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CN103965199B - A kind of heteroaromatic compounds, the medical composition and its use comprising it - Google Patents

A kind of heteroaromatic compounds, the medical composition and its use comprising it Download PDF

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Publication number
CN103965199B
CN103965199B CN201410041929.9A CN201410041929A CN103965199B CN 103965199 B CN103965199 B CN 103965199B CN 201410041929 A CN201410041929 A CN 201410041929A CN 103965199 B CN103965199 B CN 103965199B
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compound
alkyl
alkylidene
cycloalkyl
cancer
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CN103965199A (en
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习宁
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Guangdong HEC Pharmaceutical
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Add And Open Up Scientific Co
Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides some new heteroaromatic class compounds, and they are preparing the purposes for the medicine of suppression or regulatory protein kinase activity in biological sample.The present invention also relates to the pharmaceutical composition comprising the compounds of this invention, and uses the purposes and method of the medicine composite for curing mammal, particularly mankind's hyperproliferative disease.

Description

A kind of heteroaromatic compounds, the medical composition and its use comprising it
Invention field
The present invention relates to drug field, and in particular to a kind of heteroaromatic compounds, the composition comprising it and application thereof and Application method.Especially, compound of the present invention can be used for suppressing or reconciling protein kinase work in biological sample The compound of property, can be used to protect, process, treat or mitigate the proliferative diseases of patient.
Background of invention
Protein kinase (protein kinases) is also known as protein phosphorylation enzyme (protein phosphakinase) The enzyme of one class catalytic proteins phosphorylation reaction, the γ-phosphoric acid on adenosine triphosphate (ATP) can be transferred to protein molecule by it Amino acid residue on.Up to the present, it has been found that protein kinase there are about 300 kinds or so, intramolecular all exist one it is homologous The catalytic structure area being made up of about 270 amino acid residues.Wherein, receptor tyrosine kinase is the class in protein kinase, it PI3K, mTOR etc. are included again.
Phosphoinositide 3-kinase (PI3 kinases or PI3K), as a family of lipid kinase, in many cellular processes, Such as the survival of cell, important adjustment effect is played in breeding and differentiation.As receptor tyrosine kinase and G-protein-coupling Major influence factors in receptor downstream conduction, by producing phosphatide, PI3K is by the signal from all kinds of growth factors and the factor It is transmitted to intracellular, activation Ser-ine-threonine protein kinase AKT (also referred to as protein kinase B (PKB)) and other downstream passages.Suppression Oncogene or PTEN (homologous acid phosphatase-tensin) are most important reverse conditioning agents in PI3K signal paths (“Small-molecule inhibitors of the PI3K signaling network.”Future Med Chem.2011,3(5),549-565)。
Phosphoinositide 3-kinase (PI3K) path is to cause tumorigenic one common signal of interest Signal Transduction Pathways. The result of PI3K activation is to promote phosphatide -4, and 5- diphosphonic acid (PIP2) phosphorylation produces phosphatide -3,4,5- triphosphoric acids (PIP3). PIP3 can then terminate PI3K signal transductions by homologous acid phosphatase-tensin (PTEN) dephosphorylation.The PI3K of enrichment Such bars chain can be activated, first, promotes phosphoinositide dependent kinases 1 (PDK1) phosphorylated protein silk-threonine The thr308 of kinases AKT, so that AKT is activated, afterwards, the AKT activation mammal rapamycin target proteins of phosphorylation, further Guide the phosphorylation of other downstream molecules.
According to structure and property, PI3K can be divided three classes, wherein, I classes can be divided into two kinds of hypotypes of Ia and Ib again.II classes PI3K is class macromolecule (170-210kDa) albumen, and the catalysis region of albumen can mediate classical Five Protein Kinase C Isoforms Calcium/fat bonding.Group III PI3K, is representative with the Yeast protein by VSP34 gene codes, only phosphorylation PtdIns, promotes to produce PtdIns(3)P；They are regarded as attemperator (" the Targeting PI3K signaling in cancer of vesicle transport: opportunities,challenges and limitations.”Nature Review Cancer,2009,9,550)。
Ia types PI3K (PI3K α, PI3K β, PI3K γ and PI3K δ) be by catalytic subunit p110 (be respectively p110 α, P110 β, p110 γ and p110 δ) and regulator subunit p85 is (for example：P85 α, p85 β, p55 δ, p55 α and p50 α) composition dimerization Body protein.P110 subunits with catalysis activity use ATP phosphorylations Ptdlns, PtdIns4P and PtdIns (4,5) P2. The discovery of PI3K catalytic subunits α-subtype gene (PIK3CA), it was confirmed that important function of the Ia types PI3K in cancer.The base Reason p110 α are encoded, and are usually undergone mutation in human tumor and expanded, for example oophoroma (Campbell et al, Cancer Res 2004,64,7678-7681；Levine et al.,Clin Cancer Res 2005,11,2875-2878；Wang et al.,Hum Mutat 2005,25,322；Lee et al., Gynecol Oncol 2005,97,26-34), cervix cancer, breast Cancer (Bachman, et al.Cancer Biol Ther 2004,3,772-775；Levine,et al.,supra；Li et al.,Breast Cancer Res Treat 2006,96,91-95；Saal et al.,Cancer Res 2005,65, 2554-2559；Samuels and Velculescu, Cell Cycle 2004,3,1221-1224), colorectal cancer (Samuels,et al.Science 2004,304,554；Velho et al.Eur J Cancer 2005,41,1649- 1654), carcinoma of endometrium (Oda et al.Cancer Res.2005,65,10669-10673), stomach cancer (Byun et al., M J Cancer 2003,104,318-327；Li et al.,supra；Velho et al.,supra；Lee et al., Oncogene 2005,24,1477-1480), liver cancer (Lee et al., id), cellule and non-small cell lung cancer (Tang et al.,Lung Cancer 2006,Jl,181-191；Massion et al.,Am J Respir Crit Care Meaf 2004,170,1088-1094), thyroid cancer (Wu et al, J Clin Endocrinol Met α b 2005,90,4688- 4693), acute myelocytic leukemia (AML) (Sujobert et al., Blood 1997,106,1063-1066), chronic marrow Chronic myeloid leukemia (CML) (Hickey and Cotter J Biol Chem 2006,281,2441-2450), and colloid is female Cytoma (Hartmann et al.Acta Neurop α thol (Berl) 2005,109,639-642；Samuels et al., supra)。
MTOR is highly conserved silk-threonine kinase, with lipid kinase activity, be PI3K/AKT paths influence because One of element.There are two kinds of completely different compounds, mTORC1 and mTORC2, and by adjusting nutrition supply and cell energy in mTOR Amount level, plays its important function in cell propagation.The downstream targets of mTORC1 are Ribosomal protein 1 and eucaryon Biological translation initiation factor 4E Binding Protein 1s, both have important effect (" Present and to albumen synthesis future of PI3K pathway inhibition in cancer:perspectives and limitations.” Current Med.Chem.2011,18,2647-2685)。
The conclusion that the imbalance of mTOR signal transductions induces cancer comes from the research that pharmacology disturbs mTOR, and the medicine of research includes Rapamycin, its homologue has temsirolimus (CCI-779) and everolimus (RAD001).Rapamycin is mTOR suppressions Preparation, the induction G1 phases block and Apoptosis.Rapamycin and the formation of FK- Binding Protein 1s 2 (FKBP-12) compound, are recognized It is related to rapamycin growth inhibition mechanism.These compounds specifically bind mTOR, suppress its activity, prevent protein translation And cell growth.The cytosis of mTOR inhibitors is also manifested by the cell containing the PTEN with property inactivation.Therefore, thunder handkerchief The active anticancer of mycin is accepted, and a series of rapamycin homologues, such as temsirolimus and Yi Weimo Department, is also ratified for treating some type of cancer by United States food and drag administration.
Just because of PI3K and mTOR plays an important role in bioprocess and disease stage, the suppression of these kinases is researched and developed Agent is (" the Phosphatidylinositol 3-kinase isoforms as a novel drug for highly expecting targets.”Current Drug Targets,2011,12,1056-1081；“Progress in the preclinical discovery and clinical development of class I and dual class I/IV phosphoinositide 3-kinase(PI3K)inhibitors.”Current Med Chem 2011,18,2686- 2714)。
Abstract of invention
Hereinafter some aspects of the invention are only summarized, it is not limited to this.These aspects and other parts are later There is more complete explanation.All bibliography in this specification are incorporated in this by overall.Work as the disclosure of the specification When variant with citation, it is defined by the disclosure of the specification.
The present invention provides a class noval chemical compound, can be used to suppress, and controls and/or reconcile PI3K and/or mTOR, it is also possible to For treating human pcna disease, such as cancer.The present invention also provides the method for preparing this kind of compound, treats human pcna The method and the pharmaceutical composition containing such compound of property disease.
On the one hand, the present invention relates to a kind of compound, it is the compound of structure shown in formula (I) or chemical combination shown in formula (I) The stereoisomer of thing, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug：
Wherein：Each Y, R1, Z, W1, W2And W3With definition as described in the present invention.
In some embodiments, each W1, W2And W3It independently is N or CRc；
Z is D, CN, N3Or
X is H, D, C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical-C1-4 Alkylidene, C6-10Aryl or comprising 1,2,3 or 4 heteroatomic 5-10 for being independently selected from O, S and N former molecular heteroaryls Base, wherein, the C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical-C1-4Alkylene Base, C6-10Aryl and 5-10 former molecular heteroaryl is unsubstituted independently of one another or is taken by 1,2,3 or 4 substitution base In generation, the substitution base is independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-6Alkyl, C1-6Halogen Substituted alkyl, C2-6Alkenyl, C2-6Alkynyl, NC-C1-4Alkylidene, RaO-C1-4Alkylidene, RbRaN-C1-4Alkylidene, C6-10Aryl or 5- 10 molecular heteroaryls of original；
Y is C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical-C1-4Alkylene Base, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl or comprising 1,2,3 or 4 heteroatomic 5-10 atom for being independently selected from O, S and N The heteroaryl of composition, wherein, the C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocycle Base-C1-4Alkylidene, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl and 5-10 former molecular heteroaryl are not taken independently of one another In generation, is replaced by 1,2,3 or 4 substitution base, and the substitution base is independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-6Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6Alkynyl, NC-C1-4Alkylidene, RaO-C1-4Alkylene Base, RbRaN-C1-4Alkylidene, C6-10Aryl or 5-10 former molecular heteroaryl；
R1It is H, D, Cl, ORa, NRaRb, C1-6Aliphatic or C3-6Cycloalkyl, wherein, the C1-6Aliphatic and C3-6Cycloalkanes Base is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substitution base, described to replace base independently selected from D, F, Cl, CN, N3, ORa, SRaOr NRaRb；
Each RaAnd RbIt independently is H, C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C6-10Aryl, comprising 1,2,3 or 4 It is independently selected from the heteroatomic 5-10 former molecular heteroaryl of O, S and N, C6-10Aryl-C1-4Alkylidene, (5-10 atom The heteroaryl of composition)-C1-4Alkylidene, or Ra, RbWith nitrogen-atoms in connection together, it is optionally formed substituted or non-takes The 3-8 former molecular heterocycle in generation, wherein, the C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C6-10Aryl, comprising 1, 2, the 3 or 4 heteroatomic 5-10 for being independently selected from O, S and N former molecular heteroaryls, C6-10Aryl-C1-4Alkylidene, (5- 10 molecular heteroaryls of original)-C1-4Alkylidene, 3-8 former molecular heterocycle is unsubstituted independently of one another or by 1, and 2, 3 or 4 substitution bases are replaced, and 1,2,3 or 4 substitution base is independently selected from D, F, Cl, CN, N3, OH, NH2, C1-6Alkoxy Or C1-6Alkyl amino；
Each RcIt independently is H, D, F, Cl, Br, I, N3, CN, OH, NH2, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, C3-6Cycloalkyl, C3-6Heterocyclic radical, C6-10Aryl is former comprising 1,2,3 or 4 be independently selected from O, S and N heteroatomic 5-10 Molecular heteroaryl, wherein, the C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, C3-6Cycloalkyl, C3-6Heterocyclic radical, C6-10Aryl and 5-10 former molecular heteroaryl is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substitution base, The substitution base is independently selected from D, F, Cl, CN, N3, OH, NH2, C1-6Alkyl, C3-6Cycloalkyl, C1-6Haloalkyl, C1-6Alcoxyl Base or C1-6Alkyl amino.
In other embodiment, W1It is N or CRc；Each W2And W3It independently is CRc。
In other embodiment, Z is CN, N3Or
In other embodiment, X is H, D, C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4It is sub- Alkyl or C3-6Heterocyclic radical-C1-4Alkylidene, wherein, the C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4 Alkylidene and C3-6Heterocyclic radical-C1-4Alkylidene is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substitution base, described Substitution base is independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-3Alkyl, C1-3Haloalkyl, C2-4Alkenyl or C2-4Alkynyl.
In other embodiment, Y is C1-6Alkyl, C3-6Cycloalkyl, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl or bag Containing 1,2,3 or 4 heteroatomic 5-10 for being independently selected from O, S and N former molecular heteroaryl, wherein, the C1-6Alkyl, C3-6Cycloalkyl, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl and 5-10 former molecular heteroaryl are unsubstituted independently of one another Or replaced by 1,2,3 or 4 substitution base, the substitution base is independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-3Alkyl, C1-3Haloalkyl, C2-4Alkynyl, C6-10Aryl or 5-10 former molecular heteroaryl.
In other embodiment, R1It is H, D, Cl, CH3, CH2CH3, CF3, CH2CF3, OCH3Or OCH2CH3。
In other embodiment, each RcIt independently is H, D, F, Cl, N3, CN, NH2, C1-3Alkyl, C1-3Alkoxy, C1-3Alkyl amino, C3-6Cycloalkyl or C3-6Heterocyclic radical, wherein, the C1-3Alkyl, C1-3Alkoxy, C1-3Alkyl amino, C3-6Ring Alkyl and C3-6Heterocyclic radical is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substitution base, and the substitution base is independently Selected from D, F, CN, N3, OH, NH2, C1-3Alkyl, C3-6Cycloalkyl or C1-3Haloalkyl.
On the other hand, the present invention relates to a kind of pharmaceutical composition, its compound for including above-mentioned any one of the invention, with And pharmaceutically acceptable carrier, excipient, diluent, assistant agent, or medium, or combinations thereof.
In some embodiments, pharmaceutical composition of the present invention is described attached further comprising additional therapeutic agent Chemotherapeutic agent, antiproliferative, the medicine for treating atherosclerosis, or for treating lung fiber are selected from therapeutic agent The medicine of change, or combinations thereof.
In other embodiment, pharmaceutical composition of the present invention, wherein involved additional therapeutic agent is benzene Butyric acid mustargen (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), different ring phosphinylidyne Amine (ifosfamide), busulfan (busulfan), BCNU (carmustine), lomustine (lomustine), chain urea Assistant rhzomorph (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (MTX) (methotrexate), fluorouracil (fluorouracil), cytarabine (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vincaleukoblastinum (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), TPT (topotecan), Irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), dactinomycin D (dactinomycin), Doxorubicin (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), mitomycin C (mitomycin), Ipsapirone (ixabepilone), TAM (tamoxifen), Flutamide (flutamide), Gonadorelin analog (gonadorelin analogues), megestrol acetate (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon-' alpha ' (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Afatinib (afatinib), alisertib, amuvatinib, A Pa replaces Buddhist nun (apatinib), Axitinib (axitinib), bortezomib (bortezomib), bosutinib (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, gram Zhuo replace Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), many Weis replace Buddhist nun (dovitinib), Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), Ibrutinib, Conmana (icotinib), Imatinib (imatinib), iniparib, Lapatinib (lapatinib), Lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, Mo Tesaini (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, Aura Pa Ni (olaparib), pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, Regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib), Sutent (sunitinib), tasocitinib, Telatinib (telatinib), Tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, prestige Luo Feini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), brentuximab vedotin, catumaxomab (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), difficult to understand (ofatumumab), Victibix (panitumumab), rituximab list Anti- (rituximab), tositumomab (tositumomab), or Herceptin (trastuzumab), or combinations thereof.
On the other hand, it is possible to use the compounds of this invention or pharmaceutical composition of the present invention are prepared for protecting, processing, control Treat or mitigate the purposes of the medicine of patient's proliferative diseases.
In some embodiments, proliferative diseases of the present invention are metastatic carcinoma, colon cancer, sdenocarcinoma of stomach, carcinoma of urinary bladder, breast Gland cancer, kidney, liver cancer, lung cancer, cutaneum carcinoma, thyroid cancer, head and neck cancer, prostate cancer, cancer of pancreas, the cancer of central nervous system Disease, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
On the other hand, the present invention relates to be prepared in biology using the compounds of this invention or pharmaceutical composition of the present invention The purposes of the medicine of suppression or regulatory protein kinase activity in sample, the purposes is included and uses the compounds of this invention or medicine group Compound is contacted with described biological sample.
In some embodiments, protein kinase of the present invention is receptor tyrosine kinase.
In other embodiment, receptor tyrosine kinase of the present invention is phosphoinositide 3-kinase (PI3 kinases Or PI3K) and/or mTOR.
In some embodiments, the present invention relates to a kind of method of suppression PI3K or mTOR, the method includes the present inventionization Compound or its pharmaceutical composition are contacted with the kinases.In some embodiments, the present invention relates to one kind suppress PI3K or The method of mTOR signals response, the method is contacted comprising the compounds of this invention or its pharmaceutical composition with the acceptor.Other one A little embodiments are to suppress the activity of PI3K or mTOR signals response in cell or multicellular organisms.
According to method of the present invention, the method is included using the compounds of this invention or its pharmaceutical composition to described many Multicellular organism is administered.In some embodiments, the multicellular organisms refer to mammal.Implement in other Scheme, the multicellular organisms refer to the mankind.In some embodiments, the method for the invention is further comprising additional Therapeutic agent is contacted with the kinases.
On the other hand, the present invention relates to a kind of method for suppressing cell-proliferation activity, methods described is comprising using of the invention Effective therapeutic dose and cells contacting of compound or its pharmaceutical composition energy Inhibit proliferaton.In some embodiments, institute of the present invention Method is stated further comprising additional therapeutic agent and cells contacting.
In some embodiments, the present invention relates to a kind of method for treating Patient cells' proliferative diseases, methods described bag Containing being administered to patient using effective therapeutic dose of the compounds of this invention or its pharmaceutical composition.In some embodiments, this The further administration comprising additional therapeutic agent of invention methods described.
In some embodiments, the present invention relates to a kind of method for suppressing patient tumors growth, methods described is included and used Effective therapeutic dose of the compounds of this invention or its pharmaceutical composition is administered to patient.In some embodiments, institute of the present invention State the method further administration comprising additional therapeutic agent.
On the other hand, the preparation of the compound for being included the present invention relates to formula (I), the method for separating and purifying.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will below make more specific complete description.
Detailed description of the invention book
Definition and general terms
Certain embodiments of the present invention will now be described in more detail, the example is by the structural formula enclosed and chemical formula explanation.This Invention intention covers all of replacement, modification and equivalent technical solutions, and they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.In the document, patent that are combined and the one of similar material Or many it is different from the application or in the case of contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be defined by the application.
It will further be appreciated that some features of the invention, are clearly visible, carried out in multiple independent embodiments Description, but it is also possible to provide in combination in single embodiment.Conversely, various features of the invention, for brevity, It is described in single embodiment, but it is also possible to individually or with any suitable sub-portfolio provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise indicated, following definition should be obtained using used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS editions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can join Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by reference.
There are obvious conflict, article " " used herein, " one (kind) " unless otherwise indicated or in context " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the implementation method of the embodiment and use or use.
Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.It is tested right As for example also referring to primate (such as the mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described to receive Examination pair as if people.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term "comprising" is open language, i.e., including the content specified by the present invention, but be not precluded from otherwise Content.
" stereoisomer " refers to but atom or the group spatially different change of arrangement mode with identical chemical constitution Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be have with its mirror image can not overlap property molecule, and " achirality " refer to can be overlap with its mirror image Molecule.
" enantiomter " refers to the two of compound isomers that can not be overlapped but be mutually mirror.
" diastereoisomer " refers to have two or more chiral centres and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer is mixed Compound can be operated such as electrophoresis and chromatogram by high resolution analysis, and such as HPLC is separated.
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley＆Sons, Inc., New York, 1994.
Many organic compounds exist with optical active forms, i.e., they have rotates the plane of linearly polarized light Ability.When optically active compound is described, represent molecule on one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for the rotation of linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix is dextrorotation for the compound of (+) or d.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or stereospecificity when, May occur in which such case.
Any asymmetric atom (for example, carbon etc.) that the present invention discloses compound can be enriched with racemic or enantiomer Form exist, for example (R)-, (S)-or (R, S)-configuration be present.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least at least 80% enantiomeric excess, at least 90% enantiomeric excess, 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with possible isomers or they Mixture, the form of such as racemic modification and the non-corresponding isomer mixture quantity of asymmetric carbon atom (this depend on) deposits .Optically active (R)-or (S)-isomers can be used chiral synthon or chiral reagent to prepare, or be torn open using routine techniques Point.If compound contains a double bond, substitution base may be E or Z configurations；If containing dibasic cycloalkanes in compound Base, the substitution base of cycloalkyl may have cis (cis) or trans (trans) configuration.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained end-product or intermediate can be passed through into those skilled in the art with known method Familiar method splits into optical antipode, e.g., is separated by its diastereoisomeric salt for obtaining.Racemic product Thing can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is referred to, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
Term " dynamic isomer " or " tautomeric form " refer to that can build (low by low energy with different-energy Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of dynamic isomer.For example, proton tautomer (protontautomer) (also referred to as proton translocation mutually makes a variation Structure body (prototropic tautomer)) include the mutual inversion of phases that is carried out by proton migration, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electrons come The mutual inversion of phases for carrying out.The instantiation of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyls are mutual The change of tautomeric.Tautomeric another example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one dynamic isomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
" nitrogen oxides " used in the present invention refer to when compound contain several amine functional groups when, can be by 1 or more than 1 Nitrogen-atoms aoxidize to form N- oxides.The particular example of N- oxides is the N- oxides or nitrogen heterocyclic ring nitrogen-atoms of tertiary amine N- oxides.Available oxidant example, such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) process corresponding amine and form N- oxides (referring to Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages). Especially, N- oxides can be prepared (Syn.Comm.1977,7,509-514) with the method for L.W.Deady, wherein for example lazy Property solvent, such as in dichloromethane, make amines be reacted with m- chlorine benzylhydroperoxide (MCPBA).
" solvate " of the invention refers to the association that one or more solvent molecules are formed with compound of the invention Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methyl alcohol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is associated matter that water is formed.
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopted as stating and experimentally characterized.Such product can, by aoxidizing, be reduced, water by drug compound Solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc. method are obtained.Correspondingly, the present invention includes compound Metabolite, including compound of the invention and mammal are fully contacted the metabolite produced by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of compound of the invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:Described in 1-19..The salt that pharmaceutically acceptable nontoxic acid is formed is included, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphurs Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that appropriate alkali is obtained includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The quaternary ammonium salt that the compound of the group of included N is formed.Water-soluble or oil-soluble or dispersion product can be turned into by quaternary ammonium With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further includes to fit When, nontoxic ammonium, such as amine cation that quaternary ammonium salt and gegenions are formed, halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
Term " prodrug " used in the present invention, represents a compound and is converted into compound shown in formula (I) in vivo. It is such conversion hydrolyzed in blood by pro-drug or in blood or tissue through enzymatic conversion for precursor structure is influenceed.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that have of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.One for example in the present invention Compound includes hydroxyl, you can the compound of prodrug form is obtained to be acylated.Other prodrug forms include Phosphate, such as these phosphate compounds are obtained through the di on parent.Beg on pro-drug is complete By may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
As described in the invention, compound of the invention optionally can be replaced by one or more substitution bases, such as General formula compound above, or as the special example in embodiment the inside, subclass, and the class compound that the present invention is included. Should be appreciated that " optionally substituted " this term can be exchanged with " substituted or non-substituted " this term to use.Term is " optionally Ground ", " optional " or " optional " refer to then described event or situation can with but may not occur, and the description is including wherein There is the situation of the event or situation, and the situation of the event or situation does not occur wherein, such as in the present invention, Ra, RbAnd with it The nitrogen-atoms that connects together, be optionally formed substituted or non-substituted 3-8 former molecular heterocycle, be meant that Ra, Rb With nitrogen-atoms in connection together, 3-8 former molecular heterocycle can be formed, it is also possible to do not form heterocycle, and be this Other structures known to art personnel, such as N-Ra-RbOr Ra-N-RbDeng.In general, term " optionally " is whether Before term " substituted ", all represent institute to one or more hydrogen atoms in structure by specifically replaced base replace.Remove Non- other aspects show that an optional substituted radical can have a substitution base, and each commutable position is taken in group Generation.When in given structural formula more than one position can be selected from specific group one or more substitution bases replaced, that Substitution base can be replaced with identical or different in each position.Wherein described substitution base can be, but be not limited to, D, F, Cl, Br, CN, N3, NH2, OH, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxy, C1-6 Alkyl amino, C3-6Cycloalkyl, C2-6Alkenyl, C2-6Alkynyl, NC-C1-4Alkylidene, RaO-C1-4Alkylidene, RbRaN-C1-4Alkylidene, C6-10Aryl, or 5-10 former molecular heteroaryl, wherein, each RaAnd RbThere is definition as described in the present invention.
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode for being used in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used Referring in different groups, not influenceed mutually between expressed specific option between same-sign, it is also possible to represent in phase In same group, do not influenceed mutually between expressed specific option between same-sign.
In each several part of this specification, the substitution base that the present invention discloses compound is disclosed according to radical species or scope.It is special Do not point out, each independent sub-combinations thereof of each member of the present invention including these radical species and scope.For example, term “C1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each several part of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.If for example, the structure needs linking group and for this The Markush group definition of variable lists " alkyl " or " aryl ", then represented respectively it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1-20 carbon atom, saturated straight chain or The univalent hydrocarbyl group of side chain, wherein, the alkyl group can optionally by the substitution base of one or more present invention descriptions Replaced.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In some embodiments, alkyl group contains There is 1-12 carbon atom；In other embodiments, alkyl group contains 1-6 carbon atom；In other embodiment party In case, alkyl group contains 1-4 carbon atom；Also in some embodiments, alkyl group contains 1-3 carbon atom.In addition In some embodiments, alkyl group contains 1-2 carbon atom.
The example of alkyl group is included, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr ,-CH2CH2CH3), isopropyl (i-Pr, i-propyl ,-CH (CH3)2), normal-butyl (n-Bu, n-butyl ,- CH2CH2CH2CH3), isobutyl group (i-Bu, i-butyl ,-CH2CH(CH3)2), sec-butyl (s-Bu, s-butyl ,-CH (CH3) CH2CH3), the tert-butyl group (t-Bu, t-butyl ,-C (CH3)3), n-pentyl (n-pentyl ,-CH2CH2CH2CH2CH3), 2- amyl groups (- CH(CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- fourths Base (- CH (CH3)CH(CH3)2), 3- methyl isophthalic acids-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3) CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl groups (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyl groups (- CH (CH3)CH (CH3)CH2CH3), 4- methyl -2- amyl groups (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyl groups (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- diformazans Base -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Term " alkyl " and its prefix " alkane ", the saturated carbon chains all comprising straight chain and side chain.
Term " alkylidene " represents the divalence for removing the saturation obtained by two hydrogen atoms from the alkane of straight or branched Hydrocarbyl group.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom.In some embodiments, alkylidene Group contains 1-6 carbon atom；In other embodiments, alkylidene group contains 1-4 carbon atom；In other implementation In scheme, alkylidene group contains 1-3 carbon atom；Also in one embodiment, alkylidene group contains 1-2 carbon atom. Such example includes methylene (- CH2-), ethylidene (- CH2CH2-), isopropylidene (- CH (CH3)CH2-) etc..
Term " alkenyl " is represented and contains the 2-12 straight or branched monovalent hydrocarbon of carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp2Double bond, wherein, the alkenyl group can be retouched optionally by one or more present invention The substitution base stated is replaced, its positioning for including " cis " and " tans ", or " E " and " Z " positioning.In some embodiments In, alkenyl group includes 2-8 carbon atom；In other embodiments, alkenyl group includes 2-6 carbon atom；Another In a little embodiments, alkenyl group includes 2-4 carbon atom.The example of alkenyl group is included, but is not limited to, vinyl (- CH =CH2), pi-allyl (- CH2CH=CH2) etc..
Term " alkynyl " is represented and contains the 2-12 straight or branched monovalent hydrocarbon of carbon atom, wherein at least one insatiable hunger And site, that is, there is a key of carbon-to-carbon sp tri-, wherein, the alkynyl group can be retouched optionally by one or more present invention The substitution base stated is replaced.In some embodiments, alkynyl group includes 2-8 carbon atom；In other embodiments, Alkynyl group includes 2-6 carbon atom；In other embodiment, alkynyl group includes 2-4 carbon atom.Alkynyl group Example is included, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), 1- propinyls (- C ≡ C-CH3) etc..
Term " aliphatic " or " aliphatic group ", represent straight chain (non-branched) or side chain, and substituted or non-substituted is complete Saturation or the group containing one or more degree of unsaturation hydrocarbon chains.Unless otherwise detailed instructions, aliphatic group is containing 1-20 Carbon atom.In some embodiments, aliphatic group contains 1-10 carbon atom；In other embodiment, fatty group Group contains 1-8 carbon atom；In other embodiment, aliphatic group contains 1-6 carbon atom；In other embodiment party Case, aliphatic group contains 1-4 carbon atom；In other embodiment, aliphatic group contains 1-3 carbon atom；In addition Some embodiments, aliphatic group contains 1-2 carbon atom.Aliphatic group includes, but not limited to straight or branched, substitution Or non-substituted alkyl, alkenyl, or alkynyl.For example, C1-6Aliphatic group, including non-branched or side chain, it is non-substituted or properly take The C in generation1-6Alkyl, C2-6Alkenyl, or C2-6Alkynyl.Such example is included, but is not limited to, methyl, ethyl, propyl group, isopropyl Base, butyl, isobutyl group, the tert-butyl group, ethene, propylene, butylene, 2- butylene, acetylene, propine, butine, 2- butine, etc..The fat Fat race group can be independently unsubstituted or be replaced by one or more substitution bases described in the invention.
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, and alkenyl or alkoxy base are by one Individual or multiple halogen atoms are replaced, and such example is included, but is not limited to, trifluoromethyl, trifluoromethoxy etc..
Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-20 carbon atom.Some of them reality Applying example is, alkoxy base contains 1-10 carbon atom；Other embodiment is that alkoxy base contains 1-8 carbon atom； Other embodiment is that alkoxy base contains 1-6 carbon atom；Other embodiment is that alkoxy base contains 1-4 Individual carbon atom；Other embodiment is that alkoxy base contains 1-3 carbon atom.
The example of alkoxy base is included, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), 1- amoxys (n- amoxys ,-OCH2CH2CH2CH2CH3), 2- amoxys (- OCH (CH3) CH2CH2CH3), 3- amoxys (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourths Epoxide (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc..The alkoxy base can be independently unsubstituted or by one or more institutes of the present invention The substitution base of description is replaced.
Term " alkylthio group " includes C1-10The alkyl of straight or branched is connected on the sulphur atom of divalence, and some of them are implemented Example is that alkylthio group is the C of lower level1-3Alkylthio group, such example includes, but is not limited to methyl mercapto (CH3S-)。
Term " alkyl amino " or " alkylamino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group.Some of them embodiment is that alkyl amino is one or two C1-6Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms；Other embodiment is, alkyl amino be one or Two C1-3Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms.Suitable alkylamino group can be single alkane Base amino or dialkyl amido, such example are included, but is not limited to, N- methylaminos, N- ethylaminos, N, N- dimethylamino, N, N- lignocaine etc..
Term " fragrant amino " represents that amino group is replaced by one or two aromatic yl group, and such example includes, but It is not limited to N- phenylaminos.Some of them embodiment is that the aromatic ring in fragrant amino can further be substituted.
Term " aminoalkyl " includes the C replaced by one or more amino1-10Straight or branched alkyl group.Wherein Some embodiments are that aminoalkyl is the C replaced by one or more amino groups1-6" aminoalkyl of lower level ", so Example include, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
Term " carbocylic radical " or " carbocyclic ring " represented containing 3-12 carbon atom, the nonaromatic saturation of univalent or multivalence Or undersaturated monocyclic, the bicyclic or three-ring system in part, and this member ring systems has remaining of one or more tie points and molecule Part is connected.Carbon bicyclic group includes spiral shell carbon bicyclic group and condenses carbon bicyclic group, and suitable carbocylic radical group includes, but does not limit In, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of carbocylic radical group further includes, cyclopropyl, cyclobutyl, cyclopenta, 1- rings Amyl group -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, cyclohexyl, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl - 2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, ring ten Dialkyl group, etc..
Term " cycloalkyl " represented containing 3-12 carbon atom, univalent or multivalence, monocyclic, bicyclic or three rings of saturation System, and this member ring systems has one or more tie points to be connected with the remainder of molecule.In some embodiments, cycloalkyl Contain 3-12 carbon atom；In other embodiments, cycloalkyl contains 3-8 carbon atom；In other embodiment, Cycloalkyl contains 3-6 carbon atom.The group of naphthene base can be independently unsubstituted or by one or more institutes of the present invention The substitution base of description is replaced.
Term " cycloalkyl alkylidene " represents that alkyl group can be replaced by one or more groups of naphthene base, wherein alkane Base and group of naphthene base have implication as described in the present invention.Some of them embodiment is, cycloalkyl alkylidene group refer to " compared with Rudimentary cycloalkyl alkylidene " group, i.e. group of naphthene base are connected to C1-6Alkyl group on.Other embodiment is, ring Alkyl group is connected to C1-4Alkyl group on.Other embodiment is that group of naphthene base is connected to C1-3Alkyl group On.Other embodiment is that group of naphthene base is connected to C1-2Alkyl group on.Such example includes, but does not limit In, cyclopropylethyl, cyclopentyl-methyl, cyclohexyl methyl etc..The cycloalkyl alkylidene group can not taken independently In generation, is replaced by one or more substitution bases described in the invention.
Term " heterocycle ", " heterocyclic radical " or " heterocycle " is used interchangeably herein, all referring to monocyclic, bicyclic or three ring bodies System, one or more atoms are replaced by hetero atom individually optionally in its middle ring, and ring can be fully saturated or comprising one Individual or multiple degrees of unsaturation, but be definitely not the fragrant same clan, there are one or more tie points to be connected to other molecules up.One or Multiple ring hydrogen atoms can be independently unsubstituted or be replaced by one or more substitution bases described in the invention.Its In some embodiments be that " heterocycle ", " heterocyclic radical " or " heterocycle " group is 3-7 former molecular monocyclic (2-6 carbon atom With selected from N, the 1-3 hetero atom of O, P, S is optionally replaced by one or more oxygen atoms in this S or P and obtains as SO, SO2, PO, PO2Group, when described ring is the molecular ring of three originals, only one of which hetero atom), other reality Applying example is, 3-6 former, and molecular monocyclic (2-5 carbon atom and selected from N, the 1-3 hetero atom of O, P, S is optional in this S or P Ground is replaced by one or more oxygen atoms and obtains as SO, SO2, PO, PO2Group, when described ring be three originals it is molecular During ring, only one of which hetero atom), or 7-10 it is former it is molecular it is bicyclic (4-9 carbon atom and selected from N, O, P, S's 1-3 hetero atom, is optionally replaced by one or more oxygen atoms in this S or P and obtains as SO, SO2, PO, PO2Group).
Heterocyclic radical can be carbon-based or hetero atom base.The example of heterocycle is included, but is not limited to, pyrrolidinyl, tetrahydrochysene furan Mutter base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, sulphur For morpholinyl , thioxane bases, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, Glycidyl, azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 2- Pyrrolinyl, 3- pyrrolinyls, indolinyl, 2H- pyranoses, 4H- pyranoses, dioxane hexyl, 1,3- dioxy amyl group, Pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4- tetra- Hydrogen isoquinoline base.The example of heterocyclic group also includes, the hybar X base and 1,1- that two carbon atoms are replaced by oxygen (=O) on ring Dioxidothiomorpholinyl.The heterocyclyl groups can be independently unsubstituted or described in the invention be taken by one or more Replaced for base.
Term " heterocycloalkylene " represents that alkyl group can be replaced by one or more heterocyclyl groups, wherein alkane Base and heterocyclyl groups have implication as described in the present invention.Some of them embodiment is, heterocycloalkylene group refer to " compared with Rudimentary heterocycloalkylene " group, i.e. heterocyclyl groups are connected to C1-6Alkyl group on.Other embodiment is, miscellaneous Cyclic groups are connected to C1-4Alkyl group on.Such example is included, but is not limited to, 2- pyrrolidines ethyls etc..It is described Heterocycloalkylene group can be independently unsubstituted or be replaced by one or more substitution bases described in the invention.
Term " hetero atom " refers to O, S, N, P and Si, including any oxidation state of N, S and P form；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (as the NR in the pyrrolidinyl that N- replaces).
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " H " represents single hydrogen atom.Such atomic group can be connected with other groups, for example with oxygen atom phase Even, oh group is formed.
Term " D " or "2H " represents single D-atom.One such atomic group is connected with a methyl, forms list-deuterium For methyl (- CDH2), two D-atoms are connected with a methyl, form double-deuterated methyl (- CD2H), and three D-atoms with One methyl is connected, and forms three-deuterated methyl (- CD3)。
Term " azido " or " N3" represent a nitrine structure.This group can be connected with other groups, for example, Triazonmethane (MeN can be connected to form with a methyl3), or it is connected to form phenylazide (PhN with a phenyl3)。
Term " aryl " represents and contains 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, double The carbocyclic ring system of ring and three rings, wherein, at least one member ring systems are aromatic, and each of which member ring systems are former comprising 3-7 Molecular ring, and there are one or more tie points to be connected with the remainder of molecule.Term " aryl " can be with term " fragrance Ring " is exchanged and used.The example of aromatic yl group can include phenyl, naphthyl and anthryl.The aromatic yl group can be with individually optional Replaced by one or more substitution bases described in the invention.
Term " aryl alkylene " represent alkyl group can be replaced by one or more aromatic yl groups, wherein alkyl and Aromatic yl group has implication as described in the present invention, and some of them embodiment is that arylalkylene groups refer to the " virtue of lower level Base alkylidene " group, i.e. aromatic yl group is connected to C1-6Alkyl group on；Other embodiment is, arylalkylene groups Refer to containing C1-4Alkyl " benzene alkylene "；Other embodiment is that arylalkylene groups refer to that aromatic yl group is connected to C1-3Alkyl group on；Other embodiment is that arylalkylene groups refer to that aromatic yl group is connected to C1-2Alkyl base In group.Wherein instantiation includes benzyl, diphenyl methyl, phenethyl etc..The arylalkylene groups can be independently It is unsubstituted or replaced by one or more substitution bases described in the invention.
Term " heteroaryl " is represented and contains 5-14 annular atom, or 5-12 annular atom, or 5-10 annular atom, or 5-6 Monocyclic, the bicyclic and three-ring system of individual annular atom, wherein at least one member ring systems are aromatic, and at least one member ring systems bags Containing one or more hetero atoms, each of which member ring systems include 5-7 former molecular ring, and have one or more tie points It is connected with molecule remainder.Term " heteroaryl " can be exchanged and used with term " hetero-aromatic ring " or " heteroaromatics ".Institute Heteroaryl groups are stated optionally to be replaced by one or more substitution bases described in the invention.In some embodiments, 5- 10 molecular heteroaryls of original include 1,2,3 or 4 hetero atom for being independently selected from O, S and N.In other embodiments, 5-6 former molecular heteroaryl includes 1,2,3 or 4 hetero atom for being independently selected from O, S and N.
The Monocyclic examples of heteroaryl groups are included, but is not limited to, 2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazoles Base, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- Evil Oxazolyl, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), three Oxazolyl (such as 2- triazolyls and 5- triazolyls), 2- thienyls, 3- thienyls, pyrazolyl (such as 2- pyrazolyls), isothiazolyl, 1,2, 3- oxadiazolyls, 1,3,4- oxadiazolyls, 1,2,5- oxadiazolyls, 1,2,4- oxadiazolyls, 1,2,3- triazolyls, 1,2,3- sulphur For di azoly, 1,2,4- thio biphospholes base, 1,3,4- thio biphospholes base, 1,2,5- thio biphospholes base, pyrazinyl, 1,3,5- triazines Base；Also include following bicyclic, but it is bicyclic to be not limited to these：Benzimidazolyl, benzofuranyl, benzothienyl, indoles Base (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls), isoquinolyl (such as 1- isoquinolines Quinoline base, 3- isoquinolyls or 4- isoquinolyls), imidazo [1,2-a] pyridine radicals, pyrazolo [1,5-a] pyridine radicals, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1, 5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine radicals, etc..
Term " heteroarylalkylenyl " represents that alkyl group can be replaced by one or more heteroaryl groups, wherein alkane Base and heteroaryl groups have implication as described in the present invention, and some of them embodiment is, heteroarylalkylenyl group refer to " compared with Rudimentary heteroarylalkylenyl " group, i.e. heteroaryl groups are connected to C1-6Alkyl group on；Other embodiment is, miscellaneous Aromatic yl group is connected to C1-4Alkyl group on；Other embodiment is that heteroaryl groups are connected to C1-3Alkyl group On；Other embodiment is that heteroaryl groups are connected to C1-2Alkyl group on.Wherein instantiation includes 2- pyridine first Base, 3- furylethyls etc..The heteroarylalkylenyl group can be independently unsubstituted or of the invention by one or more Described substitution base is replaced.
No matter term " carboxyl ", be single use or be used in conjunction with other terms, such as " carboxyalkyl ", expression-CO2H；Term No matter " carbonyl ", be single use or be used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", represents-(C=O)-.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " and " condensed ring radical " are used interchangeably herein, all referring to list The undersaturated bridged-ring system of saturation or part of valency or multivalence, the bridged-ring system refers to the bicyclic system of non-aromatic.So System can include independent or conjugation unsaturated system, but its core texture not comprising aromatic rings or heteroaromatic (but Aromatic group can be as substitution base thereon).
Term " volution base ", " volution ", " spiral shell bicyclic group " or " spiral shell is bicyclic " are used interchangeably herein, refer to unit price or many The saturation or part unsaturation ring system of valency, one of ring originate from specific ring carbon atom on another ring.For example, as under Described by face, a bridged-ring system for saturation (ring B and B ') is referred to as " condensed-bicyclic ", and ring A and ring B is in two saturations A carbon atom is shared in member ring systems, is referred to as " volution " or " spiral shell is bicyclic ".Each ring in condensed-bicyclic base and spiral shell bicyclic group Can be carbocylic radical or heterocyclic radical, and each ring is optionally taken by one or more substitution bases described in the invention Generation.
Term " Heterocyclylalkyl " refer to the unit price containing 3-12 annular atom or multivalence saturation is monocyclic, bicyclic or three rings System, wherein at least one annular atom is selected from nitrogen, sulphur or oxygen atom.
Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular Heterocyclylalkyls of original, and 1,2,3,4- tetralyl It is 10 molecular groups of naphthene base of original.
Contain one or more degrees of unsaturation in " undersaturated " the expression group of term for being used in the present invention.
When term " blocking group " or " PG " refer to a substitution base and other reacted with functional groups, resistance is commonly used to Break or protect special feature.For example, " blocking group of amino " refers to a substitution base to be connected to block with amino group Or protection compound in amino feature, suitable amido protecting group include acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylenes oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substitution base of base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refer to the substitution base of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group refers to document：T.W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
Term " treatment " any disease as used in the present invention or illness, refer to improvement disease in some of these embodiments Disease or illness (slow down or prevent or mitigate disease or the development of its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (for example stablize perceptible symptom) or physiologically (for example stablizes body Parameter) or above-mentioned two aspects regulation disease or illness.In other embodiments, " treatment " refer to prevention or postpone disease or disease Breaking-out, generation or the deterioration of disease.
As described herein, term " pharmaceutically acceptable carrier " include any solvent, decentralized medium, coating agents, Surfactant, antioxidant, preservative (such as antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizing agent, bonding Agent, excipient, dispersant, lubricant, sweetener, flavor enhancement, colouring agent, or its composition, these carriers are all affiliated technologies Known (such as Remington's Pharmaceutical Sciences, 18th Ed.Mack of art personnel Printing Company, described in 1990, p1289-1329).Except any conventional carrier situation incompatible with active component Outward, its purposes in treatment or pharmaceutical composition is covered.
" therapeutically effective amount " of term the compounds of this invention refers to that will trigger the biology or medicinal response, example of study subject Such as reduce or inhibitory enzyme or protein active or improve symptom, relax symptom, slow down or delay progression of disease or prevention disease The amount of used the compounds of this invention.In some non-limiting embodiments, term " therapeutically effective amount " refers to work as to be applied to The amount of the compounds of this invention effective to the following used during study subject：(1) at least partly relax, suppress, prevent And/or improve (i) by PI3K imbalance mediations or (ii) relevant with PI3K activity or (iii) disease for being characterized with PI3K activity Suffer from or illness or disease；Or (2) mitigate or suppress PI3K activity.In other non-limiting embodiments, " treatment has term Effect amount " refers to, when cell or tissue or non-cellular biological material or medium is applied to, at least partly to mitigate illness or suppression The amount of the effective the compounds of this invention of PI3K；Or at least mitigate the activity of illness or suppression PI3K to a certain extent.Term " therapeutically effective amount " is except for illustrating the content of the embodiments above on PI3K, it is also possible to which application in the same manner is taken office What protein/polypeptide/the enzyme of his correlation.
Term " cancer " and " cancer " refer to or description patient in the usual physiology that is characterized with cell growth out of control Illness." tumour " includes one or more cancer cell.The example of cancer includes but is not limited to cancer (carcinoma), lymthoma, embryo Cytoma, sarcoma and leukaemia, or malignant lymph proliferative disease (lymphoid malignancies).Such cancer is more Specific example includes squamous cell carcinoma (such as epithelium squamous cell carcinoma), lung cancer (including ED-SCLC, non-small cell lung cancer (NSCLC), adenocarcinoma of lung and lung carcinoma squamosum), peritoneal cancer, hepatocellular carcinoma (hepatocellular cancer), stomach cancer (gastric Or stomach cancer) (including human primary gastrointestinal cancers), cancer of pancreas, glioblastoma, cervical carcinoma, oophoroma, liver cancer (liver Cancer), carcinoma of urinary bladder, hepatoma (hepatoma), breast cancer, colon and rectum carcinoma, colorectal cancer, carcinoma of endometrium or The cancer of the uterus, salivary-gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, carcinoma of vulva, thyroid gland Cancer, liver cancer (hepatic carcinoma), cancer of anus, carcinoma of penis and head and neck cancer.
The description of compound of the invention
Heteroaromatic class compound of the present invention, its pharmaceutically acceptable salt, and its pharmaceutical preparation, swash to albumen The treatment of enzyme, especially PI3K or the disease or illness of mTOR regulations has potential purposes.
Particularly, on the one hand, the present invention relates to a kind of compound, it is the compound of structure shown in formula (I) or formula (I) institute Show the stereoisomer of compound, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, Pharmaceutically acceptable salt or its prodrug：
Wherein：Each Y, R1, Z, W1, W2And W3With definition as described in the present invention.
In some embodiments, each W1, W2And W3It independently is N or CRc；
Z is D, CN, N3Or
X is H, D, C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical-C1-4 Alkylidene, C6-10Aryl or comprising 1,2,3 or 4 heteroatomic 5-10 for being independently selected from O, S and N former molecular heteroaryls Base, wherein, the C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical-C1-4Alkylene Base, C6-10Aryl and 5-10 former molecular heteroaryl is unsubstituted independently of one another or is taken by 1,2,3 or 4 substitution base In generation, the substitution base is independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-6Alkyl, C1-6Halogen Substituted alkyl, C2-6Alkenyl, C2-6Alkynyl, NC-C1-4Alkylidene, RaO-C1-4Alkylidene, RbRaN-C1-4Alkylidene, C6-10Aryl or 5- 10 molecular heteroaryls of original；
Y is C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical-C1-4Alkylene Base, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl or comprising 1,2,3 or 4 heteroatomic 5-10 atom for being independently selected from O, S and N The heteroaryl of composition, wherein, the C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocycle Base-C1-4Alkylidene, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl and 5-10 former molecular heteroaryl are not taken independently of one another In generation, is replaced by 1,2,3 or 4 substitution base, and the substitution base is independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-6Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6Alkynyl, NC-C1-4Alkylidene, RaO-C1-4Alkylene Base, RbRaN-C1-4Alkylidene, C6-10Aryl or 5-10 former molecular heteroaryl；
R1It is H, D, Cl, ORa, NRaRb, C1-6Aliphatic or C3-6Cycloalkyl, wherein, the C1-6Aliphatic and C3-6Cycloalkanes Base is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substitution base, described to replace base independently selected from D, F, Cl, CN, N3, ORa, SRaOr NRaRb；
Each RaAnd RbIt independently is H, C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C6-10Aryl, comprising 1,2,3 or 4 It is independently selected from the heteroatomic 5-10 former molecular heteroaryl of O, S and N, C6-10Aryl-C1-4Alkylidene, (5-10 atom The heteroaryl of composition)-C1-4Alkylidene, or Ra, RbWith nitrogen-atoms in connection together, it is optionally formed substituted or non-takes The 3-8 former molecular heterocycle in generation, wherein, the substitution base is unsubstituted independently of one another or by 1,2,3 or 4 substitution base Replaced, the substitution base is independently selected from D, F, Cl, CN, N3, OH, NH2, C1-6Alkoxy or C1-6Alkyl amino；
Each RcIt independently is H, D, F, Cl, Br, I, N3, CN, OH, NH2, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, C3-6Cycloalkyl, C3-6Heterocyclic radical, C6-10Aryl is former comprising 1,2,3 or 4 be independently selected from O, S and N heteroatomic 5-10 Molecular heteroaryl, wherein, the C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, C3-6Cycloalkyl, C3-6Heterocyclic radical, C6-10Aryl and 5-10 former molecular heteroaryl is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substitution base, The substitution base is independently selected from D, F, Cl, CN, N3, OH, NH2, C1-6Alkyl, C3-6Cycloalkyl, C1-6Haloalkyl, C1-6Alcoxyl Base or C1-6Alkyl amino.
In other embodiment, W1It is N or CRc；Each W2And W3It independently is CRc。
In other embodiment, Z is CN, N3Or
In other embodiment, X is H, D, C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4It is sub- Alkyl or C3-6Heterocyclic radical-C1-4Alkylidene, wherein, the C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4 Alkylidene and C3-6Heterocyclic radical-C1-4Alkylidene is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substitution base, described Substitution base is independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-3Alkyl, C1-3Haloalkyl, C2-4Alkenyl or C2-4Alkynyl.
In other embodiment, Y is C1-6Alkyl, C3-6Cycloalkyl, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl or bag Containing 1,2,3 or 4 heteroatomic 5-10 for being independently selected from O, S and N former molecular heteroaryl, wherein, the C1-6Alkyl, C3-6Cycloalkyl, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl and 5-10 former molecular heteroaryl are unsubstituted independently of one another Or replaced by 1,2,3 or 4 substitution base, the substitution base is independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-3Alkyl, C1-3Haloalkyl, C2-4Alkynyl, C6-10Aryl or 5-10 former molecular heteroaryl.
In other embodiment, R1It is H, D, Cl, CH3, CH2CH3, CF3, CH2CF3, OCH3Or OCH2CH3。
In other embodiment, each RcIt independently is H, D, F, Cl, N3, CN, NH2, C1-3Alkyl, C1-3Alkoxy, C1-3Alkyl amino, C3-6Cycloalkyl or C3-6Heterocyclic radical, wherein, the C1-3Alkyl, C1-3Alkoxy, C1-3Alkyl amino, C3-6Ring Alkyl and C3-6Heterocyclic radical is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substitution base, and the substitution base is independently Selected from D, F, CN, N3, OH, NH2, C1-3Alkyl, C3-6Cycloalkyl or C1-3Haloalkyl.
It is several the present invention relates to the compound of one of or its stereoisomer in other embodiment What isomers, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, but It is not limited to these compounds：
Application of the present invention also comprising compound of the invention and its pharmaceutically acceptable salt, i.e., for producing medical product The disease of product treatment acute and chronic blood vessel generation mediation, including those are described in the invention.Compound of the invention is anti-in production Application in cancer drug.Compound of the invention is equally used for producing a kind of medical supplies mitigating, prevent, control or treat by The disease that PI3K or mTOR are mediated.The present invention includes pharmaceutical composition, and the pharmaceutical composition includes the chemical combination representated by formula (I) Thing and at least one pharmaceutically acceptable carrier, the effective treatment consumption needed for the combination of assistant agent or excipient.
The same disease mediated comprising treatment patient vessel of the invention, or the method sensitive to this illness, the method Comprising being treated to patient using the therapeutically effective amount of compound representated by formula (I).
Unless other aspects show, all of stereoisomer of compound of the invention, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to model of the invention Enclose.
In some embodiments, the salt refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refers to thing The mammal that matter or composition must be treated with other compositions comprising preparation and/or with it is chemically and/or in toxicology It is compatible.
The salt of compound of the invention is also included for preparing or purifying the intermediate of compound shown in formula (I) or formula (I) The salt of the enantiomter that shown compound is separate, but it is not necessarily pharmaceutically acceptable salt.
Pharmaceutically useful acid-addition salts can be formed with inorganic acid and organic acid, for example acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.
The inorganic acid that salt can be obtained by its derivative is including such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc..
The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, butanedioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, pyruvic acid, p-methyl benzenesulfonic acid, Sulfosalicylic acid etc..Pyrans saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Amino Acid, such as asparatate and glutamic acid；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, ethyl sulfonic acid, etc. Deng.
Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.
The inorganic base of salt can be obtained by its derivative includes, the metal of I races to the XII races of such as ammonium salt and periodic table. In some embodiments, the salt is derived from sodium, potassium, lithium, ammonium, calcium, magnesium, iron, aluminium, silver, manganese, zinc and copper；Particularly suitable salt bag Include ammonium, potassium, sodium, calcium and magnesium salts.
The organic base that salt can be obtained by its derivative include primary amine, secondary amine and tertiary amine, substitution amine it is (including naturally occurring Substituted amine), cyclic amine (such as morpholine and piperazine), alkali metal hydroxide, alkaline earth metal hydroxide or alkali ion hand over Change resin etc..Some organic amines, e.g., isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol Amine, diethylamine, lysine, meglumine (meglumine), piperazine and tromethamine.Some amino acid, such as glycine and smart ammonia Acid.
Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalescence or acidic moiety. In general, such salt can by make the free acid form of these compounds and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or by making the free alkali form of these compounds and chemistry The suitable acid reaction of metered amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile in the case of appropriate. Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts：Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) in can find the list of the suitable salt of other.
And, the compounds of this invention, can also be obtained with its hydrate forms including its salt, or be used for it including other The solvent of crystallization.The compounds of this invention can form the solvation with acceptable solvent (including water) inherently or by designing Thing；Therefore, the invention is intended to include solvation and unsolvated form.
On the other hand, the invention provides the preparation of compound shown in formula (I), the method for separating and purifying.The present inventionization Compound might have the form of several asymmetric centers or generally described raceme mixture.Further bag of the invention Containing racemic mixture, the mixture of partial racemization and isolated enantiomer and diastereomer.
Compound of the invention can be with possible isomers, rotational isomer, atropisomer, dynamic isomer The form of a kind of form or its mixture is present, and the present invention can further include isomers, rotational isomer, resistance and turn isomery The mixture of body, dynamic isomer, or isomers, rotational isomer, atropisomer, dynamic isomer part mixes Or isomers, rotational isomer, atropisomer, the dynamic isomer for separating.
Any structural formula that the present invention is given is also intended to the form and isotope mark for representing that these compounds are not labeled The form of note.The compound of isotope marks has the structure that the formula that the present invention is provided is described, except one or more atoms Replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention include The isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H,3H,11C,13C,14C,15N,18F,32P,36S,37Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention with various isotope marks, For example, wherein there is radio isotope, such as3H,14C and18Those compounds of F, or wherein there is non radioactive isotope, Such as2H and13C.The compound of such isotope marks can be used for metabolism research and (use14C), Reaction kinetics research (use example Such as2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including medicine or substrate tissue distribution survey Fixed SPECT (SPECT), or can be used in the radiotherapy of patient.18The compound pair of F or mark It is especially desirable for PET or SPECT researchs.Formula (I) compound of isotope marks can be by those skilled in the art Substituted using suitable isotope labeling reagent described by embodiment and preparation process in familiar routine techniques or the present invention Originally prepared by used unmarked reagent.
Additionally, higher isotope particularly deuterium is (i.e.,2H or D) substitution some treatment advantages can be provided, these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increases or volume requirements are reduced or therapeutic index obtains improving band Come.It should be appreciated that the deuterium in this context is seen as the substitution base of formula (I) compound.Isotope enrichment factor can be used To define the concentration of such higher isotope particularly deuterium.Term " isotope enrichment factor " used in the present invention refers to meaning Determine the ratio between the isotope abundance of isotope and natural abundance.If the substitution base of the compounds of this invention is designated as deuterium, The compound has at least 3500 (at each specified D-atoms 52.5% deuterium mix), at least for each D-atom specified 4000 (60% deuterium is mixed), at least 4500 (67.5% deuterium is mixed), at least 5000 (75% deuterium is mixed), at least 5500 (82.5% deuterium is mixed), at least 6000 (90% deuterium is mixed), at least 6333.3 (95% deuterium is mixed), at least 6466.7 The isotope enrichment of (97% deuterium is mixed), at least 6600 (99% deuterium is mixed) or at least 6633.3 (99.5% deuterium is mixed) The factor.The pharmaceutically useful solvate of the present invention can be such as D of isotope substitution including wherein recrystallisation solvent2O, acetone-d6、 DMSO-d6Those solvates.
The composition of compound of the invention, preparation and administration
According on the other hand, including the compound of formula (I) the characteristics of pharmaceutical composition of the invention, listed by the present invention Compound, or embodiment 1-11 compound, and pharmaceutically acceptable carrier, assistant agent, or excipient.Composition of the invention The amount of middle compound effectively can detectably suppress the protein kinase in biological sample or patient's body.
There is free form in compound of the invention, or suitably, as pharmaceutically acceptable derivates.According to this hair Bright, pharmaceutically acceptable derivates are included, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of esters, or energy Directly or indirectly according to other any adducts or derivative being administered the need for patient, described by other aspects of the invention Compound, its metabolite or his residue.
As described in the invention, pharmaceutically acceptable composition of the invention further includes pharmaceutically acceptable load Body, assistant agent, or excipient, these are applied as the present invention, including any solvent, diluent, or other liquid excipients, point Powder or suspending agent, surfactant, isotonic agent, thickener, emulsifying agent, preservative, solid binder or lubricant, etc., It is suitable for distinctive target formulation.As described by documents below：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins, Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick The content of the comprehensive documents herein of and J.C.Boylan, 1988-1999, Marcel Dekker, New York., shows different Carrier can be applied to the preparation and their known preparation methods of pharmaceutically acceptable composition.Except any conventional carrier The medium scope incompatible with compound of the invention, such as produced any bad biological effect or with can pharmaceutically connect What any other component for the composition received was produced in harmful manner interacts, and their purposes is also that the present invention is considered Scope.
Can be included, but is not limited to as the material of pharmaceutically acceptable carrier, ion-exchanger, aluminium, aluminum stearate, ovum Phosphatide, such as haemocyanin, human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturation vegetable butter The partial glyceride mixtures of fat acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination Sodium, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymerization Body, lanolin, such as sugar, lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；Cellulose and its derivative Such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder；Auxiliary material such as cocoa bean Fat and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycols chemical combination Thing, such as propane diols and polyethylene glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer such as magnesium hydroxide and Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethanol, phosphate buffer solution, and other are nontoxic Suitable lubricant such as Sodium Laurylsulfate and magnesium stearate, colouring agent, releasing agent, coating agents, sweetener, flavor enhancement and perfume (or spice) Material, preservative and antioxidant.
Composition of the invention can be administered orally, drug administration by injection, Aerosol inhalation, local administration, per rectum administration, Nose administration, buccal administration or is administered vagina administration by implantable medicine box.Term used herein " through injection " includes It is subcutaneous, vein, intramuscular, it is IA, it is intrasternal in synovial membrane (chamber), in film, intraocular, in liver, focus It is interior, and encephalic injection or infusion techniques.Preferred composition is oral administration, to Intraperitoneal medication or intravenous injection.This The injection system of the composition sterile of invention can be water or oil suspension.These suspension can be according to known skill Art is manufactured using suitable dispersant, wetting agent and suspending agent by formula.Aseptic injection can be aseptic parenteral solution or suspension Liquid, is injection nontoxic acceptable diluent or solvent, such as 1,3-BDO solution.These acceptable excipient and solvent Can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic non-volatile oil can be made by convention It is solvent or suspension media.
With this end in view, any gentle non-volatile oil can be the list or DG of synthesis.Fat Acid, such as oleic acid and its glyceride ester derivatives can be used for the preparation of injectable, used as natural pharmaceutically acceptable oil Fat, such as olive oil or castor oil, particularly their polyoxyethylene deriv.These oil solutions or suspension can include long-chain Alcohol diluent or dispersant, such as carboxymethylcellulose calcium or similar dispersing agents, are generally used for the medicine system of pharmaceutically acceptable formulation Agent includes emulsion and suspension.Other conventional surfactants, such as Tweens, spans and other emulsifying agents or biological medicament The hardening agent of efficiency, is generally used for pharmaceutically acceptable solid, liquid, or other formulations, it is possible to be applied to drug target The preparation of preparation.
The pharmaceutically acceptable composition of the present invention can be administered orally with any acceptable peroral dosage form, its In include, but is not limited to, capsule, tablet, water suspension or solution.Orally used on tablet, carrier generally comprises breast Sugar and cornstarch.Lubricant, such as magnesium stearate, are all typically added.For capsule oral administration, suitable diluent bag Include lactose and dry cornstarch.When being administered orally as water suspension, its active ingredient is made up of emulsifying agent and suspending agent. If expecting these formulations, some sweeteners, flavor enhancement or colouring agent can also be added.
In addition, pharmaceutically acceptable composition of the invention can in the form of suppository rectally.These can pass through Reagent is mixed with suitable non-perfusing adjuvant and is formed, this adjuvant at room temperature for solid but at a temperature of rectum then It is liquid, so as to melt in the rectum and discharge medicine.Such material includes cocoa butter, beeswax, and polyethylene glycols.This When inventing pharmaceutically acceptable composition and can be local administration, particularly local application, it is related to controlling for region or organ Treat target easily to reach, such as the disease of eye, skin or lower intestinal tract.Suitable topical preparations can be prepared and are applied to These fields or organ.
Rectal suppository (see above content) or suitable enema can apply to the local application of lower intestine.Local skin Skin spot is it is also possible that medication.For local application, pharmaceutically acceptable composition can be prepared into properly by formulation method Ointment, the ointment packets are suspended or dissolved in one or more carriers containing active component.It is supported that part of the invention is administered Compound includes, but is not limited to mineral oil, atoleine, albolene, propane diols, polyoxyethylene, polyoxypropylene compound, breast Change wax and water.In addition, pharmaceutically acceptable composition can be prepared into suitable lotion or emulsion, the lotion or emulsion are included Active component is suspended in or is dissolved in one or more pharmaceutically acceptable carriers.Suitable carrier is included, but is not limited to, ore deposit Thing oil, Arlacel-60 (Arlacel-60), Tween-60 (polysorbate 60), cetyl esters wax, palmityl alcohol, 2- Octyldodecanol, phenmethylol and water.
Preparation can be prepared into for ophthalmically acceptable, pharmaceutically acceptable composition, such as isotonic micronized suspension, pH The Sterile Saline of regulation or other aqueous solution, it is preferable that isotonic solution and the Sterile Saline or other aqueous solution of pH regulations, can be with Addition disinfection preservative such as benzalkonium chloride.In addition, for ophthalmically acceptable, pharmaceutically acceptable composition can be by pharmaceutical formulation system It is standby into ointment such as vaseline oil.The pharmaceutically acceptable composition of the present invention can by the gaseous solvents of nose or inhalant carry out to Medicine.Such composition can be prepared according to the known technology of pharmaceutical formulation, or can be prepared into salting liquid, use benzene first Alcohol or other suitable preservatives, sorbefacient, fluorocarbon or other conventional solubilizer or dispersant improve biology Availability.
The liquid dosage form of oral administration is included, but is not limited to, pharmaceutically acceptable emulsion, microemulsion, solution, is suspended Liquid, syrup and elixir.In addition to the active compound, liquid dosage form can include known general inert diluent, for example, water Or other solvents, solubilizer and emulsifying agent, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, phenmethylol, Ergol, Propane diols, 1,3-BDO, dimethylformamide, grease (particularly cottonseed, peanut, corn, microorganism, olive, castor-oil plant and Sesame oil), glycerine, Tetrahydrofurfuryl Alcohol, polyethylene glycol, sorbitan alcohol fatty acid ester, and their mixture.Except lazy Property diluent outside, Orally administered composition can also include assistant agent such as wetting agent, emulsifying agent or suspending agent, sweetener, flavor enhancement And aromatic.
Injection, such as aseptic parenteral solution or oil suspension can according to known technology using suitable dispersant, Wetting agent and suspending agent are prepared by pharmaceutical formulation.Aseptic injection can be nontoxic through parenterally acceptable diluent Or aseptic parenteral solution, suspension or the emulsion that solvent is made, for example, 1,3-BDO solution.Acceptable excipient and solvent Can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic non-volatile oil is by convention As solvent or suspension media.With this end in view any gentle non-volatile oil can include that the list or two Portugal's bases of synthesis are sweet Oily diester.In addition, aliphatic acid such as oleic acid can apply to injection.
Injection can be aseptic, such as defend filter by bacterium and filter, or in the form of aseptic solid composite Bactericidal agent is mixed, in being dissolved in or being scattered in disinfectant or other sterile injectable mediums using preceding bactericidal agent.In order to prolong The effect of length compound of the invention, it usually needs slow down the absorption of compound by hypodermic injection or intramuscular injection.So Can realize solving the problems, such as crystal or AMAT poorly water-soluble using liquid suspension.The absorptivity of compound is depended on Its dissolution rate, successively depending on grain size and crystal shape.Furthermore it is possible to pass through compound be dissolved in oil vehicles Or delay of the dispersion to complete compound injection administration absorbs.
Injection storage form is that, by biodegradable polymer, such as many lactic acid-polyglycolide forms chemical combination What the microcapsule matrix of thing was completed.The controlled release ratio of compound depends on the ratio and particular polymer that compound forms polymer Property.Other biodegradable polymers include poly- (positive esters) and poly- (acid anhydrides).Injection storage form can also pass through The compound insertion liposome compatible with bodily tissue or microemulsion are prepared.
Some of them embodiment is, the composition of rectum or vagina administration is suppository, and suppository can be by will be of the invention Compound mixes to prepare with the auxiliary material or carrier of suitable non-perfusing, such as cocoa butter, and polyethylene glycol, or suppository is wax-like Thing, they are solid in room temperature but are then under body temperature liquid, therefore release of active conjunction is just melted in vagina or cavity of tunica vaginalis Thing.
The solid dosage forms of oral administration includes capsule, tablet, pill, pulvis and granula.In these formulations, active ingredient Thing mixes with least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or filler or a) Filler such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) adhesive such as carboxymethylcellulose calcium, alginates are bright Glue, polyvinyl pyrrolidone, sucrose and Arabic gum, c) NMF such as glycerine, d) disintegrant such as agar, calcium carbonate, potato starch Or tapioca, alginic acid, some silicate and sodium carbonate, e) block agent solution such as paraffin, f) sorbefacient such as quaternary ammonium Compound, g) wetting agent such as hexadecanol and glycerin monostearate, h) absorbent such as white bole and bentonite, i) lubricant such as talcum Powder, calcium stearate, magnesium stearate, solid polyethylene glycol, Sodium Laurylsulfate, and their mixture.As for capsule, tablet and ball Agent, these formulations can include buffer.
The solid composite of similar type can be that filler riddles soft or hard capsule, and the auxiliary material for being used has breast Sugared and high molecular polyethylene glycol etc..Solid dosage forms photo agent, lozenge, capsule, pill and granula can be by coating, shell addings As known coating method is prepared on enteric coating and other drugs preparation.They can optionally include opacifier, or Preferably, in certain part of enteron aisle, arbitrarily, the sole active agent in composition is discharged in the method for postponing.As being implanted into Composition can include multimeric species and wax.
Reactive compound can form microcapsule formulations together with one or more excipient described in the invention.Solid The agent of formulation photo, lozenge, capsule, pill and granula can be by coating or shell addings, such as enteric coating, controlled release coat and other public affairs The drug formulation process known.In these solid dosage forms, reactive compound can mix with least one inert diluent, such as sugarcane Sugar, lactose or starch.Such formulation can also include additive besides inert diluents as general application, such as Tableting lubricant and other compression aids such as magnesium stearate and microcrystalline cellulose.As for capsule, tablet and pill, these formulations can With comprising buffer.They can optionally include sedative, or preferably, in certain part of enteron aisle, with any delay Sole active agent in method release composition.Applicable implant compositions can be included, but is not limited to, polymer and Wax.
Compound of the invention includes ointment by local or through percutaneous drug delivery formulation, and paste, emulsion, lotion coagulates Jelly, pulvis, solution, spray, inhalant, paster.Active component under sterile conditions with pharmaceutically acceptable carrier Mixed with any required preservative or required buffer.The pharmaceutical preparation of ophthalmology, auristilla and eye drops are all this hairs The scope of bright consideration.In addition, present invention further contemplates that the application of transdermal patch, it is delivered to aspect in vivo in control compound has More advantages, such formulation can be by dissolving or dispersion compound is prepared in suitable medium.Absorb and promote Enter agent can increase compound through skin flow, through-rate control film or by compound be scattered in polymer matrix or Gelatin controls its speed.
Compound of the invention is preferably prepared into dosage unit form to mitigate the equal of dosage and dosage by pharmaceutical formulation Even property.Term " dosage " unit type " obtains the physical dispersion unit of medicine needed for appropriate treatment referred to herein as patient.However, should Understand the daily total usage of compound of the invention or composition will by the doctor in charge according to reliable medical science scope judge come It is determined that.Specific effective dose level will include being controlled for any one special patient or organism depending on many factors The illness for the treatment of and the seriousness of illness, the activity of particular compound, concrete composition used, the age of patient, body weight, health The discharge rate of situation, sex and eating habit, administration time, method of administration and particular compound used, treatment it is lasting when Between, medicinal application is combined in drug combination or with specific compound, and factor known to some other pharmaceutical field.
The change that the consumption of the compound of the invention of the carrier mass single dosage form composition of generation can be combined is depended on Cure mainly and special mode of administration.Some of them embodiment is that composition can be prepared into dosage in 0.01- by formulation method The inhibitor of 200mg/kg body weight/days, receives the amount of composition to be administered by patient.
Compound of the invention can be with only pharmaceutical agents or with reference to one or more other additional treatment (pharmacy ) agent is administered, wherein drug combination causes acceptable adverse reaction, and this has for the treatment of proliferative disease high such as cancer There is special meaning.In this case, compound of the invention can combine known cytotoxic agent, and single transduction suppresses Agent or other antitumor and anticancer agents, and their mixture and combination.As used in the present invention, additional therapeutic agent normally control by administration Treat special disease, exactly known " suitably treating disease "." additional therapeutic agent " used in the present invention includes Chemo-Therapy Treating medicine or other antiproliferative medicines can combine compounds for treating proliferative diseases of the invention or cancer.
Chemotherapeutic agent or other anti-proliferative drugs include histon deacetylase (HDAC) (HDAC) inhibitor, including but simultaneously It is not limited to, SAHA, MS-275, MGO103, and the compound described by those following patents：WO 2006/010264,WO 03/024448,WO 2004/069823,US 2006/0058298,US 2005/0288282,WO 00/71703,WO 01/ 38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO2005/030705, WO 2005/092899, and Demethylating agent is included, but is not limited to, the miscellaneous nitrogen -2 of 5- '-deoxycytidine (5-aza-dC), azacitidine (Vidaza), Compound described by his shore (Decitabine) of west and documents below：US 6,268137,US 5,578,716,US5,919, 772, US 6,054,439, US 6,184,211, US 6,020,318, US 6,066,625, US 6,506,735, US 6, 221,849,US 6,953,783,US 11/393,380。
Other embodiment is that chemotherapeutics or other anti-proliferative drugs can increase with reference to compounds for treating of the invention Growing property disease and cancer.Known chemotherapeutics is included, but is not limited to, can be used with anti-cancer agent in combination of the present invention other Therapy or cancer therapy drug, operation, radiotherapy (a little example such as γ is radiated, neutron beam radiotherapy, electron beam evaporation therapy, Proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, taxanes (taxol (Taxol), Docetaxel (Taxotere)), (cis-platinum (Cisplatin), carboplatin (Carboplatin) is difficult to understand husky for platinum derivatives Sharp platinum (oxaliplatin), Satraplatin (satraplatin)), BRM (interferon, interleukin), tumour is bad Necrosis factor (TNF, TRAIL receptor target thing), overheat and cold therapy, mitigate the reagent (such as antiemetic) of any adverse reaction, With other approved chemotherapeutics, including but not limited to, alkylating drug (mustargen (mechlorethamine), benzenebutanoic acid nitrogen Mustard (chlorambucil), endoxan (cyclophosphamide), melphalan (melphalan), ifosfamide (Ifosfamide)), antimetabolite (methotrexate (MTX) (Methotrexate), pemetrexed (Pemetrexed)), purine antagonism Agent and Pyrimidine antagonists (6-MP (6-Mercaptopurine), 5 FU 5 fluorouracil (5-Fluorouracil), cytarabine (Cytarabile), gemcitabine (Gemcitabine)), spindle poison (vincaleukoblastinum (Vinblastine), vincristine (Vincristine), vinorelbine (Vinorelbine)), podophyllotoxin (Etoposide (Etoposide), Irinotecan (Irinotecan), Hycamtin (Topotecan)), antibiotic (adriamycin (Doxorubicin), bleomycin (Bleomycin), mitomycin (Mitomycin)), nitroso ureas (BCNU (Carmustine), lomustine (Lomustine)), (KSP is suppressed CDC inhibitor by mitotic kinesin inhibitors, CENP-E and CDK Agent), enzyme (asparaginase (Asparaginase)), hormone (tamoxifen (Tamoxifen), Leuprorelin (Leuprolide), Flutamide (Flutamide), megestrol acetate (Megestrol), dexamethasone (Dexamethasone) etc. Deng).Anti-angiogenesis reagent (Avastin (Avastin) etc.).Monoclonal antibody (Baily monoclonal antibody (Belimumab), Brentuximab, Cetuximab (Cetuximab), WAY-CMA 676 (Gemtuzumab), her monoclonal antibody (Ipilimumab), Ofatumumab, handkerchief Buddhist nun's monoclonal antibody (Panitumumab), Lucentis (Ranibizumab), Rituximab (Rituximab), tositumomab (Tositumomab), Herceptin (Trastuzumab)).Kinase inhibitor (Imatinib (Imatinib), Sutent (Sunitinib), Sorafenib (Sorafenib), Tarceva (Erlotinib), Gefitinib (Gefitinib), up to sand For Buddhist nun (Dasatinib), AMN107 (Nilotinib), Lapatinib (Lapatinib), gram Zhuo replaces Buddhist nun (Crizotinib), Ruxolitinib, Vemurafenib, Vandetanib, Pazopanib, etc.).The approach of Drug inhibition or activation cancer is such as MTOR, HIF (hypoxia inducible factor) approach and other.Http sees in the wide forum for the treatment of of cancer:// The oncologic inventory of www.nci.nih.gov/, FDA accreditation is shown in http://www.fda.gov/cder/cancer/ Druglist-rame.htm and Merck Manual, the 18th edition .2006, all of content are all combined with bibliography.
Other embodiment is that compound of the invention can combine cytotoxic anticancer agent.Such anticancer can Found with the 13rd edition Merck index (2001) is inner.These anticancers include, but are not limited to, asparaginase, win and Mycin, carboplatin, BCNU, Chlorambucil, cis-platinum, L-ASP, endoxan, cytarabine, Dacarbazine is put Line rhzomorph D, daunorubicin, adriamycin (Doxorubicin), epirubicin, Etoposide, 5-fluor-uracil, hexamethyl melamine Amine, hydroxycarbamide, ifosfamide, Irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna, first ammonia butterfly Purine, mitomycin C, mitoxantrone, prednisolone, metacortandracin, procarbazine, Raloxifene, streptozocin, TAM, sulphur Guanine, Hycamtin, vincaleukoblastinum, vincristine, and eldisine.
Other suitable cytotoxic drugs with compound drug combination of the invention are included, but is not limited to, these The compound of ND treatment is admittedly applied to, as described in documents below：Goodman and Gilman's The Pharmacological Basis of Therapeutics(Ninth Edition,1996,McGraw-Hill.)；This A little anticancers include, but are not limited to, aminoglutethimide (Aminoglutethimide), ASP, imuran, 5- Azacytidine, Cladribine (cladribine), busulfan (busulfan), diethylstilbestrol, 2,2'- difluoro dCDP courages Alkali, Docetaxel, red hydroxyl nonyl adenine (erythrohydroxynonyladenine), ethinylestradiol, 5- fluorine Uracil deoxyribonucleoside, floxuridine monophosphate, fludarabine phosphate (fludarabine phosphate), Fluoxymesterone Ketone (fluoxymesterone), Flutamide (flutamide), hydroxyprogesterone caproate, idarubicin (idarubicin), interferon, Medroxyprogesterone acetate, megestrol acetate, melphalan (melphalan), mitotane (mitotane), taxol, Pentostatin (pentostatin), N- phosphates base-L-Aspartic acid (PALA), plicamycin (plicamycin), methyl cyclohexane nitrous Urea (semustine), Teniposide (teniposide), testosterone propionate, phosphinothioylidynetrisaziridine (thiotepa), trimethyl melamine Amine, urinates nucleosides and vinorelbine.
Other suitably include newfound cell with the cytotoxin class anticancer of compound use in conjunction of the invention Toxic substance, including, but be not limited to, oxaliplatin (oxaliplatin), gemcitabine (gemcitabine), card training His shore (capecitabine), macrolides antineoplastic and its natural or synthetic derivative, Temozolomide (temozolomide) (Quinn et al., J.Clin.Oncology, 2003,21 (4), 646-651), tositumomab (bexxar), Trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004,23, abstract 3181), and drive albumen spindle protein inhibitor Eg5 (Wood et al.,Curr.Opin.Pharmacol.2001,1,370-377)。
Other embodiment is that compound of the invention can combine other signal transduction inhibitors.What is interesting is letter Number transduction inhibitor using EGFR families as target, such as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000, 60(Suppl.l),15-23；Harari et al., Oncogene, 2000,19 (53), 6102-6114) and their own match somebody with somebody Body.Such reagent includes, but is not limited to, antibody therapy such as Herceptin (trastuzumab), Cetuximab (cetuximab), her monoclonal antibody (ipilimumab) and handkerchief trastuzumab (pertuzumab).Such therapy also includes, but It is not limited to, small molecule kinase inhibitors such as Imatinib (imatinib), Sutent (sunitinib), Sorafenib (sorafenib), Tarceva (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), Ni Luo For Buddhist nun (nilotinib), Lapatinib (lapatinib), gram Zhuo replaces Buddhist nun (crizotinib), ruxolitinib, Vemurafenib, vandetanib, pazopanib, Afatinib (afatinib), amuvatinib, Axitinib (axitinib), SKI-606 (bosutinib), brivanib, canertinib, cabozantinib, AZD2171 (cediranib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, Ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, Masitinib (masitinib), Momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), niraparib, oprozomib, Olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, plug Block and replace Buddhist nun (saracatinib), saridegib, tandutinib, tasocitinib, telatinib, tivantinib, Tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941 (Folkes, et al., J.Med.Chem.2008,51,5522), BZE235, etc..
Other embodiment is that compound of the invention can be with bonding histone deacetylase inhibitors.It is such Reagent includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings Of the American Society for Clinical Oncology, 2004,23, abstract 3024), LBH-589 (Beck et al.,Proceedings of the American Society for Clinical Oncology,2004, 23, abstract 3025), MS-275 (Ryan et al., Proceedings of the American Association Of Cancer Research, 2004,45, abstract 2452), FR-901228 (Piekarz et al., Proceedings of the American Society for Clinical Oncology,2004,23,abstract 3028) with MGCDOI 03 (US 6,897,220).
Other embodiment is, compound of the invention can combine other anticancers such as proteasome inhibitor with MTOR inhibitors.These include, but are not limited to, bortezomib (bortezomib) (Mackay et al., Proceedings Of the American Society for Clinical Oncology, 2004,23, Abstract 3109), and CCI- 779(Wu et al.,Proceedings of the American Association of Cancer Research, 2004,45,abstract 3849).Compound of the invention can be combined with other anticancers such as topoisomerase enzyme inhibitor, Including but not limited to camptothecine.
Those additional therapeutic agents can separately be administered with the composition comprising compound of the invention, used as many dosage regimens A part.Or, those therapeutic agents can be a part for one-pack type, mix to form list with compound of the invention Individual composition.If be administered as a part for many dosage regimens, two activating agents can be simultaneously continuously or in a period of time Interior mutual transmission, so as to obtain destination agent activity.
Can combine carrier mass produce one-pack type compound and additional therapeutic agent consumption (those comprising one add The composition of therapeutic agent is as described in the invention) change depend on cure mainly and special mode of administration.Normally, it is of the invention The amount of composition additional therapeutic agent will include therapeutic agent as the normal amount administered of unique activating agent no more than composition.Separately On the one hand, the scope of the amount of existing disclosed composition additional therapeutic agent is about the 50%-100% of existing composition normal amount, Comprising reagent as sole active therapeutic agent.In those compositions comprising additional therapeutic agent, additional therapeutic agent will be with this The compound of invention plays synergy.
The purposes of compound of the invention and composition
The feature of pharmaceutical composition of the invention includes the compound shown in formula (I) or the compound listed by the present invention, And pharmaceutically acceptable carrier, assistant agent or excipient.The amount of compound can effectively can be visited in composition of the invention Geodetic suppresses the activity of protein kinase such as PI3K or mTOR.The compounds of this invention will be treated as antineoplastic to patient Or reduce the illeffects of PI3K or mTOR signals response.
Compound of the invention will be applied to, but be not limited to, and use compound of the invention or the effective dose of composition Prevent patient's administration or treat patient's proliferative diseases.Such disease includes cancer, especially metastatic carcinoma, and artery is athero- Hardening and pulmonary fibrosis.
The treatment that compound of the invention will be applied to knurl includes cancer and metastatic carcinoma, further includes but is not limited to, Cancer such as carcinoma of urinary bladder, breast cancer, colon cancer, kidney, liver cancer, lung cancer (including ED-SCLC), cancer of the esophagus, carcinoma of gallbladder, ovary Cancer, cancer of pancreas, stomach cancer, cervical carcinoma, thyroid cancer, prostate cancer, and cutaneum carcinoma (including squamous cell carcinoma)；Lymphatic system hematopoiesis Tumour (including leukaemia, the Cystic leukaemia of acute lymphoblastic, acute lymphoblastic leukemia, B cell lymphoma, T cell Lymthoma, He Jiejin (family name) lymthoma, non-hodgkin's (family name) lymthoma, hairy cell leukemia and Burkitt lymphoma)；Marrow System hematopoetic tumor (including the white blood of acute and chronic myelocytic leukemia, RAEB, and promyelocyte Disease)；The tumour (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, such as soft tissue and cartilage) of mesenchymal cell origin； Maincenter peripheral nervous system knurl (including astrocytoma, neuroblastoma, glioma, and neurinoma)；And other Tumour (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pitmentosum, keratoacanthoma, thyroid follicle knurl With card ripple Ji (family name) sarcoma).
Compound of the invention can also be used to treat eye disease such as corneal graft rejection, and the new vessels of eye is formed, Retinal neovascularazation includes damaging or metainfective new vessels is formed；Diabetic retinopathy；It is fine after crystalline lens Dimensional tissue hyperplasia disease, and neovascular glaucoma；Treat retinal ischemic；Vitreous hemorrhage；Ulcer disease such as gastric ulcer；Pathology The blood vessel of situation such as hemangioma learn but non-malignant, including baby's hemangioendothelioma, nasopharynx and ANB is fine Dimension knurl；Female repro ductive system is disorderly such as mullerianosis.These compounds are equally also used for treating oedema and vascular permeability Too high situation.
Compound of the invention can be used for the treatment situation such as diabetic retinopathy and micro- blood related to diabetes Pipe disease.Compound of the invention is equally used for the situation of cancer patient's CBF reduction.Compound of the invention is to patient tumors Transfer is reduced also beneficial effect.
Compound of the invention applies also for veterinary treatment pet, introduced variety in addition to beneficial to human treatment Animal and farm animal, including mammal, rodent etc..The example of other animal include horse, dog and Cat.Here, compound of the invention includes its pharmaceutically acceptable derivates.
In the case where plural form is applied into compound, salt etc., it also means single compound, salt etc..
Comprising the treatment method that compound of the invention or composition are administered, further include to patient's additional therapeutic agent The administration of (therapeutic alliance), wherein additional therapeutic agent are selected from：Chemotherapy, antiproliferative or antiinflammatory, wherein additional therapeutic agent Suitable for the disease treated, and additional therapeutic agent can with compound of the invention or composition administering drug combinations, it is of the invention Compound or composition compound as single formulation or separate or composition as multi-form a part.Additional treatment Agent can be administered simultaneously with compound of the invention or not be administered simultaneously.The situation of the latter, administration can stagger to be carried out as 6 is small When, carry out within 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
The method of the same cell growth inhibition comprising to expressing PI3K or mTOR of the invention, the method includes of the invention Compound or composition and cells contacting, so as to suppress cell growth.The cell that growth can be suppressed includes：Breast cancer cell, Colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate gland cancer cell, lymphoma cell, colon cancer cell, pancreas Cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cell, human osteosarcoma cell, kidney cancer cell, liver is thin Born of the same parents' cancer cell, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, MC and leukaemia.
Method the invention provides PI3K or mTOR activity is suppressed in biological sample, the method includes will be of the invention Compound or composition are contacted with biological sample.Term used in the present invention " biological sample " refers to the sample of vitro, Including but not limited to, cell culture or cell extraction；From the biopsy material that mammal or its extract are obtained；Blood Liquid, saliva, urine, excrement, seminal fluid, tears, or other living tissue liquid substances and its extract.Suppress kinases in biological sample Activity, particularly PI3K or mTOR activity, can be used for multiple use known to one of ordinary skill in the art.Such purposes bag Include, but be not limited to, hematometachysis, organ transplant, biological sample is stored and bioassay.
" effective dose " or " effective dose " of compound of the invention or pharmaceutically acceptable composition refer to treatment or Mitigate the effective dose that one or more present invention are previously mentioned the severity of illness.The method according to the invention, compound and combination Thing can be any dosage and any method of administration is efficiently used for processing or mitigating the order of severity of disease.Required standard True amount changes the situation according to patient, this depend on race, the age, the general condition of patient, the order of severity of infection, Special factor, administering mode, etc..Compound or composition can with one or more other therapeutic agents administering drug combinations, such as What the present invention was discussed.
Compound of the invention or its pharmaceutical composition can apply to the coating of implantable medical device, such as prosthese, Artificial valve, artificial blood vessel, stem and catheter.For example, vascular stem, have been used for overcoming ISR (vessel wall after injury Shrink again).However, patient will have the risk of clot formation or platelet activation using stem or other implantable devices.These Unfavorable effect can be hindered by using the pharmaceutically acceptable composition precoating device comprising compound of the invention Only or mitigate.
Suitable coating is typically prepared method in document US 6,099,562 with the coating of implantable device；US 5, 886,026；With US 5, it is described in 304,121, coating is the polymeric material such as hydrogel of typically bio-compatible Condensate, the silicon ether of poly- methyl two, polycaprolactone, polyethylene glycol, PLA, ethane-acetic acid ethyenyl ester, and its mixture.Bag Clothing optionally further can be suitably coated to be covered, such as fluoro dimeticone, polysaccharase, polyethylene glycol, phosphatide Class, or combinations thereof, carry out the feature of performing combination thing control release.Another aspect of the present invention includes using of the inventionization The implantable device of compound coating.Compound of the invention can also be coated on the medical instruments in implantable, such as pearl Thing, or provide " medicine storage institute " with polymer or other molecular mixings, therefore compare with pharmaceutical aqueous solution administering mode, permit Perhaps insoluble drug release has longer time limit.
General building-up process
It is the description present invention, is listed below embodiment.But it is to be understood that the invention is not restricted to these embodiments, simply The method of the present invention is put into practice in offer.
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein substitution base definition such as formula (I) shown in.Following reaction scheme and embodiment are used to that this to be further illustrated The content of invention.
The professional of art will be recognized that：Chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds more of the invention, and be considered as in model of the invention for preparing other methods of compound of the invention Within enclosing.For example, the synthesis of the compound according to those non-illustrations of the invention can successfully by those skilled in the art Completed by method of modifying, such as appropriate protection interference group, by using other known reagents except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all of temperature is set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all not by being further purified when using, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao's purchase Can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether is dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is that drying is used in advance through anhydrous sodium sulfate.
Below reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb all suitable rubber stoppers beyond the Great Wall, substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.The survey of proton nmr spectra Strip part is：Under room temperature condition, the nuclear magnetic resonance spectrometer of Brooker (Bruker) 400MHz or 600MHz, with CDC13、DMSO-d6、CD3OD Or acetone-d6It is solvent (in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.It is many when occurring When weight peak, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, it is triple Peak), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), Dt (doublet of triplets, double triplets).Coupling constant, is represented with hertz (Hz).
The test condition of Algorithm (MS) data is：Agilent 6120Quadrupole HPLC-MS (pillars Model：Zorbax SB-C18,2.1x 30mm, 3.5 μm, 6min, flow velocity is 0.6mL/min, mobile phase：5%-95% (contains The CH of 0.1% formic acid3CN) in (H containing 0.1% formic acid2O the ratio in)), detected with UV in 210nm/254nm, use electron spray Ionization pattern (ESI).
The characteristic manner of compound purity is：The preparative high performance liquid chromatographies of Agilent 1260 (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (pillar model：NOVASEP, 50/80mm, DAC), 210nm/254nm is detected with UV.
The use of brief word below is through the present invention：
Ac2O acetic anhydrides
BBr3Boron tribromide
Double diphenyl phosphine -1,1'- the dinaphthalenes of BINAP 2,2'-
BOC, Boc tert-butoxycarbonyl
BSA bovine serum albumin(BSA)s
CDC13Deuterochloroform
CHCl3Chloroform
CH2Cl2, DCM dichloromethane
CH3SO2Cl, MsCl paratoluensulfonyl chloride
Cs2CO3Cesium carbonate
Cu copper
CuI cuprous iodides
DAST diethylaminosulfur trifluorides
Carbon -7- the alkene of DBU 1,8- diazabicyclos [5.4.0] 11
DEAD diethyl azodiformates
DIAD diisopropyl azodiformates
DIBAL diisobutyl aluminium hydrides
DIEA, DIPEA diisopropyl ethyl amine
DMAP DMAPs
DME glycol dimethyl ethers
DMF N, N'- dimethylformamides
DMSO dimethyl sulfoxide (DMSO)s
DMSO-d 6Deuterated dimethyl sulfoxide
DPPA diphenyl phosphate azides
EDCI 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
EtOAc, EA ethyl acetate
Et2O ether
Et3N, TEA triethylamine
FBS hyclones
Fe iron
G grams
H hours
HATU O- (7- nitrogen BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester
HBr hydrobromic acids
HBTU O- BTAs-N, N, N', N'- tetramethylurea hexafluorophosphates
HCl hydrochloric acid
H2Hydrogen
H2O water
H2O2Hydrogen peroxide
HOAc, AcOH acetic acid
HOBt I-hydroxybenzotriazoles
i-Pr2NH diisopropylamines
K2CO3Potassium carbonate
KOH potassium hydroxide
LiHMDS LHMDSs
LDA lithium diisopropyl amidos
MCPBA metachloroperbenzoic acids
MeCN, CH3CN acetonitriles
MeI iodomethane
MeOH, CH3OH methyl alcohol
2-MeTHF 2- methyltetrahydrofurans
MgSO4Magnesium sulfate
MsCl mesyl chlorides
ML, ml milliliter
N2Nitrogen
NaBH4Sodium borohydride
NaBH3CN sodium cyanoborohydrides
NaCl sodium chloride
NaClO2Sodium chlorite
NaH sodium hydrides
NaHCO3Sodium acid carbonate
Na2CO3Sodium carbonate
NaH2PO4Sodium dihydrogen phosphate
NaI sodium iodides
NaO (t-Bu) sodium tert-butoxide
NaOH NaOH
Na2SO4Sodium sulphate
NBS N- bromo-succinimides
NIS N- N-iodosuccinimides
NH3Ammonia
NH4C1 sal-ammoniacs
NMP 1-METHYLPYRROLIDONEs
PBS phosphate buffered saline (PBS)s
P(t-Bu)3Three (tert-butyl group) phosphines
Pd/C palladiums/carbon
Pd2(dba)3Double (dibenzyl subunit acetone) palladiums
Pd(dppf)Cl2Double (diphenylphosphino) the ferrocene palladium chlorides of 1,1'-
Pd(dppf)Cl2·CH2Cl2[double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex
Pd(OAc)2Palladium
Pd(OH)2Palladium dydroxide
Pd(PPh3)4Tetrakis triphenylphosphine palladium
Pd(PPh3)2Cl2Double (triphenylphosphine) palladium chlorides
PE petroleum ethers (60-90 DEG C)
POC13POCl3
PCl5Phosphorus pentachloride
PyBop 1H- BTA -1- base oxygen tripyrrole alkyl hexafluorophosphates
RT, rt, r.t. room temperature
Rt retention times
TBAB TBABs
TBAF tetrabutyl ammonium fluorides
TBAHSO44-butyl ammonium hydrogen sulfate
TBTU O- (1H- BTA -1- bases)-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester
TFA trifluoroacetic acids
TEAC bis- (tetraethyl ammonium) carbonate
THF tetrahydrofurans
μ L microlitre
X-Phos 2- dicyclohexyl phosphorus -2', 4', 6'- tri isopropyl biphenyls
Synthetic schemes 1-3 lists the experimental procedure for preparing compound disclosed in the present invention.Wherein, each R1, W1, W2, W3, Y There is definition as described in the present invention with Z.X ' is Cl, Br or I.
Synthetic schemes 1
Compound as shown in chemical formula (I) formula can be prepared by the method described in synthetic schemes 1. First, using go back original reagent by nitropyridine derivatives (1) be reduced into aminopyrazole derivatives (2), compound (2) again with sulphonyl Chlorine (3) react in the basic conditions, obtain compound (4), afterwards, compound (4) and connection boric acid pinacol ester (5) what is be adapted to It is coupled in the presence of Pd catalyst, generation boronic acid derivatives (6)。
Compound (12) it is also to be prepared by the method described in synthetic schemes 1.First, halogenated compound (7) in Room temperature condition and NIS occur iodide reaction generation compound (8), next, compound (8) and compound (9) (e.g., acetylene class Derivative, cyanide or azido compound, etc.) there is coupling reaction in the basic conditions, generation intermediate (10).Finally, Intermediate (10) and boronic acid derivatives (6) suitable Pd catalyst (11) the lower generation coupling reaction of effect, obtain final change Compound (12)。
Synthetic schemes 2
Some compounds in the present invention can be prepared by the method described in synthetic schemes 2.First, compound (7) and (chlorine methylene) alkyl dimethyl ammonium chloride (13) reaction obtain aldehyde (14), aldehyde (14) again with hydroxylamine hydrochloride (15) be condensed Generation oxime (16).Compound (16) further with acetic anhydride (17) the generation nitrile compounds that react (18).Finally, nitrile Compound (18) by with boronic acid derivatives (6) suitable Pd catalyst (11) generation coupling reaction is changed into finally down for effect Compound (19)。
Synthetic schemes 3
Other compounds in the present invention can also be prepared by the method described in synthetic schemes 3.First, halogen Generation compound (7) by with boronic acid derivatives (6) suitable Pd catalyst (11) the lower generation coupling reaction of effect Compound (20).Next, compound (20) in room temperature condition and NIS occur iodide reaction generation compound (21).Finally, chemical combination Thing (21) and compound (9) (e.g., acetylene analog derivative, cyanide or azido compound, etc.) generation is even in the basic conditions Connection reaction change into final compound (12)。
Specific embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.
Embodiment 1 The fluoro- N- of 2,4- bis- (5- (3- (3- hydroxyl propyl- 1- alkynes -1- bases) pyrazolo [1,5-a] pyrimidine -5- bases) - 2- methoxypyridine -3- bases) benzsulfamide
Step 1) the bromo- 2- methoxyl groups -3- nitropyridines of 5-
Sodium methoxide (0.52g, 9.64mmol) is dissolved in 10mL methyl alcohol, after being cooled to 0 DEG C, is added in reaction solution The chloro- 3- nitropyridines (0.57g, 2.41mmol) of the bromo- 2- of 5-.Reaction solution is warmed to room temperature after 0 DEG C of stirring reaction 1 hour, continues After stirring reaction 18 hours, 20mL water quenchings are added to go out reaction, reaction solution is adjusted to pH=7 by the HCl/water solution for then adding 3M. Suction filtration, filtrate is stood, point liquid, and target compound is obtained after organic phase is concentrated under reduced pressure for light yellow solid (0.4g, 71.4%).
MS(ESI,pos.ion)m/z:233.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):3.93(s,3H),8.08(s,1H),8.89(s,1H)。
Step 2) the bromo- 2- methoxypyridines -3- amine of 5-
The bromo- 2- methoxyl groups -3- nitropyridines (0.4g, 1.72mmol) of compound 5- are suspended in 5mL ethanol and 5mL water In mixed solvent, then to addition iron powder (0.38g, 6.87mmol) and NH in reaction solution4Cl(0.39g,7.21mmol).Reaction After liquid is stirred at reflux 1 hour, it is concentrated under reduced pressure, after residue is diluted with 10mL ethyl acetate, suction filtration, filtrate ethyl acetate (10mL x 3) is extracted.The organic phase saline solution (10mL) of merging is washed, and with anhydrous sodium sulfate drying, is finally concentrated under reduced pressure to give Target compound is yellow solid (0.30g, 86%).
MS(ESI,pos.ion)m/z:203.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):3.92 (s, 3H), 4.86 (s, 2H), 7.03 (d, J=2.0Hz, 1H), 7.41 (d, J=2.0Hz, 1H).
Step 3) N- (the bromo- 2- methoxypyridines -3- bases of 5-) -2,4 difluorobenzene sulfonamide
The bromo- 2- methoxypyridines -3- amine (10.15g, 50mmol) of compound 5- are dissolved in 50mL pyridines, 0 is cooled to After DEG C, to being slowly added to 2,4- difluorobenzene -1- sulfonic acid chlorides (11.68g, 60mol) in reaction solution.Reaction solution is stirred in room temperature condition After reaction 19 hours, it is concentrated under reduced pressure, residue is dissolved in 100mL methyl alcohol, then to adding hydrogen-oxygen in the methanol solution for obtaining Change sodium (2.50g, 60mmol), the reaction solution for obtaining is concentrated under reduced pressure after room temperature condition continues stirring reaction 12 hours, will remain Thing is dissolved in 50mL water, and the mixed liquor for obtaining is extracted with dichloromethane (100mL x 3).The organic phase saline solution of merging (100mL x 3) is washed, with anhydrous sodium sulfate drying, be finally concentrated under reduced pressure to give target compound for brown solid (16.90g, 89.1%).
MS(ESI,pos.ion)m/z:379.0[M+H]+。
Step 4) the fluoro- N- of 2,4- bis- (2- methoxyl groups -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- Base) pyridin-3-yl) benzsulfamide
By compound N-(the bromo- 2- methoxypyridines -3- bases of 5-) -2,4 difluorobenzene sulfonamide (16.90g, 44.6mmol) Be suspended in 300mL Isosorbide-5-Nitraes-dioxane, then to sequentially added in reaction solution connection boric acid pinacol ester (13.59g, 53.5mmol), Pd (dppf) Cl2·CH2Cl2(3.67g, 4.5mmol) and potassium acetate (13.12g, 133.8mmol).Will reaction After liquid substitutes gas (nitrogen) 3 times, 90 DEG C and stirring reaction 7 hours are heated to, are subsequently cooled to room temperature, add 100mL water quenchings to go out Reaction, mixture is extracted with ethyl acetate (500mL x 3).Organic phase saline solution (500mL x 3) after merging is washed, with nothing Aqueous sodium persulfate is dried, and is finally concentrated under reduced pressure to give target compound for faint yellow solid (24.00g, 100%).MS(ESI, pos.ion)m/z:427.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.25 (d, J=1.0Hz, 1H), 8.04 (s, 1H), 7.85 (m, 1H), 7.14(s,1H),6.93(m,2H),3.91(s,3H),1.33(s,12H)。
Step 5) chloro- 3- iodine pyrazolo [1,5-a] pyrimidines of 5-
Compound 5- chlorine pyrazolo [1,5-a] pyrimidine (200mg, 1.30mmol) is dissolved in 2mL DMF, then to anti- Addition NIS (322mg, 1.86mmol) in liquid is answered, is stirred overnight under room temperature condition, be subsequently adding the dilution of 100mL ethyl acetate anti- Liquid is answered, the mixed liquor for obtaining uses 50mL water successively, the aqueous solution and 50mL the salt washing of 50mL saturated sodium thiosulfates divide liquid, It is concentrated under reduced pressure after the organic phase anhydrous sodium sulfate drying for obtaining, residue is through silica gel column chromatography (EtOAc/PE (v/v)=1/4) Purifying obtains target compound for faint yellow solid (390mg, 100%).
MS(ESI,pos.ion)m/z:279.9[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.57 (d, J=7.2Hz, 1H), 8.16 (s, 1H), 6.86 (d, J= 7.2Hz,1H)。
Step 6) 3- (5- chlorine pyrazolo [1,5-a] pyrimidin-3-yl) propyl- 2- alkynes -1- alcohol
By chloro- 3- iodine pyrazolo [1, the 5-a] pyrimidines (363mg, 1.30mmol) of compound 5-, Pd (PPh3)2Cl2(91mg, 0.13mmol), CuI (25mg, 0.13mmol) and triethylamine (658mg, 6.50mmol) are suspended in 15mL DMF, then to anti- Answer and propyl- 2- alkynes -1- alcohol (73mg, 1.30mmol) is added in liquid, after reaction solution is substituted into gas (nitrogen) 3 times, at ambient temperature Stirring reaction 20 hours, then to adding 15mL water quenchings to go out reaction, the mixed liquor for obtaining ethyl acetate (50mL x in reaction solution 3) extract.The organic phase saline solution (50mL x 3) of merging is washed, and with anhydrous sodium sulfate drying, is concentrated under reduced pressure, and residue is through silicon Plastic column chromatography (EtOAc/PE (v/v)=1/2) purifying obtains target compound for yellow solid (220mg, 81.5%).
MS(ESI,pos.ion)m/z:208.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.58 (d, J=7.4Hz, 1H), 8.23 (s, 1H), 6.90 (d, J= 7.2Hz,1H),4.58(s,2H)。
Step 7) the fluoro- N- of 2,4- bis- (5- (3- (3- hydroxyl propyl- 1- alkynes -1- bases) pyrazolo [1,5-a] pyrimidine -5- bases) -2- Methoxypyridine -3- bases) benzsulfamide
By compound 3- (5- chlorine pyrazolo [1,5-a] pyrimidin-3-yl) propyl- 2- alkynes -1- alcohol (208mg, 1mmol), 2,4- Two fluoro- N- (2- methoxyl groups -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) benzene sulfonyls Amine (618mg, 1.5mmol) and Pd (dppf) Cl2·CH2Cl2(82mg, 0.1mmol) is suspended in 20mL DME, then to anti- Liquid is answered to add Na2CO3Water (2.5mL) solution of (318mg, 3mmol), after substituting gas (nitrogen) 3 times, 100 is heated to by reaction solution DEG C, stirring reaction is after 5 hours, is cooled to room temperature, adds 20mL water quenchings to go out reaction, the mixed liquor for obtaining ethyl acetate (500mL X 3) extraction.The organic phase saline solution (50mL x 3) of merging is washed, and with anhydrous sodium sulfate drying, is concentrated under reduced pressure, residue warp Silica gel column chromatography (EtOAc/PE (v/v)=1/2) purifying obtains target compound for yellow solid (80mg, 17%).
MS(ESI,pos.ion)m/z:472.0[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):10.46 (s, 1H), 9.23 (d, J=7.4Hz, 1H), 8.88 (d, J =1.7Hz, 1H), 8.42 (d, J=2.1Hz, 1H), 8.41 (s, 1H), 7.82 (dd, J=8.4,6.2Hz, 1H), 7.76 (d, J =7.5Hz, 1H), 7.59 (td, J=10.0,2.2Hz, 1H), 7.24 (td, J=8.6,2.0Hz, 1H), 5.38 (t, J= 5.9Hz, 1H), 4.41 (d, J=5.9Hz, 2H), 3.72 (s, 3H).
Embodiment 2 N- (5- (3- cyano pyrazoles simultaneously [1,5-a] pyrimidine -5- bases) -2- methoxypyridine -3- bases) -2,4- two Fluorobenzenesulfonamide
Step 1) 5- chlorine pyrazolo [1,5-a] pyrimidine -3- formaldehyde
Compound 5- chlorine pyrazolo [1,5-a] pyrimidine (295mg, 1.92mmol) is dissolved in 10mL dichloromethane, so (chlorine methylene) alkyl dimethyl ammonium chloride (1.06g, 6mmol) is added in backward reaction solution, after reaction solution is stirred overnight at 45 DEG C, is subtracted Pressure concentration, residue is dissolved in the sodium bicarbonate aqueous solution of 50mL saturations, and the mixture for obtaining is with ethyl acetate (50mL x 3) Extraction.The organic phase anhydrous sodium sulfate drying of merging, be concentrated under reduced pressure to give target compound for light yellow solid (380mg, 100%).
MS(ESI,pos.ion)m/z:182.2[M+H]+。
Step 2) (E) -5- chlorine pyrazolo [1,5-a] pyrimidine -3- formaldoximes
By compound 5- chlorine pyrazolo [1,5-a] pyrimidine -3- formaldehyde (380mg, 2.1mmol) be suspended in 20mL ethanol and In the mixed solvent of 10mL water, then to addition hydroxylamine hydrochloride (220mg, 3.15mmol) in reaction solution, reaction solution is stirred at 85 DEG C After mixing reaction 2 hours, it is concentrated under reduced pressure, adds saturated sodium bicarbonate aqueous solution that residue is adjusted into pH=7, suction filtration is true by filter cake Sky obtains target compound for yellow solid (280mg, 74.4%) after drying.
MS(ESI,pos.ion)m/z:197.1[M+H]+。
Step 3) 5- chlorine pyrazolo [1,5-a] pyrimidine -3- formonitrile HCNs
Compound (E) -5- chlorine pyrazolo [1,5-a] pyrimidine -3- formaldoximes (280mg, 1.42mmol) and 20mL acetic anhydrides Mixture after 140 DEG C of stirring reactions 18 hours, be cooled to room temperature, be concentrated under reduced pressure, residue is washed with 20mL ether, and vacuum is done Target compound is obtained after dry for yellow solid (106mg, 42%).
MS(ESI,pos.ion)m/z:179.1[M+H]+。
Step 4) N- (5- (3- cyano pyrazoles simultaneously [1,5-a] pyrimidine -5- bases) -2- methoxypyridine -3- bases) -2,4- difluoros Benzsulfamide
By the fluoro- N- of compound 2,4- bis- (2- methoxyl groups -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes - 2- yls) pyridin-3-yl) benzsulfamide (383mg, 0.9mmol), 5- chlorine pyrazolo [1,5-a] pyrimidine -3- formonitrile HCNs (106mg, 0.6mmol), Pd (dppf) Cl2·CH2Cl2(49mg, 0.06mmol) and sodium carbonate (254mg, 2.5mmol) are placed in two-mouth bottle In, after substituting gas (nitrogen) 3 times, 12mL Isosorbide-5-Nitraes-dioxane and 2mL water are sequentially added, after gas (nitrogen) 3 times is substituted again, 90 DEG C are heated to, stirring reaction is cooled to room temperature after 5 hours, and suction filtration concentrates filtrate decompression, and residue is through silica gel column chromatography (PE/EtOAc (v/v)=4/3) purifying obtains target compound for light yellow solid (200mg, 75.3%).
MS(ESI,pos.ion)m/z:443.2[M+H]+；HPLC:97%；
1H NMR(400MHz,DMSO-d6)δ(ppm):10.51 (s, 1H), 9.41 (d, J=7.4Hz, 1H), 8.93 (d, J =2.1Hz, 1H), 8.81 (s, 1H), 8.45 (d, J=2.2Hz, 1H), 7.99 (d, J=7.5Hz, 1H), 7.85-7.78 (m, 1H), 7.61-7.52 (m, 1H), 7.25 (t, J=8.4Hz, 1H), 3.77 (s, 3H).
The N- of embodiment 3 (5- (3- cyano pyrazoles simultaneously [1,5-a] pyridine -5- bases) -2- methoxypyridine -3- bases) -2,4- two Fluorobenzenesulfonamide
Step 1) 5- bromines pyrazolo [1,5-a] pyridine
Compound ethyl 5- bromines pyrazolo [1,5-a] Nicotinicum Acidum ester (240mg, 0.89mmol) and 40%H2SO4 The mixture of (12mL) is cooled to room temperature after 100 DEG C of stirring reactions 4 hours, under condition of ice bath, to adding 6M in mixture Sodium hydrate aqueous solution be adjusted to PH=7, mixture is extracted with dichloromethane (25mL x 2), the organic phase nothing of merging Aqueous sodium persulfate is dried, and is concentrated under reduced pressure to give target compound for light yellow solid (175mg, 99.5%).
MS(ESI,pos.ion)m/z:196.9[M+H]+。
Step 2) 5- bromines pyrazolo [1,5-a] pyridine -3- formaldehyde
Compound 5- bromines pyrazolo [1,5-a] pyridine (175mg, 0.89mmol) is dissolved in 6mL dichloromethane, then To addition (chlorine methylene) alkyl dimethyl ammonium chloride (632mg, 3.56mmol) in reactant, after reaction solution is stirred overnight at 44 DEG C, It is concentrated under reduced pressure, residue is dissolved in 25mL saturated sodium bicarbonate aqueous solutions, the mixture for obtaining ethyl acetate (25mL x 3) extract.The organic phase anhydrous sodium sulfate drying of merging, obtains target compound for light yellow solid after being concentrated under reduced pressure (225mg, 100%).
MS(ESI,pos.ion)m/z:225.0[M+H]+。
Step 3) (E) -5- bromines pyrazolo [1,5-a] pyridine -3- formaldoximes
Compound 5- bromines pyrazolo [1,5-a] pyridine -3- formaldehyde (225mg, 1mmol) is suspended in 10mL ethanol and 5mL In the mixed solvent of water, then to adding hydroxylamine hydrochloride (104mg, 1.5mmol) in reaction solution, in 85 DEG C of stirring reactions 2 hours Afterwards, room temperature is cooled to, is concentrated under reduced pressure, add saturated sodium bicarbonate aqueous solution that residue is adjusted into pH=7, suction filtration, filter cake vacuum Target compound is obtained after drying for yellow solid (240mg, 99%).
MS(ESI,pos.ion)m/z:240.0[M+H]+。
Step 4) 5- bromines pyrazolo [1,5-a] pyridine -3- formonitrile HCNs
Compound (E) -5- bromines pyrazolo [1,5-a] pyridine -3- formaldoximes (240mg, 1mmol) and 6mL acetic anhydrides it is mixed Compound is cooled to room temperature after 140 DEG C of stirring reactions 18 hours, is then concentrated under reduced pressure, and residue is washed with 1mL ether, and vacuum is done Target compound is obtained after dry for yellow solid (44mg, 22.5%).
MS(ESI,pos.ion)m/z:222.0[M+H]+。
Step 5) N- (5- (3- cyano pyrazoles simultaneously [1,5-a] pyridine -5- bases) -2- methoxypyridine -3- bases) -2,4- difluoros Benzsulfamide
By the fluoro- N- of compound 2,4- bis- (2- methoxyl groups -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes - 2- yls) pyridin-3-yl) benzsulfamide (612mg, 1.5mmol), 5- bromines pyrazolo [1,5-a] pyridine -3- formonitrile HCNs (222mg, 1mmol), Pd (dppf) Cl2·CH2Cl2(16mg, 0.02mmol) and sodium carbonate (85mg, 0.8mmol) are placed in two-mouth bottle, are taken out After ventilation (nitrogen) 3 times, 5mL Isosorbide-5-Nitraes-dioxane and 1mL water are added, after gas (nitrogen) 3 times is substituted again, be heated to 90 DEG C And stirring reaction 5 hours.After reaction solution is cooled to room temperature, suction filtration concentrates filtrate decompression, and residue is through silica gel column chromatography (PE/ EtOAc (v/v)=1/2) purifying obtains target compound for light yellow solid (400mg, 81.6%).
MS(ESI,pos.ion)m/z:442.0[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):10.37 (s, 1H), 9.02 (d, J=7.2Hz, 1H), 8.67 (s, 1H), 8.60 (d, J=2.2Hz, 1H), 8.26-8.16 (m, 2H), 7.82-7.72 (m, 1H), 7.57 (dd, J=13.2, 5.8Hz, 2H), 7.21 (t, J=8.5Hz, 1H), 3.67 (s, 3H).
Embodiment 4 The fluoro- N- of 2,4- bis- (5- (3- (3- hydroxyl propyl- 1- alkynes -1- bases) pyrazolo [1,5-a] pyridine -5- bases) - 2- methoxypyridine -3- bases) benzsulfamide
Step 1) 5- bromines pyrazolo [1,5-a] pyridine
Compound ethyl 5- bromines pyrazolo [1,5-a] Nicotinicum Acidum ester (1.2g, 4.46mmol) and 40%H2SO4 The mixture of (60mL) is cooled to room temperature after 100 DEG C of stirring reactions 4 hours, and the NaOH of 6M is added under condition of ice bath The aqueous solution is adjusted to pH=7, and the mixture for obtaining is extracted with dichloromethane (120mL x 2).The organic phase of merging is with anhydrous Sodium sulphate is dried, and target compound is obtained after being concentrated under reduced pressure for light yellow solid (900mg, 100%).
MS(ESI,pos.ion)m/z:196.9[M+H]+。
Step 2) bromo- 3- iodine pyrazolo [1,5-a] pyridines of 5-
Compound 5- bromines pyrazolo [1,5-a] pyridine (900mg, 4.46mmol) is dissolved in 100mL methyl alcohol, is cooled down To -10 DEG C, then to being slowly added to NIS (1g, 4.46mmol) in reaction solution, reaction solution after -10 DEG C of stirring reaction half an hour, It is warmed to room temperature, after room temperature condition stirring reaction 18 hours, is concentrated under reduced pressure, residue is dissolved in 200mL dichloromethane. To mixture washed with the aqueous solution of 200mL saturated sodium thiosulfates, point liquid obtains target after the organic phase for obtaining is concentrated under reduced pressure Compound is light pink solid (1.4g, 97.5%).
MS(ESI,pos.ion)m/z:322.8[M+H]+。
Step 3) 3- (5- bromines pyrazolo [1,5-a] pyridin-3-yl) propyl- 2- alkynes -1- alcohol
Bromo- 3- iodine pyrazolo [1, the 5-a] pyridines (644mg, 2mmol) of compound 5-, propyl- 2- alkynes -1- alcohol (112mg, 2mmol), Pd (PPh3)2Cl2(140mg, 0.2mmol), CuI (38mg, 0.2mmol), DIPEA (645mg, 5mmol) and 32mL DMF mixture under nitrogen protection, in after room temperature condition stirring reaction 3 hours, add 200mL water dilute Release, mixture is extracted with ethyl acetate (200mL x 3).The organic phase anhydrous sodium sulfate drying of merging, is concentrated under reduced pressure, residual Thing obtains target compound for yellow solid (200mg, 4%) through silica gel column chromatography (absolute dichloromethane) purifying.
MS(ESI,pos.ion)m/z:251.0[M+H]+。
Step 4) the fluoro- N- of 2,4- bis- (5- (3- (3- hydroxyl propyl- 1- alkynes -1- bases) pyrazolo [1,5-a] pyridine -5- bases) -2- Methoxypyridine -3- bases) benzsulfamide
By the fluoro- N- of compound 2,4- bis- (2- methoxyl groups -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes - 2- yls) pyridin-3-yl) benzsulfamide (509mg, 1.2mmol), 3- (5- bromines pyrazolo [1,5-a] pyridin-3-yl) propyl- 2- alkynes- 1- alcohol (200mg, 0.8mmol), Pd (dppf) Cl2·CH2Cl2(65mg, 0.08mmol) and sodium carbonate (339mg, 3.2mmol) It is placed in two-mouth bottle, after substituting gas (nitrogen) 3 times, adds 15mL Isosorbide-5-Nitraes-dioxane and 2.5mL water, gas (nitrogen is substituted again Gas) after 3 times, it is heated to 90 DEG C and stirring reaction 5 hours.After reaction solution is cooled to room temperature, suction filtration concentrates filtrate decompression, residual Stay thing through silica gel column chromatography (PE/EtOAc (v/v)=3/1) purifying obtain target compound for white solid (122mg, 32.5%).
MS(ESI,pos.ion)m/z:471.0[M+H]+；HPLC:91%；
1H NMR(400MHz,DMSO-d6)δ(ppm):10.37 (s, 1H), 8.83 (d, J=7.2Hz, 1H), 8.53 (d, J =2.3Hz, 1H), 8.23 (s, 1H), 8.05 (d, J=2.3Hz, 1H), 7.87 (s, 1H), 7.77 (dd, J=14.8,8.5Hz, 1H), 7.59 (dd, J=13.9,5.9Hz, 1H), 7.33 (dd, J=7.3,1.9Hz, 1H), 7.22 (t, J=8.4Hz, 1H), 5.33 (t, J=5.9Hz, 1H), 4.39 (d, J=5.8Hz, 2H), 3.67 (s, 3H).
Embodiment 5 The fluoro- N- of 2,4- bis- (5- (3- (3- hydroxyl -1- butine -1- bases) pyrazolo [1,5-a] pyrimidine -5- bases) - 2- methoxypyridine -3- bases) benzsulfamide
Step 1) the fluoro- N- of 2,4- bis- (2- methoxyl groups -5- (pyrazolo [1,5-a] pyrimidine -5- bases) pyridin-3-yl) benzene sulfonyl Amine
Compound 5- chlorine pyrazolo [1,5-a] pyrimidine (0.46g, 3.0mmol) is dissolved in 60mL DME, then to it Middle addition Pd (dppf)2Cl2·CH2Cl2Water (8mL) solution of (0.25g, 0.3mmol) and sodium carbonate (0.95g, 9.0mmol), After mixture is substituted into gas (nitrogen) 3 times, a moment is stirred at room temperature, then adds the fluoro- N- of 2,4- bis- (2- methoxyl groups -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) benzsulfamide (1.53g, 3.6mmol). After mixture substitutes gas (nitrogen) 3 times again, then stirring reaction 6 hours at 100 DEG C, are cooled to room temperature, are concentrated under reduced pressure. Gained residue obtains title compound for yellow solid through silica gel column chromatography (DCM/MeOH (v/v)=20/1) purifying (1.24g, 100%).
MS(ESI,pos.ion)m/z:418.2[M+H]+。
Step 2) the fluoro- N- of 2,4- bis- (5- (3- iodine pyrazolo [1,5-a] pyrimidine -5- bases) -2- methoxypyridine -3- bases) benzene Sulfonamide
By the fluoro- N- of compound 2,4- bis- (2- methoxyl groups -5- (pyrazolo [1,5-a] pyrimidine -5- bases) pyridin-3-yl) benzene sulphur Acid amides (1.98g, 10.0mmol) is dissolved in methyl alcohol (50mL), at room temperature, to being dividedly in some parts iodo succinyl in reaction solution Imines (2.47g, 11.0mmol), mixture stirring reaction at 45 DEG C after 10 hours, is concentrated under reduced pressure, and adds the water (40mL) will be residual Thing is stayed to dilute, after gained mixture is stirred at room temperature 2 hours, suction filtration, the solid of collection is diluted in PE/EtOAc (40mL/ In mixed solvent 4mL), after gained suspension is stirred at room temperature 1 hour, suction filtration obtains title compound for pale yellow colored solid Body (1.05g, 80.57%).
MS(ESI,pos.ion)m/z:544.0[M+H]+。
Step 3) the fluoro- N- of 2,4- bis- (5- (3- (3- hydroxyl -1- butine -1- bases) pyrazolo [1,5-a] pyrimidine -5- bases) -2- Methoxypyridine -3- bases) benzsulfamide
By the fluoro- N- of compound 2,4- bis- (5- (3- iodine pyrazolo [1,5-a] pyrimidine -5- bases) -2- methoxypyridine -3- bases) Benzsulfamide (2.32g, 4.27mmol), Pd (PPh3)2Cl2(0.31g, 0.43mmol) and CuI (82mg, 0.43mmol) suspend In 15mL DMF, then to addition triethylamine (2.15g, 21.3mmol) in reaction solution, after mixture is substituted into gas several times, then 3- butyne-2-alcohols (1.08g, 15.4mmol) are added thereto to syringe, mixture is anti-in 50 DEG C of stirrings under nitrogen protection After answering 6 hours, add water (40mL) that reaction is quenched.After gained mixture is stirred 1 hour, suction filtration.Filter cake is through silica gel column chromatography (EtOAc/PE (v/v)=1/2) is purified, and obtains crude product, is subsequently adding the mixing of DCM/MeOH/PE (15mL/3mL/65mL) Solvent dilutes crude product, and after the mixture for obtaining is stirred 2 hours, suction filtration obtains title compound for faint yellow solid (1.01g, 48.77%).
MS(ESI,neg.ion)m/z:484.1[M-H]-；
1H NMR(600MHz,DMSO-d6)δ(ppm):10.45 (s, 1H), 9.21 (d, J=7.4Hz, 1H), 8.88 (d, J =2.0Hz, 1H), 8.44 (d, J=2.0Hz, 1H), 8.38 (s, 1H), 7.80 (dd, J=14.8,8.4Hz, 1H), 7.75 (d, J =7.4Hz, 1H), 7.58 (t, J=8.8Hz, 1H), 7.23 (t, J=7.4Hz, 1H), 4.69 (dd, J=13.1,6.5Hz, 1H), 3.72 (s, 3H), 1.45 (d, J=6.6Hz, 3H).
((3- (3- hydroxy-3-methyl -1- butine -1- bases) pyrazolo [1,5-a] is phonetic for 5- for the fluoro- N- of 6 2,4- of embodiment bis- Pyridine -5- bases) -2- methoxypyridine -3- bases) benzsulfamide
By the fluoro- N- of compound 2,4- bis- (5- (3- iodine pyrazolo [1,5-a] pyrimidine -5- bases) -2- methoxypyridine -3- bases) Benzsulfamide (1.05g, 1.93mmol), Pd (PPh3)2Cl2(0.136g, 0.19mmol) and CuI (37mg, 0.19mmol) dissolve In 5mL DMF, then to diisopropylethylamine (0.98g, 7.60mmol) is added in reaction solution, reactant mixture is substituted into gas (nitrogen) several times after, be then added thereto to 2- methyl -3- butyne-2-alcohols (0.49g, 5.79mmol) with syringe.Mixture Under nitrogen protection in after 50 DEG C of stirring reactions 4 hours, it is concentrated under reduced pressure, is subsequently adding water (25mL) and is quenched, the mixing that will be obtained After thing is stirred 1 hour, suction filtration.Gained solid is purified through silica gel column chromatography (PE/EtOAc (v/v)=3/1), obtains title compound Thing is yellow solid (520mg, 53.99%).
MS(ESI,neg.ion)m/z:498.0[M-H]-；HPLC:96.74%；
1H NMR(600MHz,DMSO-d6)δ(ppm):10.45 (s, 1H), 9.22 (d, J=7.4Hz, 1H), 8.89 (d, J =1.8Hz, 1H), 8.48 (d, J=2.1Hz, 1H), 8.36 (s, 1H), 7.80 (dd, J=14.8,8.5Hz, 1H), 7.76 (d, J =7.4Hz, 1H), 7.65-7.53 (m, 1H), 7.24 (td, J=8.5,2.3Hz, 1H), 5.52 (s, 1H), 3.74 (s, 3H), 1.54(s,6H)。
Fluoro- N- (2- methoxyl groups -5- (3- (1- propine -1- bases) pyrazolo [1,5-a] pyrimidine -5- of 7 2,4- of embodiment bis- Base) pyridin-3-yl) benzsulfamide
By the fluoro- N- of compound 2,4- bis- (5- (3- iodine pyrazolo [1,5-a] pyrimidine -5- bases) -2- methoxypyridine -3- bases) Benzsulfamide (1.50g, 2.76mmol), Pd (PPh3)2Cl2(0.189g, 0.27mmol) and CuI (52mg, 0.27mmol) dissolve In the DMF of 20mL, then to diisopropylethylamine (1.78g, 13.8mmol) is added in reaction solution, mixture is substituted into gas (nitrogen) several times after, add propine (0.44g, 11.04mmol) with syringe, mixture is anti-in 45 DEG C of stirrings under nitrogen protection After answering 10 hours, it is concentrated under reduced pressure, adds water (40mL) that reaction is quenched, after the mixture that will be obtained is stirred 1 hour, suction filtration, gained Solid through silica gel column chromatography (DCM/MeOH (v/v)=300/1) purifying obtain title compound for yellow solid (220mg, 17.52%).
MS(ESI,pos.ion)m/z:456.1[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):10.46 (s, 1H), 9.18 (d, J=7.3Hz, 1H), 8.86 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 7.78 (dd, J=14.6,8.0Hz, 1H), 7.72 (d, J=7.3Hz, 1H), 7.58 (t, J=9.1Hz, 1H), 7.21 (t, J=7.6Hz, 1H), 3.71 (s, 3H), 2.14 (s, 3H).
Embodiment 8 The fluoro- N- of 2,4- bis- (5- (3- (3- hydroxy-3-methyl -1- butine -1- bases) pyrazolo [1,5-a] pyrroles Pyridine -5- bases) -2- methoxypyridine -3- bases) benzsulfamide
Step 1) the fluoro- N- of 2,4- bis- (2- methoxyl groups -5- (pyrazolo [1,5-a] pyridine -5- bases) pyridin-3-yl) benzene sulfonyl Amine
By compound 5- bromines pyrazolo [1,5-a] pyridine (197mg, 1mmol), 2,4- bis- fluoro- N- (2- methoxyl groups -5- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) benzsulfamide (639mg, 1.5mmol), Na2CO3(318mg, 3.0mmol) and Pd (PPh3)2Cl2(35mg, 0.05mmol) is dissolved in 1,4- dioxane/water (5mL/ In 1mL), mixture monitors reaction under nitrogen protection in 90 DEG C of stirring reactions with thin-layered chromatography (TLC).After having reacted, Reactant mixture is cooled to room temperature, and is extracted with ether (10mL), the organic phase saline solution (10mL x 2) for obtaining is washed, so Anhydrous sodium sulfate drying being used afterwards, being concentrated under reduced pressure, gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=30/1), Title compound is obtained for white solid (303mg, 73%).
MS(ESI,pos.ion)m/z:416.9[M+H]+。
Step 2) the fluoro- N- of 2,4- bis- (5- (3- iodine pyrazolo [1,5-a] pyridine -5- bases) -2- methoxypyridine -3- bases) benzene Sulfonamide
By the fluoro- N- of compound 2,4- bis- (2- methoxyl groups -5- (pyrazolo [1,5-a] pyridine -5- bases) pyridin-3-yl) benzene sulphur Acid amides (2.3g, 5.52mmol) is dissolved in DMF (10mL), then at room temperature, to being dividedly in some parts N- iodo fourths in reaction solution Imidodicarbonic diamide (1.3g, 5.8mmol), after reactant mixture is stirred at room temperature reaction 1 hour, adds saturation Na2S2O3The aqueous solution (10mL) is quenched reaction, by gained mixture suction filtration, obtains title compound for white solid (2.87g, 96%).
MS(ESI,pos.ion)m/z:542.9[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.52 (d, J=7.2Hz, 1H), 8.19 (d, J=2.2,1H), 8.03- 7.98 (m, 2H), 7.97-7.91 (m, 1H) 7.49 (d, J=1.0Hz, 1H), 7.32 (s, 1H), 7.05-6.91 (m, 2H), 4.00 (s,3H),2.80(s,1H)。
Step 3) the fluoro- N- of 2,4- bis- (5- (3- (3- hydroxy-3-methyl -1- butine -1- bases) pyrazolo [1,5-a] pyridine - 5- yls) -2- methoxypyridine -3- bases) benzsulfamide
By the fluoro- N- of compound 2,4- bis- (5- (3- iodine pyrazolo [1,5-a] pyridine -5- bases) -2- methoxypyridine -3- bases) Benzsulfamide (1.0g, 1.85mmol), 2- methyl -3- butyne-2-alcohols (0.23g, 2.76mmol), Pd (PPh3)2Cl2(0.13g, 0.19mmol), CuI (36mg, 0.19mmol) and diisopropylethylamine (0.74g, 0.57mmol) are dissolved in 20mL DMF, are mixed Compound be stirred at room temperature reaction 3 hours after, be concentrated under reduced pressure, gained residue through silica gel column chromatography (PE/EtOAc (v/v)= 10/1) purify, obtain title compound for faint yellow solid (0.42g, 46%).
MS(ESI,pos.ion)m/z:499.0[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.52 (d, J=6.1Hz, 1H), 8.20 (d, J=2.1Hz, 1H), 8.08 (s, 1H), 8.03 (d, J=2.1Hz, 1H), 7.92 (dd, J=14.5,8.3Hz, 1H), 7.68 (s, 1H), 7.59-7.52 (m,1H),7.51-7.42(m,1H),7.05-6.94(m,2H),4.00(s,3H),1.60(s,6H)。
Embodiment 9 N- (5- (3- cyano pyrazoles simultaneously [1,5-a] pyridine -5- bases) -2- methoxypyridine -3- bases) sulphur of ring third Acid amides
Compound 5- bromines pyrazolo [1,5-a] pyridine -3- formonitrile HCNs (50mg, 0.225mmol) is dissolved in 1,4- dioxies six In ring (5mL) and water (0.5mL), then under nitrogen protection, to sequentially added in reaction solution N- (2- methoxyl groups -5- (4,4,5, 5- tetramethyl -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) cyclopropyl-sulfonylamide (96mg, 0.270mmol), Na2CO3 (48mg, 0.45mmol) and Pd (dppf) Cl2·CH2Cl2(37mg,0.045mmol).Reaction solution is under nitrogen protection in 90 DEG C After stirring reaction 3.5 hours, room temperature is cooled to, stirring was continued at room temperature overnight, is subsequently adding ethyl acetate (30mL) dilution Reaction solution, the mixture for obtaining by suction filtered through kieselguhr, wash by filter cake ethyl acetate (20mL), filtrate successively with water (30mL) and Saline solution (30mL) is washed, point liquid, and the organic phase anhydrous sodium sulfate drying for obtaining is concentrated under reduced pressure, and gained residue is through silicagel column Chromatography (DCM/EtOAc (v/v)=10/1) purifying, obtains title compound for white solid (55mg, 66%).
MS(ESI,pos.ion)m/z:370.0[M+H]+；
1H NMR(300MHz,CDCl3)δ(ppm):8.61 (d, J=7.26Hz, 1H), 8.27-8.25 (m, 2H), 8.09 (d, J=2.07Hz, 1H), 7.87 (s, 1H), 7.21 (dd, J=1.77,7.35Hz, 1H), 6.80 (br s, 1H), 4.11 (s, 3H),2.60-2.51(m,1H),1.33-1.22(m,2H),1.07-0.99(m,2H)。
Embodiment 10 N- (5- (3- cyano pyrazoles simultaneously [1,5-a] pyridine -5- bases) -2- methoxypyridine -3- bases) -2,2, 2- trifluoroethyl sulfonamide
Step 1) N- (the bromo- 2- methoxypyridines -3- bases of 5-) -2,2,2- trifluoroethyl sulfonamide
The bromo- 2- methoxypyridines -3- amine (500mg, 2.46mmol) of compound 5- are dissolved in pyridine (10mL), then To 2,2,2- trifluoroethyl sulfonic acid chlorides (898mg, 4.92mmol) are added dropwise in reaction solution, reaction solution is stirred at room temperature reaction After 18 hours, it is concentrated under reduced pressure, is subsequently adding water (30mL) and dilutes residue, gained mixture is with dichloromethane (20mL x 3) Extraction, the organic phase of merging is washed with water (25mL x2) and saline solution (25mL) respectively, with anhydrous sodium sulfate drying, is concentrated under reduced pressure Title compound is obtained for yellow solid (859mg, 100%), the solid is directly used in next step anti-without being further purified Should.
MS(ESI,pos.ion)m/z:348.9[M+H]+；
1H NMR(300MHz,CDCl3)δ(ppm):8.03 (d, J=2.19Hz, 1H), 7.91 (d, J=2.22Hz, 1H), 7.00 (br s, 1H), 4.00 (s, 3H), 3.87 (q, J=8.73Hz, 2H).
Step 2) the fluoro- N- of 2,2,2- tri- (2- methoxyl groups -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes - 2- yls) pyridin-3-yl) ethyl sulfonamide
By compound N-(the bromo- 2- methoxypyridines -3- bases of 5-) -2,2,2- trifluoroethyls sulfonamide (500mg, 1.43mmol), connection boric acid pinacol ester (1.45g, 5.729mmol) and KOAc (562mg, 5.729mmol) are dissolved in Isosorbide-5-Nitrae-two In the ring of oxygen six (10mL), after mixture is substituted into gas (nitrogen) several times, Pd (dppf) Cl is added2·CH2Cl2(248mg, 0.304mmol).Reaction solution stirring reaction at 80 DEG C after 3.5 hours, is concentrated under reduced pressure, and is subsequently adding dichloromethane (50mL) dilute Residue is released, by suction filtered through kieselguhr, gained filtrate uses water (25mL x 3) and saline solution (35mL) to the mixture for obtaining successively Wash, point liquid, the organic phase anhydrous sodium sulfate drying for obtaining is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purify, obtain title compound for yellow oil (395mg, 70%).
MS(ESI,pos.ion)m/z:397.0[M+H]+；
1H NMR(300MHz,CDCl3)δ(ppm):8.36 (d, J=1.59Hz, 1H), 8.05 (d, J=1.59Hz, 1H), 6.94 (br s, 1H), 4.04 (s, 3H), 3.85 (q, J=7.82Hz, 2H), 1.33 (s, 12H).
Step 3) N- (5- (3- cyano pyrazoles simultaneously [1,5-a] pyridine -5- bases) -2- methoxypyridine -3- bases) -2,2,2- three Fluoro ethyl sulfonamide
Compound 5- bromines pyrazolo [1,5-a] pyridine -3- formonitrile HCNs (100mg, 0.450mmol) is dissolved in 1,4- dioxies six In ring (20mL) and water (4mL), then under nitrogen protection, to adding 2,2,2- tri- fluoro- N- (2- methoxyl groups -5- in reaction solution (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) ethyl sulfonamide (196mg, 0.495mmol), KOAc (88mg, 0.900mmol) and Pd (dppf) Cl2·CH2Cl2(74mg,0.09mmol).Reaction solution is in nitrogen In after 90 DEG C of stirring reactions 2.5 hours under gas shielded, it is cooled to room temperature and continues to be stirred overnight, mixture is concentrated under reduced pressure, so Ethyl acetate (35mL) dilution residue, gained mixture is added to be rushed with ethyl acetate (35mL) through suction filtered through kieselguhr, filter cake afterwards Wash, the filtrate for obtaining uses water H successively2O (15mL) and saline solution (20mL) are washed, organic phase anhydrous sodium sulfate drying, decompression Concentration, the residue for obtaining is purified through silica gel column chromatography (PE/EtOAc (v/v)=2.5/1), obtains title compound for yellow Solid (94mg, 51%).
MS(ESI,pos.ion)m/z:412.0[M+H]+；
1H NMR(300MHz,DMSO-d6)δ(ppm):10.15 (s, 1H), 9.03 (d, J=7.32Hz, 1H), 8.67 (s, 1H), 8.65 (d, J=2.25Hz, 1H), 8.24 (d, J=1.05Hz, 1H), 8.18 (d, J=2.28Hz, 1H), 7.59 (dd, J =1.80,7.26Hz, 1H), 4.63 (q, J=9.78Hz, 2H), 4.00 (s, 3H).
Embodiment 11 N- (the chloro- 5- of 2- (3- cyano pyrazoles simultaneously [1,5-a] pyridine -5- bases) pyridin-3-yl) -2,4- difluoros Benzsulfamide
Compound 5- bromines pyrazolo [1,5-a] pyridine -3- formonitrile HCNs (110mg, 0.5mmol) is dissolved in 1,4- dioxane In (20mL), then to sequentially adding N- (the chloro- 5- of 2- (4,4,5,5- tetramethyl -1, the boron of 3,2- dioxane penta in reaction solution Alkane -2- bases) pyridin-3-yl) -2,4- difluorobenzenesulfonamides (235mg, 0.55mmol), KOAc (98mg, 1mmol), H2O(2mL) With Pd (dppf) Cl2·CH2Cl2(81mg, 0.1mmol), reaction solution in after 93 DEG C of stirring reactions 2 hours, subtracts under nitrogen protection Pressure concentration, residue with Ethyl acetate (20mL x 3) extraction, the organic phase anhydrous sodium sulfate drying of merging is concentrated under reduced pressure, Gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=4.5/1), obtains title compound for white solid (130mg, 59%).
MS(ESI,pos.ion)m/z:446.0[M+H]+；
1H NMR(300MHz,DMSO-d6)δ(ppm):10.98 (br s, 1H), 9.08 (d, J=7.29Hz, 1H), 8.87 (d, J=2.67Hz, 1H), 8.71 (s, 1H), 8.41-8.39 (m, 2H), 7.84-7.76 (m, 1H), 7.63-7.54 (m, 2H), 7.26-7.20(m,1H)。
Biologic test
The compounds of this invention can be evaluated as the activity of PI3K and mTOR kinase inhibitors by following experiments 's.Result of study shows that the compounds of this invention can effectively suppress the activity of PI3K and mTOR kinases.
Bioanalytical method
The LC/MS/MS systems of analysis include the serial vacuum degassing furnace of Agilent 1200, binary syringe pump, orifice plate from Dynamic sampler, post insulating box, charged spray ionizes the Agilent G6430 three-level level Four bar mass spectrographs in (ESI) source.Quantitative analysis Carried out under MRM patterns, the parameter of MRM conversions is as in Table A：
Table A
Many reaction detection scannings 490.2→383.1
Fragmentation voltage 230V
Capillary voltage 55V
Dryer temperature 350℃
Atomizer 40psi
Drier flow velocity 10L/min
Analysis uses Agilent XDB-C18,2.1x 30mm, 3.5 μM of posts to inject 5 μ L samples.Analysis condition：Mobile phase It is 0.1% aqueous formic acid (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient is eluted As shown in tableb：
Table B
Time The gradient of Mobile phase B (0.1% formic acid methanol solution)
0.5min 5%
1.0min 95%
2.2min 95%
2.3min 5%
5.0min stop
Additionally, also have the series LC/MS/MS spectrometers of Agilent 6330 for what is analyzed, equipped with G1312A binary note Penetrate pump, G1367A automatic samplers and G1314C UV detectors；LC/MS/MS spectrometers use ESI radioactive sources.Use titer Suitable cation model treatment and MRM conversions are carried out to each analyte carries out optimal analysis.Used during analyzing Capcell MP-C18 posts, specification is：100x4.6mm I.D., 5 μM (Phenomenex, Torrance, California, USA).Mobile phase is 5mM ammonium acetates, 0.1% methanol aqueous solution (A)：5mM ammonium acetates, 0.1% methanol acetonitrile solution (B) (70/ 30, v/v)；Flow velocity is 0.6mL/min；Column temperature is maintained at room temperature；Inject 20 μ L samples.
Embodiment A：Stability of the compound in people and rat liver microsomes
People or rat liver microsomes are placed in polypropylen tubes and are incubated, and guide it to replicate.It is typical to be incubated mixed liquor Including people or rat liver microsomes (0.5mg protein/mL), target compound (5 μM) and the NADPH that cumulative volume is 200 μ L (PBS, 100mM, pH value are 7.4), compound to be dissolved in DMSO to (1.0mM) kaliumphosphate buffer, and using PBS that its is dilute Release, the concentration for making its final DMSO solution is 0.05%.And be incubated in the water-bath communicated with air at 37 DEG C, incubate in advance Educate and add in 3 minutes backward mixed liquors albumen and start reaction.At different time points (0,5,10,15,30 and 60 minute), plus Enter same volume ice-cold acetonitrile terminating reaction.Sample at -80 DEG C in preserving until carrying out LC/MS/MS analyses.
Concentration of the compound in people or rat liver microsomes mixtures incubated is determined by the method for LC/MS/MS 's.The range of linearity of concentration range is determined by each test-compound.
It is parallel to be incubated experiment and use the microsome of denaturation as negative control, hatch at 37 DEG C, react when different Between point (0,15 and 60 minute) terminate.
Dextromethorphan (70 μ Μ) is hatched as positive control at 37 DEG C, reaction different time point (0,5,10, 15,30 and 60 minutes) terminate.All include positive and negative control sample in each assay method, to ensure that microsome is hatched The integrality of system.Additionally, stability data of the compound of the present invention in people or rat liver microsomes also can be by following Experiment is obtained.People or rat liver microsomes are placed in polypropylen tubes and are incubated, and guide it to replicate.Typical mixtures incubated Including people or rat liver microsomes (ultimate density：0.5mg albumen/mL), compound (ultimate density：1.5 μM) and cumulative volume be The K- cushioning liquid (EDTA containing 1.0mM, 100mM, pH 7.4) of 30 μ L.Compound is dissolved in DMSO, and is buffered with K- molten Liquid dilutes, and the ultimate density for making DMSO is 0.2%.After preincubate 10 minutes, 15 μ L NADPH (ultimate densities are added：2mM) enter Row enzymatic reaction, whole experiment is carried out in 37 DEG C of incubation tube.At different time points (0,15,30 and 60 minute), add 135 μ L acetonitriles (containing IS) terminating reaction.It is centrifuged 10 minutes with 4000rpm, except deproteinized, collects supernatant liquor, uses LC-MS/MS Analysis.
In above-mentioned experiment, ketanserin (1 μM) is selected as positive control, hatches at 37 DEG C, reacts in the different time Point terminates for (0,15,30 and 60 minute).All include positive control sample in each assay method, to ensure that microsome hatches body The integrality of system.
Data analysis
For each reaction, concentration (as a percentage) of the compound in people or rat liver microsomes are incubated is pressed With respect to the plotted as percentage of zero time point, internal CLint CL is inferred with thisint(ref.:Naritomi Y, Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.“Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans”,Drug Metabolism and Disposition,2001,29,1316-1324)。
Stability data of the embodiment of the present invention of table 1 in people and rat liver microsomes
The result of table 1 shows that the compounds of this invention is relatively stable in the hepatomicrosome of people and rat.
Embodiment B：Pharmacokinetic Evaluation after the injection of mouse, rat, dog and monkey and oral the compounds of this invention
Pharmacokinetic of the present invention to the compounds of this invention in mouse, rat, dog or monkey body is commented Estimate.The compounds of this invention is with the aqueous solution or the aqueous solution of 2%HPMC+1% Tween-80s, the saline solution of 5%DMSO+5%, 4% MC or capsule form are administered.It is administered for intravenous injection, animal gives the dosage of 1 or 2mg/kg.For oral dose (p.o.), rat and mouse are 5 or 10mg/kg, and dog and monkey are 10mg/kg.It is 0.25,0.5,1.0,2.0 at time point, Blood (0.3mL) is taken within 3.0,4.0,6.0,8.0,12 and 24 hours, and is centrifuged 10 minutes under 3,000 or 4,000rpm.Collect blood Slurry solution, and analyzed until carrying out above-mentioned LC/MS/MS in being preserved at -20 DEG C or -70 DEG C.
Pharmacokinetic data of the embodiment of the present invention of table 2 in rat body
Pharmacokinetic data of the embodiment of the present invention of table 3 in mouse, dog and monkey body
Table 2,3 results show that the compounds of this invention is good in mouse, rat, dog and monkey body absorption, and half-life period is reasonable.
Embodiment C：Kinase activity assays
The compounds of this invention can be evaluated as the activity of PI3K and mTOR kinase inhibitors by following experiments.
The general description of kinase assay
Kinase assay by detect mix γ-33The myelin basic protein (MBP) of P-ATP is come what is completed.Prepare 20 μ g/ MBP (Sigma#M-1891) trishydroxymethylaminomethane buffer salt solution (TBS of mL；50mM Tris pH 8.0,138mM NaCl, 2.7mM KCl), white 384 orifice plate (Greiner) of associativity high is coated with, per the μ L of hole 60.4 DEG C, it is incubated 24 hours.Afterwards With 100 μ L TBS board-washings 3 times.Kinase reaction is in kinase buffer liquid (the 5mM Hepes pH 7.6,15mM that cumulative volume is 34 μ L NaCl, 0.01% bovine serum albumin(BSA) (Sigma#I-5506), 10mM MgCl2, 1mM DTT, 0.02%TritonX-100) in Carry out.Compound is dissolved in DMSO, is added in each hole, the ultimate density of DMSO is 1%.Twice of each data determination, often The measure of individual compound is at least tested twice.Such as, the ultimate density of enzyme is 10nM or 20nM.Addition does not have markd ATP (10 μM) and γ-33The ATP of P marks is (per hole 2 × 106Cpm, 3000Ci/mmole) start reaction.Reaction is shaken at room temperature Swinging carries out 1 hour.The 384 orifice plates PBS of 7x, is subsequently adding the scintillation solution of the μ L of every hole 50.Counted with Wallac Trilux Number device testing result.To those of ordinary skill in the art, this is only the one kind in numerous detection methods, other methods Also may be used.
The IC that above-mentioned test method can be inhibited50And/or inhibition constant Ki。IC50It is defined as under test conditions, suppression Make compound concentration during 50% enzymatic activity.Made comprising 10 curves of concentration point, estimation using the extension rate of 1/2log IC50Value by following compound concentration (for example, make a typical curve：10μM,3μM,1μM,0.3μM,0.1μM,0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM and 0 μM).
The ordinary test scheme of PI3 kinases
PI3K (p110 α/p85 α) (h) [cold test]
PI3K (p110 α/p85 α) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is according to need Ask determination) cushioning liquid in be incubated.After adding ATP solution, start reaction.30 minutes are incubated at room temperature afterwards, are added thereto Enter the terminate liquid containing EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acids and carry out terminating reaction.Finally, detection buffering is added Liquid, including the anti-GST monoclonal antibodies that europium is marked, the GRP1PH domains and streptavidin-allophycocyanin of GST marks.Orifice plate when Between reading under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000x (Em665nm/ Em620nm) determine.
PI3K (p110 β/p85 α) (h) [cold test]
PI3K (p110 β/p85 α) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is according to need Ask determination) cushioning liquid in be incubated.After adding ATP solution, start reaction.30 minutes are incubated at room temperature afterwards, are added thereto Enter the terminate liquid containing EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acids and carry out terminating reaction.Finally, detection buffering is added Liquid, including the anti-GST monoclonal antibodies that europium is marked, the GRP1PH domains and streptavidin-allophycocyanin of GST marks.Orifice plate when Between reading under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000x (Em665nm/ Em620nm) determine.
PI3K (p110 δ/p85 α) (h) [cold test]
PI3K (p110 δ/p85 α) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is according to need Ask determination) cushioning liquid in be incubated.After adding ATP solution, start reaction.30 minutes are incubated at room temperature afterwards, are added thereto Enter the terminate liquid containing EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acids and carry out terminating reaction.Finally, detection buffering is added Liquid, including the anti-GST monoclonal antibodies that europium is marked, the GRP1PH domains and streptavidin-allophycocyanin of GST marks.Orifice plate when Between reading under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000x (Em665nm/ Em620nm) determine.
PI3K (p120 γ) (h) [cold test]
PI3K (p120 γ) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is true according to demand It is incubated in cushioning liquid calmly).After adding ATP solution, start reaction.30 minutes are incubated at room temperature afterwards, are added thereto to contain There are EDTA and the terminate liquid of biotin phosphatidylinositols -3,4,5- triphosphoric acids to carry out terminating reaction.Finally, detection buffer solution is added, Anti- GST monoclonal antibodies including europium mark, the GRP1PH domains and streptavidin-allophycocyanin of GST marks.Orifice plate is in the time point Reading under fluorescence mode is distinguished, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000x (Em665nm/ Em620nm) determine.
mTOR(h)
MTOR (h) is in the HEPES that 50mM pH value is 7.0,1mM EDTA, 0.01% Tween-20,2mg/mL substrates, 3mM Manganese chloride and [γ-33P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) incubated under conditions of existing Educate.Start reaction after adding MnATP mixtures.40 minutes are incubated at room temperature afterwards, are added thereto to 3% phosphoric acid solution and are terminated anti- Should.10 μ L reaction solutions are distributed on P30 filters in mottled, and were cleaned 3 times in 5 minutes with 75mM phosphoric acid, and dry Preservation in methanol solution is put into before dry and scinticounting at once.
Kinase assay in the present invention be completed by Millipore companies of Britain (Millipore UK Ltd, Dundee Technology Park,Dundee DD2 1SW,UK)。
The kinase inhibiting activity data of the embodiment of the present invention of table 4
The result of table 4 shows that the compounds of this invention can effectively suppress the activity of PI3K and mTOR kinases, and PI3K is swashed Different subtype in enzyme family has good selectivity, so as to show that the compounds of this invention has different choosings to PI3K and mTOR The inhibitory activity of selecting property.
The kinase inhibiting activity of the compounds of this invention can also be tested by KINOMEscanTM, and it is mainly based upon quantitative The experiment of determination sample and the fixed, part and kinases competitive binding ability that active site is oriented to.It is complete that this is tested Into need combine following three elements：Kinases, the part and testing sample of fixation of DNA- marks.Testing sample and fixed ligands The ability of competitive binding kinases can be determined by determining the amount of the PCR in DNA marker.
For most of experiments, the T7 phage strains of kinases-mark are the large intestine bars that origin comes from BL21 bacterial strains Bacterium host prepare.I.e. first by Escherichia coli culture to exponential phase, then infected with T7 bacteriophages, and by its Under continuous concussion, by lysate centrifugation, suction filtration, cell fragment is removed in 32 DEG C of hatchings until cracking.It is remaining in HEK-293 And then the kinases of intracellular generation is marked with DNA, for the detection of qPCR.It is coated with the magnetic bead and biology of Streptavidin After the smaller ligand of elementization reacts 30 minutes at room temperature, the affine resin for kinase assay is generated.The magnetic bead being coordinated Blocked by excessive biotin, with blocking buffer (SEABLOCKTM(Pierce), 1%BSA, 0.05% Tween-20,1mM DTT) washing removes free part, to reduce non-specific binding.Association reaction is all by kinases, the compatibility being coordinated Magnetic bead and testing sample in 1x combination buffers (20%SEABLOCKTM, 0.17x PBS, 0.05% Tween-20,6mM DTT) Middle completion.All reactions are carried out in 96 orifice plates of the final volume for the polystyrene of 0.135mL.The orifice plate of experiment is even Hatch 1 hour in room temperature condition under continuous concussion, the magnetic bead of compatibility uses lavation buffer solution (1x PBS, 0.05% Tween-20) Washing, is then resuspended to elution buffer (1x PBS, 0.05% Tween-20,0.5 μM of non-biotinylated affinity ligands) In, and hatch 30 minutes in room temperature condition under continuous concussion.Kinase concentration in eluent is determined by qPCR.
Kinase assay in the present invention is the KINOMEscanTM Analysis Services by DiscoveRx companies to be completed (42501Albrae St.Fremont,CA 94538,USA)。
Embodiment D：Xenograft Tumor Models
The drug effect of the compounds of this invention is the standard Murine models by transplantation tumor to be evaluated.Human tumor cells After (U87MG glioma cells, ATCC) culture, collection, in rear veutro subcutaneous vaccination in the female nude mice body of 6-7 week old (BALB/cA nu/nu, Hunan SLAC Animal Lab.s) is (for solvent group and each dosage group：N=6-10).When tumour body Product reaches 100-250mm3When, animal is randomly divided into solvent control group (5%DMSO+70%(30%), 7% HCl (pH1), 18%(30%)；Or 7%DMSO, 7%HCl (pH1), 70%(30%), 16%) and compound group (30%).It is follow-up that gastric infusion is carried out using compound on animals, connect from tumour cell Anywhere starting in 0 to 15 days after kind, and generally carry out once daily in test.
Tumor growth inhibition (TGI) is analyzed
The crystallization growth of tumour is evaluated by the relation of gross tumor volume and time.The major axis of hypodermic tumour (L) determined weekly twice by caliper with short axle (W), the volume (TV) of tumour passes through formula (L × W2)/2) are calculated. TGI is calculated by the intermediate value of solvent group mouse tumor volume and the difference of medicine group mouse tumor volume-median, with solvent The percentage of control group gross tumor volume intermediate value is represented, calculated by following formula：
Primary statistics analysis is completed by repeating variance measure analysis (RMANOVA).Followed by Scheffe Psot hoc test methods carry out Multiple range test.Separate solvent (5%DMSO+70%(30%), 7%HCl (pH1), 18%(30%)；Or 7%DMSO, 7%HCl (pH1), 70%(30%), 16%(30%)) it is negative control.
Xenograft Tumor Models (U87MG) data of the embodiment of the present invention of table 5
The result of table 5 shows that the compounds of this invention can significantly inhibit the growth of glioma U87MG xenograft tumors, and Obvious dose dependent is presented, these compound on glial knurls have good curative effect.
Finally it should be noted that also other modes are used for implementing the present invention.Correspondingly, embodiments of the invention are To illustratively illustrate, but be not limited to content described in the invention, it is also possible to be made within the scope of the present invention Modification or the equivalents added in the claims.All publications or patent cited in the present invention all will be used as this hairs Bright bibliography.

Claims (14)

1. a kind of compound, it is the compound of structure shown in formula (I) or compound pharmaceutically acceptable salt shown in formula (I)：
Wherein：
W1It is N or CRc；Each W2And W3It independently is CRc；
Z is D, CN, N3Or
X is H, D, C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical-C1-4Alkylene Base, C6-10Aryl or comprising 1,2,3 or 4 heteroatomic 5-10 for being independently selected from O, S and N former molecular heteroaryls, its In, the C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical-C1-4Alkylidene, C6-10Aryl and 5-10 former molecular heteroaryl is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substitution base, The substitution base is independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-6Alkyl, C1-6Halo Alkyl, C2-6Alkenyl, C2-6Alkynyl, NC-C1-4Alkylidene, RaO-C1-4Alkylidene, RbRaN-C1-4Alkylidene, C6-10Aryl or 5-10 Individual former molecular heteroaryl；
Y is C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical-C1-4Alkylidene, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl or comprising 1,2,3 or 4 heteroatomic 5-10 atom group for being independently selected from O, S and N Into heteroaryl, wherein, the C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocycle Base-C1-4Alkylidene, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl and 5-10 former molecular heteroaryl are not taken independently of one another In generation, is replaced by 1,2,3 or 4 substitution base, and the substitution base is independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-6Alkyl, C1-6Haloalkyl, C2-6Alkenyl, C2-6Alkynyl, NC-C1-4Alkylidene, RaO-C1-4Alkylene Base, RbRaN-C1-4Alkylidene, C6-10Aryl or 5-10 former molecular heteroaryl；
R1It is H, D, Cl, ORaOr NRaRb；
Each RaAnd RbIt independently is H, C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C6-10Aryl, comprising 1,2,3 or 4 independence Selected from the heteroatomic 5-10 former molecular heteroaryl of O, S and N, C6-10Aryl-C1-4Alkylidene, (5-10 atom composition Heteroaryl)-C1-4Alkylidene, or Ra, RbWith nitrogen-atoms in connection together, it is optionally formed substituted or non-substituted 3-8 former molecular heterocycle, wherein, the C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C6-10Aryl, comprising 1,2,3 or The 4 heteroatomic 5-10 for being independently selected from O, S and N former molecular heteroaryls, C6-10Aryl-C1-4Alkylidene, (5-10 Former molecular heteroaryl)-C1-4Alkylidene, 3-8 former molecular heterocycle is unsubstituted independently of one another or by 1,2,3 or 4 Individual substitution base is replaced, and 1,2,3 or 4 substitution base is independently selected from D, F, Cl, CN, N3, OH, NH2, C1-6Alkoxy or C1-6Alkyl amino；
RcIt is H.
2. compound according to claim 1, wherein, Z is CN, N3Or
3. compound according to claim 1, wherein, X is H, D, C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6Ring Alkyl-C1-4Alkylidene or C3-6Heterocyclic radical-C1-4Alkylidene, wherein, the C1-6Alkyl, C3-6Cycloalkyl, C3-6Heterocyclic radical, C3-6 Cycloalkyl-C1-4Alkylidene and C3-6Heterocyclic radical-C1-4Alkylidene is unsubstituted independently of one another or by 1,2,3 or 4 substitution base institute Substitution, the substitution base is independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-3Alkyl, C1-3 Haloalkyl, C2-4Alkenyl or C2-4Alkynyl.
4. compound according to claim 1, wherein, Y is C1-6Alkyl, C3-6Cycloalkyl, C2-6Alkenyl, C2-6Alkynyl, C6-10 Aryl or comprising 1,2,3 or 4 heteroatomic 5-10 for being independently selected from O, S and N former molecular heteroaryls, wherein, it is described C1-6Alkyl, C3-6Cycloalkyl, C2-6Alkenyl, C2-6Alkynyl, C6-10Aryl and 5-10 former molecular heteroaryl are independently of one another Unsubstituted or replaced by 1,2,3 or 4 substitution base, the substitution base is independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb,-C (=O) NRaRb, C1-3Alkyl, C1-3Haloalkyl, C2-4Alkynyl, C6-10Aryl or 5-10 original are molecular miscellaneous Aryl.
5. compound according to claim 1, wherein, R1It is H, D, Cl, OCH3Or OCH2CH3。
6. compound according to claim 1, the structure with one of：
7. a kind of pharmaceutical composition, comprising the compound described in claim 1-6 any one, and pharmaceutically acceptable load Body, excipient, diluent, assistant agent, or medium, or combinations thereof.
8. pharmaceutical composition according to claim 7, wherein further including additional therapeutic agent, the additional treatment Agent is selected from chemotherapeutic agent, antiproliferative, the medicine for treating atherosclerosis, or for treating the medicine of pulmonary fibrosis Thing, or combinations thereof.
9. pharmaceutical composition according to claim 8, wherein described additional therapeutic agent is Chlorambucil (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), BCNU (carmustine), lomustine (lomustine), chain urea assistant Rhzomorph (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin) reaches Carbazine (dacarbazine), Temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (MTX) (methotrexate), fluorouracil (fluorouracil), cytarabine (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vincaleukoblastinum (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), TPT (topotecan), Irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), dactinomycin D (dactinomycin), Doxorubicin (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), mitomycin C (mitomycin), Ipsapirone (ixabepilone), TAM (tamoxifen), Flutamide (flutamide), Gonadorelin (gonadorelin), first Ground progesterone (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon-' alpha ' (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Afatinib (afatinib), alisertib, amuvatinib, Ah handkerchief replace Buddhist nun (apatinib), A Xi For Buddhist nun (axitinib), bortezomib (bortezomib), bosutinib (bosutinib), brivanib, Cabozantinib, AZD2171 (cediranib), crenolanib, gram Zhuo replace Buddhist nun (crizotinib), dabrafenib, Dacomitinib, danusertib, Dasatinib (dasatinib), many Weis replace Buddhist nun (dovitinib), Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), Imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib, Linifanib, linsitinib, Masitinib (masitinib), momelotinib, Mo Tesaini (motesanib) come that For Buddhist nun (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib (olaparib), handkerchief Azoles handkerchief Buddhist nun (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib) relax Buddhist nun replace Buddhist nun (sunitinib), tasocitinib, Telatinib (telatinib), tivantinib, tivozanib, Tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), Vismodegib, volasertib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), brentuximab Vedotin, catumaxomab (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab) is lucky Trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), difficult to understand (ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab , or Herceptin (trastuzumab), or combinations thereof (tositumomab).
10. the pharmaceutical composition described in compound described in claim 1-6 any one or claim 7-9 any one exists Prepare the purposes of the medicine for protecting, processing, treat or mitigating patient's proliferative diseases.
11. purposes according to claim 10, wherein described proliferative diseases are metastatic carcinomas, colon cancer, sdenocarcinoma of stomach, wing Guang cancer, breast cancer, kidney, liver cancer, lung cancer, cutaneum carcinoma, thyroid cancer, head and neck cancer, prostate cancer, cancer of pancreas, central nervous system The cancer of system, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
The pharmaceutical composition described in compound or claim 7-9 any one described in 12. claim 1-6 any one exists The purposes for the medicine of suppression or regulatory protein kinase activity in biological sample is prepared, the purposes will comprising usage right Ask compound described in 1-6 any one or the pharmaceutical composition and described biology described in usage right requirement 7-9 any one Sample is contacted.
13. purposes according to claim 12, wherein, the protein kinase is receptor tyrosine kinase.
14. purposes according to claim 13, wherein, the receptor tyrosine kinase is PI3K and/or mTOR.
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