [5,4-g] isoquinolin -2- formamide (compound 23)
The synthesis of intermediate 10A:
Step 1: under condition of ice bath, to the bromo- 2- fluorin benzyl amine (1.0g, 4.9mmol) of 4- and triethylamine (743mg, 7.4mmol) Methylene chloride (30mL) solution in be added di-tert-butyl dicarbonate (1.1g, 5.1mmol).It is stirred at room temperature 3 days, reaction solution is straight Connect concentration after with silica gel column chromatography (petrol ether/ethyl acetate=10/1) purify obtain the bromo- 2- fluorin benzyl amine of N-Boc-4- (1.4g, Yield: 94%) being colourless oil liquid.
Step 2: by palladium acetate (18.5mg, 0.082mmol) be added to the bromo- 2- fluorin benzyl amine of N-Boc-4- (500mg, 1.64mmol), N methyl piperazine (164mg, 1.64mmol), 2- dicyclohexyl phosphorus -2', 6'- diisopropoxy -1,1'- biphenyl In Isosorbide-5-Nitrae-dioxane (15mL) of (RuPhos, 76.8mg, 0.164mmol) and cesium carbonate (804mg, 2.47mmol), nitrogen Displacement 3 times is warming up to 110 DEG C and stirs 2 hours.It is cooled to room temperature and filters, is concentrated, residue rapid column chromatography (acetic acid second Ester) purifying obtains N-Boc- (the fluoro- 4- of 2- (4- methylpiperazine-1-yl) phenyl) methylamine (460mg, yield: 87%) solid for white Body.m/z:[M+H]+324.2.
Step 3: trifluoroacetic acid (2mL) is added drop-wise to N-Boc- (the fluoro- 4- of 2- (4- methylpiperazine-1-yl) phenyl) methylamine In methylene chloride (20mL) solution of (460mg, 1.42mmol), reaction system is stirred at room temperature 2 hours.Then reaction solution is used 10% aqueous sodium carbonate is neutralized to pH=7, separates water phase, organic phase saturated common salt water washing, layering, and organic phase is with anhydrous Sodium sulphate is dry, filter, be concentrated to get (the fluoro- 4- of 2- (4- methylpiperazine-1-yl) phenyl) methylamine (10A, 180mg, yield: It 57%) is oily liquids.m/z:[M+H]+224.2.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 10A and obtains compound 23 For brown solid.m/z:[M+H]+466.2,1H NMR(400MHz,CDCl3):δ9.60(s,0.7H),9.53(s,0.3H), 9.19 (dd, J=3.6,4.8Hz, 1H), 8.14 (d, J=4.8Hz, 0.3H), 8.07 (d, J=5.2Hz, 0.7H), 7.76- 7.78 (m, 1H), 7.32 (d, J=8.8Hz, 1H), 6.62-6.69 (m, 2H), 4.65 (d, J=6.0Hz, 2H), 3.40 (s, 4H),2.83(s,4H),2.54(s,3H).
- 4,9- dioxo -4,9- thiazoline is simultaneously by embodiment 24:N- (2- methyl -4- (4- methylpiperazine-1-yl) benzyl) The synthesis of [5,4-g] isoquinolin -2- formamide (compound 24)
The synthesis of intermediate 11A:
Step 1: palladium acetate (57.3mg, 0.255mmol) is added to the bromo- 2- methyl cyanophenyl (1g, 5.1mmol) of 4-, N- The Isosorbide-5-Nitrae-two of methyl piperazine (510mg, 5.1mmol), BINAP (238mg, 0.51mmol) and cesium carbonate (2.5g, 7.65mmol) In six ring of oxygen (20mL), nitrogen is replaced 3 times, is warming up to 110 DEG C and is stirred two hours.Reaction system is cooled to room temperature and filters, Solution concentration, residue rapid column chromatography (ethyl acetate) purifying obtain 2- methyl -4- (4- methylpiperazine-1-yl) cyanophenyl (1.17g, yield: 87%) being brown solid.
Step 2: under condition of ice bath, it is fluoro- that borine (tetrahydrofuran solution of 16.3mL, 16.3mmol, 1M) being added drop-wise to 2- In the anhydrous tetrahydro furan of 4- (4- methylpiperazine-1-yl) cyanophenyl (1.17g, 5.43mmol) (20mL), continue to stir in this temperature It mixes 1 hour, then stays overnight reaction system return stirring.Reaction solution is cooled to room temperature, with being directly concentrated after methanol quenching reaction, Residue silica gel column chromatography (methylene chloride/methanol=20/1) purifying obtains (2- methyl -4- (4- methylpiperazine-1-yl) benzene Base) (11A, 600mg, yield: 50%) being brown solid to methylamine.m/z:[M+H]+220.2.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 11A and obtains compound 24 For brown solid.m/z:[M+H]+462.2,1H NMR(400MHz,CDCl3):δ9.58(s,0.7H),9.53(s,0.3H), 9.18 (d, J=4.8Hz, 1H), 8.12 (d, J=4.8Hz, 0.3H), 8.07 (d, J=4.8Hz, 0.7H), 7.61-7.64 (m, 1H), 7.23 (d, J=8.0Hz, 1H), 6.76 (br.s, 2H), 4.61-4.62 (d, J=5.6Hz, 2H), 3.59 (s, 2H), 3.20-3.30(m,4H),2.94(s,2H),2.73(s,3H),2.36(s,3H).
Embodiment 25:4,9- dioxo-N- (pyridin-4-yl methyl) -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- The synthesis of formamide (compound 25)
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into pyridin-4-yl methylamine hydrochloride and is obtained It is grey black solid to compound 25.m/z:[M+H]+351.0,1H NMR(400MHz,CD3OD):δ9.47(s,1H),9.42 (br.s, 1H), 8.52 (d, J=8.0Hz, 2H), 8.19 (br.s, 1H), 7.48 (d, J=8.0Hz, 2H), 4.70 (s, 2H)
Embodiment 26:4,9- dioxo-N- (pyridin-3-yl methyl) -4,9- thiazoline simultaneously [5,4-g] isoquinolin -2- The synthesis of formamide (compound 26)
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into pyridin-3-yl methylamine and obtains chemical combination Object 26 is yellow solid.m/z:[M+H]+351.0,1H NMR(400MHz,DMSO-d6):δ9.45(s,0.45H),9.40(s, 0.55H), 9.25 (t, J=5.2Hz, 1H), 8.91 (s, 1H), 8.81 (d, J=5.2Hz, 1H), 8.42 (d, J=7.6Hz, 1H), 8.15 (d, J=4.8Hz, 0.55H), 8.10 (d, J=5.2Hz, 0.45H), 7.95-7.91 (m, 1H), 4.74 (s, 2H)
- 4,9- dioxo -4,9- thiazoline is simultaneously by embodiment 27:N- (3- methyl -4- (4- methylpiperazine-1-yl) benzyl) The synthesis of [5,4-g] isoquinolin -2- formamide (compound 27)
The synthesis of intermediate 12A: it using the synthetic method of intermediate 8A, reacts to obtain (3- first with the bromo- 3- methyl cyanophenyl of 4- Base -4- (4- methylpiperazine-1-yl) phenyl) methylamine (12A) be yellow oil.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 12A and obtains compound 27 For grey black solid.m/z:[M+H]+462.2,1H NMR(400MHz,DMSO-d6):δ9.93(s,1H),9.37(br.s,1H), 8.39 (br.s, 1H), 7.15-7.13 (m, 3H), 6.98 (d, J=8.0Hz, 1H), 4.41 (s, 2H), 2.80 (m, 5H), 2.22- 2.19(m,9H).
- 4,9- dioxo -4,9- thiazoline is simultaneously by embodiment 28:N- (the fluoro- 4- of 3- (4- methylpiperazine-1-yl) benzyl) The synthesis of [5,4-g] isoquinolin -2- formamide (compound 28)
The synthesis of intermediate 13A: using the synthetic method of intermediate 8A, react to obtain that (3- is fluoro- with the bromo- 3- fluorobenzonitrile of 4- 4- (4- methylpiperazine-1-yl) phenyl) methylamine (13A) be yellow oil.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 13A and obtains compound 28 For grey black solid.m/z:[M+H]+466.2,1H NMR(400MHz,CD3OD):δ10.78(s,1H),10.16(s,1H), 8.89 (s, 1H), 7.95-7.90 (m, 2H), 7.80 (t, J=8.0Hz, 1H), 5.24 (d, J=4.0Hz, 2H), 3.79 (br.s, 4H),3.03(s,3H),2.89(br.s,4H).
- 4,9- dioxo -4,9- thiazoline is simultaneously by embodiment 29:N- (4- (4- methyl 3- oxypiperazin -1- base) benzyl) The synthesis of [5,4-g] isoquinolin -2- formamide (compound 29)
The synthesis of intermediate 14A: anti-with 4- Brominal and 1- methyl piperazine -2- ketone using the synthetic method of intermediate 8A Should obtain 4- (4- (amino methyl) phenyl) -1- methyl piperazine -2- ketone (14A) is yellow oil.
Using the synthetic method of compound 13, the intermediate 1A in step 3 is replaced with into intermediate 14A and obtains compound 29 For grey black solid.m/z:[M+H]+462.2,1H NMR(400MHz,CD3OD):δ9.44(s,1H),8.15(br.s,1H), 7.46 (d, J=8.0Hz, 1H), 7.34 (d, J=8.0Hz, 2H), 6.96 (d, J=8.0Hz, 2H), 4.54 (s, 2H), 3.51 (s, 4H), 3.01 (s, 3H), 2.20 (t, J=8.0Hz, 1H), 2.03 (br.s, 1H)
- 4,9- dioxo -4,9- thiazoline is simultaneously [5,4-g] by embodiment 30:N- (4- (4- methylpiperazine-1-yl) benzyl) The synthesis of quinoline-2-formamide (compound 30)
Step 1: at room temperature, sodium chlorate is added into concentrated hydrochloric acid (60mL) solution of 5- aminoquinoline (10g, 0.07mol) The aqueous solution (3mL) of (14.7g, 0.14mol), reaction system stir 1 hour at 77 DEG C.Then reaction system is cooled to room Temperature adds water (200mL) to dilute, and methylene chloride (200mL × 3) extraction, organic phase anhydrous sodium sulfate is dry, and it is molten that removing is concentrated under reduced pressure Agent, residue obtain 6,7- dichloroquinoline -5,8- diketone through rapid column chromatography (petrol ether/ethyl acetate=4/1) purifying (5.5g, yield: 35%) being yellow solid.
Step 2: at room temperature, to Isosorbide-5-Nitrae-dioxane of 6,7- dichloroquinoline -5,8- diketone (2.5g, 11.0mmol) Be added in (20mL) and ethyl alcohol (20mL) mixed solution sodium bicarbonate (4.2g, 50.4mmol) and thio-oxamide ethyl ester (1.7g, 12.7mmol), reaction system stirs 3 hours at 90 DEG C.Reaction system is cooled to room temperature, is concentrated under reduced pressure and removes solvent, it is residual Stay object that ethyl acetate (150mL) is added to dilute, organic phase washed with water (50mL) and saturated salt solution (50mL) washing separate organic Xiang Bingyong anhydrous sodium sulfate is dry, is concentrated under reduced pressure and removes solvent, residue is through rapid column chromatography (petrol ether/ethyl acetate=1/ 1) purifying obtain 4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] quinaldic acid's ethyl ester (200mg, yield: 6%) for Huang Color solid.
Step 3: by 4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] quinaldic acid's ethyl ester (200mg, 0.69mmol) and the tetrahydrofuran (2mL) of a hydronium(ion) lithia (87mg, 2.08mmol), water (1mL) and ethyl alcohol (2mL) Mixed solution is stirred at room temperature overnight, and is then adjusted pH=6~7 with dilute hydrochloric acid (1N), is concentrated under reduced pressure to give 4,9- dioxo- Simultaneously (180mg, yield: 100%) being gray solid to [5,4-g] quinoline -2- formic acid to 4,9- thiazolines.
Step 4: to the N of 4,9- dioxo -4,9- thiazoline simultaneously [5,4-g] quinoline -2- formic acid (27mg, 0.1mmol), DIPEA (27mg, 0.21mmol), HATU (59mg, 0.15mmol), 4- (4- are added in dinethylformamide (2.0mL) solution Methylpiperazine-1-yl) benzylamine (21mg, 0.1mmol), 40 DEG C of reaction system are stirred 2 hours.Reaction system is diluted with water, acetic acid Ethyl ester extraction, through prep-HPLC (NH after organic phase reduced pressure4HCO3System) purifying obtain compound 30 (2.25mg, yield: It 5%) is grey black solid.m/z:[M+H]+448.1,1H NMR(400MHz,CDCl3): δ 9.06 (d, J=3.6Hz, 1H), 8.60 (d, J=7.6Hz, 1H), 7.73-7.63 (m, 3H), 6.93-6.83 (m, 3H), 4.51 (d, J=6.0Hz, 2H), 3.24- 3.15(m,4H),2.52–2.47(m,4H),2.29(s,3H).
Biological test embodiment: the measurement of STAT3 bioactivity
Embodiment 1: intracellular STAT3 phosphorylation assay
Hela cell (being purchased from ATCC) is inoculated in 96 orifice plates with 25000 cells/wells, inhales abandon after its is adherent overnight Supernatant adds the fresh culture medium Nature enemy without serum of 50uL 4 hours.The concentration gradient dilution of 3 times of the hole 25uL/ is then added Untested compound, the wherein final concentration of 10uM of the highest of compound, minimum final concentration of 0.0015uM.Cell is put back into culture It is incubated for 60 minutes in case, is then added IFN-α (R&D system, article No.: 11100-1) solution of the 4 times of concentration in the hole 25uL/, 37 DEG C continue to be incubated for 30 minutes.It finally inhales and abandons the supernatant addition prepared lysate in the hole 75uL/, be placed in shaker at room temperature oscillation 30 Minute.Every hole is drawn 16uL and is added in 384 orifice plates, and the hole 4uL/ prepared detection antibody-solutions (Cisbio, article No. is added 62AT3PEG), sealing plate ambient temperature overnight.Fluorescent value (665nm and 620nm) is read using TECAN M1000Pro, and is calculated 665nm/620nm ratio is positively correlated with Intracellular phosphorylation STAT3 content.Using Graphpad Prism Software on Drawing agent Response curve is measured, and analyzes the IC50 value of untested compound.
The intracellular STAT3 phosphorylation test result of quinone derivatives of the present invention, IC50 value are as shown in the table:
Embodiment 2: cancer cell multiplication inhibits test
By FADU cell (being purchased from Nanjing section one hundred) with 5000/hole be inoculated in 96 saturating black holes plates of bottom (Corning, article No.: 4520) in, overnight after its is adherent, 10 times of diluted untested compounds of concentration gradient of 10uL are added in every hole, wherein compound Highest final concentration of 10uM, minimum final concentration of 0.0015uM.Cell is put back to and is incubated for 72h in incubator, then every hole is added The hole 100uL/ configured CellTiter-Glo (Promega, article No. G7573) working solution, room temperature is protected from light incubation after mixing 10min.Luminous value is read using TECAN M1000Pro.Using Graphpad Prism Software on Drawing dose response curve, and Analyze the IC50 value of untested compound.
Quinone derivatives cancer cell multiplication inhibitory activity test result of the present invention, IC50 value are as shown in the table:
Embodiment 3: the inhibition test of cancer cell balling-up ability
Use Cancer stem cell culture medium (DMEM/F12+2%B27supplement+5ug/ml insulin+ 20ng/ml EGF+10ng/ml bFGF+1%P/S) FADU cell (being purchased from Nanjing section one hundred) is configured to cell suspension, it is inoculated in In low adsorption plate, it is cultivated 3-6 days in cell incubator, to form the microballoon of partial size > 50 cell.
Microballoon is digested using pancreatin, and is inoculated in 1000 cells/wells by Poly-HEMA (Sigma, article No. P3932- 10G) in coated 96 orifice plate (Grenier, article No. 655094).The test dense liquid storage of compound, compound starting are prepared with DMSO Concentration is 10uM, and gradient 3 is diluted to 9 concentration points again.Untested compound is added in each instrument connection into 96 porocyte plates, it is negative Final concentration of 0.1% DMSO is added in control group hole, 10uM positive drug is added in positive controls hole, is all provided with multiple holes control. Cell plates are put into cell incubator and are handled 4 days.Later, configured CellTiter-Glo working solution is added into every hole (Promega, article No. G7573) slightly shakes after 30s room temperature avoid light place 20 minutes, uses TECAN M1000 readings.Chemical combination Object inhibiting rate percentage is calculated by following equation:
%Inhibition=(1- (instrument connection value-Positive control wells value)/(negative control hole value-Positive control wells Value)) * 100.
By the inhibiting rate percentage handled under each test concentrations of compound in software with log concentration-inhibiting rate percentage Than carrying out nonlinear regression analysis, the IC50 value and suppression curve of compound are obtained.
The inhibitory activity test result of quinone derivatives cancer cell balling-up ability of the present invention, IC50 value such as following table institute Show:
Compound number IC50(nM) Compound number IC50(nM)
1 51.5 19 6.3
4 13.1 23 10.5
8 8.6 29 23.1
15 5.2 30 92.5
16 8.2 Ref.A 137
In biological Examples 1-3, Ref.A are as follows: 2- acetyl furan simultaneously -1,4-naphthoquinone (CAS No.:83280-65-3), Ref.B are as follows: 2- (1- fluoro ethyl) thieno [2,3-g] isoquinolin -4,9- diketone (CN106459071A, embodiment 30).

Claims (10)

1. a kind of compound as shown in formula (I), its stereoisomer or pharmaceutically acceptable salt；
Wherein, A ring is
X is-C (O)-or-C (O) NR4-；
Y is connecting key or-C (R5R5a)n-；The integer that n is 1~6；
Z is O or S；
R is phenyl or 5-10 unit's heteroaryl, and the R is unsubstituted, alternatively, selectivity is by one or more RAGroup replaces in office Meaning position；RAFor-CN ,-ORa、-C(O)N(Rb)2、-OC(O)Ra、-OC(O)ORa、-OC(O)N(Rb)2、-C(O)ORa、-C(O) Ra、-N(Rb)2、-NRaC(O)Ra、-NRaC(O)ORa、-NRaC(O)N(Rb)2、-NRaS(O)2Ra、-NRaS(O)2N(Ra)2、-S (O)0-2Rb、-S(O)2N(Rb)2, halogen, C1-6Alkyl, C3-8Naphthenic base or 3-10 membered heterocycloalkyl；RAIn, the C1-6Alkyl, C3-8Naphthenic base or 3-10 membered heterocycloalkyl are unsubstituted, or selectivity is by 1~3 RBGroup replaces at an arbitrary position；RBFor- OH、-NH2、-CN、-C(O)Ra、-C(O)ORa、-S(O)2Ra、-S(O)2N(Rb)2, oxo base, halogen, C1-6Alkyl, C1-6Alkoxy Or C1-6Alkylamino；RBIn, the C1-6Alkyl, C1-6Alkoxy or C1-6Alkylamino is unsubstituted, or further by 1~3 Selected from-OH ,-NH2, halogen, C1-4Alkoxy and C1-4The substituent group of alkylamino replaces at an arbitrary position；
R1、R2And R3Separately it is selected from Ra1、-CN、-N(Rb1)2、-NHC(O)Rb1、-NHS(O)2Rb1、-ORa1、-OC(O) Rb1、-S(O)0-2Rb1、-C(O)Rb1、-C(O)ORa1、-C(O)N(Rb1)2Or halogen；
R4For H or C1-6Alkyl；
R5And R5aIt is separately H or C1-6Alkyl；Alternatively, R5And R5aC is formed together with the C atom that they connect jointly3-8 Naphthenic base；
Each Ra、Ra1、Ra2And Ra3It independently is H or C1-6Alkyl；The C1-6Alkyl is unsubstituted or selectivity is by 1~3 halogen Element replaces at an arbitrary position；
Each Rb、Rb1、Rb2And Rb3It independently is H or C1-6Alkyl.
2. as described in claim 1 such as formula (I) compound represented, stereoisomer or pharmaceutically acceptable salt, It is characterized in that, the R is phenyl, pyridyl group, pyrazinyl, thienyl, thiazolyl or pyrimidine radicals；The R is unsubstituted, alternatively, Selectivity is by one or more RAGroup replaces at an arbitrary position；RAFor F, Cl, hydroxyl, amino, cyano, methyl, ethyl, isopropyl Base, methoxyl group, ethyoxyl, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, piperazinyl, morpholine base, pyrrolidinyl,
3. as described in claim 1 such as formula (I) compound represented, stereoisomer or pharmaceutically acceptable salt, It is characterized in that, R1、R2And R3Separately it is selected from H, F, Cl or methyl；
R4For H or methyl；
R5And R5aIt independently is H or methyl；Alternatively, R5And R5aC is formed together with the C atom that they connect jointly3-6Naphthenic base；
The integer that n is 1~4.
4. as described in claim 1 such as formula (I) compound represented, stereoisomer or pharmaceutically acceptable salt, It is characterized in that, Y is-CH2-、-CH2CH2-、-CH(CH3)-、-C(CH3)2Or
5. as described in claim 1 if formula (I) compound represented is following compound:
6. a kind of pharmaceutical composition comprising the active component of therapeutically effective amount and pharmaceutically acceptable auxiliary material；The work Property component includes quinone derivatives as claimed in any one of claims 1 to 5 (I), its stereoisomer or pharmaceutically acceptable Salt.
7. the compound as claimed in any one of claims 1 to 5 as shown in formula (I), its stereoisomer or pharmaceutically acceptable Salt, or as claimed in claim 6 pharmaceutical composition preparing the application in STAT3 inhibitor.
8. the compound as claimed in any one of claims 1 to 5 as shown in formula (I), its stereoisomer or pharmaceutically acceptable Salt, or as claimed in claim 6 pharmaceutical composition preparation treatment and/or alleviate by STAT3 it is horizontal it is not normal caused by it is related Application in the drug of disease.
9. application as claimed in claim 8, it is characterised in that: described to be by the horizontal not normal caused related disease of STAT3 Cancer.
10. the compound as claimed in any one of claims 1 to 5 as shown in formula (I), its stereoisomer or pharmaceutically acceptable Salt, or as claimed in claim 6 pharmaceutical composition preparation treating cancer drug in application.
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