CN108570048A - Substituted heteroaryl compound and combinations thereof and purposes - Google Patents

Substituted heteroaryl compound and combinations thereof and purposes Download PDF

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CN108570048A
CN108570048A CN201810159088.XA CN201810159088A CN108570048A CN 108570048 A CN108570048 A CN 108570048A CN 201810159088 A CN201810159088 A CN 201810159088A CN 108570048 A CN108570048 A CN 108570048A
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alkylidene
alkyl
compound
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CN108570048B (en
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习宁
李晓波
李敏雄
张涛
胡海洋
吴彦君
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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

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Abstract

The present invention provides heteroaryl compound of one kind substitution and combinations thereof and their purposes.The compound is stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug of compound shown in formula (I) compound represented or formula (I).The present invention also provides the pharmaceutical compositions for including the compound, the compound and pharmaceutical composition can be with regulatory protein kinases, the especially activity of Aurora A and jak kinase, for preventing, handling, treat and mitigating the disease or disorder that protein kinase, especially jak kinase activity mediate.

Description

Substituted heteroaryl compound and combinations thereof and purposes
Invention field
The invention belongs to drug fields, and in particular to a new class of substituted heteroaryl compound, its is pharmaceutically acceptable Salt and pharmaceutical composition comprising the compound and the compound and its pharmaceutical composition to prepare treatment lactation dynamic The proliferative diseases of object, the medicine of autoimmune disease, anaphylactia, inflammatory disease, graft rejection, cancer or other diseases Purposes in object.More specifically, compound of the present invention can adjust jak kinase family (including JAK1, JAK2, JAK3 and TYK2), FLT3 kinases (also referred to as FLK-2) and Aurora A (including Aurora-A, Aurora-B and Aurora-C) Activity, and then adjust intraor extracellular signal transduction.
Background of invention
Protein kinase family includes a big relevant enzyme of class formation, they control intracellular various signal transduction processes, Similar 250-300 amino acid catalytic domain is usually contained, the phosphorylation of target proteins matter substrate is catalyzed.It was reported that many diseases It is related with the abnormal cell response that protein kinase mediated event causes.These diseases include benign and pernicious proliferative disease Disease, allograft rejection, graft versus host disease, autoimmune caused by disease, the inappropriate activation of immune system Disease, inflammatory disease, bone disease, metabolic disease, neurological disease and neurodegenerative disease, cancer, angiocardiopathy, allergy and Asthma, Alzheimer disease and hormone related condition.Correspondingly, medicinal chemistry arts largely make great efforts to find as controlling Treat the effective kinases inhibitor of agent.
Kinases can be divided into multiple families (for example, protein-tyrosine, protein-silk ammonia by the substrate of phosphorylation Acid/threonine, lipid, etc.).Tyrosine phosphorylation is to adjust various biological process such as cell Proliferation, migration, differentiation and lifes One of central event deposited.The receptors of multiple families and nonreceptor tyrosine kinase family listed business these events：Catalytic phosphatase from ATP is transferred to the tyrosine residues of specific cells protein target.Currently, having confirmed that above-mentioned each kinase families general homology Motif (Hanks et al., FASEB J., 1995,9,576-596；Knighton et.al.,Science,1991,253, 407-414；Garcia-Bustos en al.EMBO J.,1994,13:2352-2361).Kinases in protein kinase family Example includes, but are not limited to Aurora, Axl, abl, Akt, bcr-abl, Blk, Brk, Btk, c-Met, c-src, c-fms, CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Flt-3, Fak, fes, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, Fps, Frk,Fyn,Hck,JAK,IGF-1R,INS-R,KDR,Lck,Lyn,MEK,p38,PDGFR,PIK,PKC,PYK2,ros,Tie, Tie-2, TRK, Yes and Zap70, etc..
Aurora A family is the related serine/threonine kinase of a kind of height, is mitotic crucial tune Agent is saved, the accurate and equal separation (segtion) for the genomic material from mother cell to daughter cell is required.Aurora The member of kinase families includes the related kinases of three classes, and referred to as Aurora-A, Aurora-B and Aurora-C (are also referred to as Aurora-1, Aurora-2 and Aurora-3).Although these kinases have significant program homology, localization and work( Can still there are different (Richard D.Carvajal, et al., Clin.Cancer Res., 2006,12 (23) greatly each other:6869- 6875；Daruka Mahadevan,et al.,Expert Opin.Drug Discov.,2007,2(7):1011-1026).
Aurora-A generally expresses and adjusts the cell cycle events occurred from the phase in late period S through the M phases, including centerbody at Ripe (Berdnik D, et al., Curr.Biol., 2002,12:640-647), mitosis enter (Hirota T, et al., Cell,2003,114:585-598；Dutertre S,et al.,J.Cell Sci.,2004,117:2523-2531), center Body detaches (Marumoto T, et al., J.Biol.Chem., 2003,278:51786-51795), the two poles of the earth mitotic spindle assembly object (Eyers PA,et al.,Curr Biol.,2003,13:691-7), (the Marumoto T, et of the Chromosomal arrangement on equatorial plate al.,J.Biol.Chem.,2003,278:51786-95；Kunitoku N,et al.,Dev Cell,2003,5:853-64), Cytokinesis (Marumoto T, et al., J Biol Chem., 2003,278:51786-95), terminate with mitosis.From G2 increases through M phases Aurora-A protein level and kinase activity, and peak activity is in the prometaphase.Once activation, Aurora- A converts acid curling by including that centrosome protein (centrosomin) interaction mediates its multiple functions with various substrates - crimp protein, cdc25b, Eg5 and centromere protein matter A.
Aurora-B is that accurate chromosome is isolated, cytokinesis (Hauf S, et al., J.Cell Biol., 2003,161:281-94；Ditchfield C,et al.,J.Cell Biol.,2003,161:267-280；Giet R,et al.,J.Cell Biol.,2001,152:669-682；Goto H,et al.,J.Biol.Chem.,2003,278:8526- 8530), (Murata-Hori M, et are adhered in protein localization to kinetochore and centromere, correct micro-pipe-centromere al.,Curr.Biol.,2002,12:894-899), and adjust Mitotic checkpoint key chromosome passenger's albumen. Localization is in chromosome first during early period by Aurora-B, and then localization dyes list in sisters during prometaphase and mid-term Between body interior kinetochore area (Zeitlin SG, et al., J.Cell Biol., 2001,155:1147-1157).Aurora- The biology that B participates in establishing chromosome is orientated, and wherein sisters centromere is connected to the opposite pole of the two poles of the earth spindle via double orientation attachment. The mistake of the process shows as partially oriented connection status (centromere is connected to from bipolar micro-pipe) or the altogether company of orientation State (two sisters centromeres are connected to the micro-pipe from same stages) is connect, if the not correction up before the later stage starts, will be led Cause the unstability and aneuploidy of chromosome.It is that repairing is incorrect micro- in the main function of the Aurora-B of mitosis point The attachment of pipe-centromere (Hauf S, et al., J.Cell Biol., 2003,161:281-294；Ditchfield C,et al.,J.Cell Biol.,2003,161:267-280；Lan W,et al.,Curr.Biol.,2004,14:273-286). In the case that Aurora-B is inactivated, Mitotic checkpoint is damaged, and causes increased number of aneuploid cell, mrna instability Qualitative and tumour occur (Weaver BA, et al., Cancer Cell, 2005,8:7-12).
Aurora-A overexpressions are the tumorigenic required features of Aurora-A- inductions.It is overexpressed in tool Aurora-A Cell in, mitotic feature be there are multiple centerbodies and multipolar spindle (Meraldi Pet al., EMBO J., 2002,21:483-492).Although obtaining the attachment of abnormal microtubule-centromere, cell still abolish Mitotic checkpoint and from mid-term into Exhibition causes many chromosome separation defects to the later stage.Cytokinesis will not occur for these cells, and develop other cell Period, polyploidy and progressive chromosome instability (Anand S, et al., Cancer Cell, 2003,3:51-62).
Verified Aurora is overexpressed and a variety of malignant proliferative disorders, such as the carcinoma of the rectum, breast cancer, lung cancer, cancer of pancreas, preceding Row gland cancer, carcinoma of urinary bladder, head and neck cancer, cervix cancer, oophoroma, liver cancer and gastric cancer etc. are closely related, excite exploitation and are used for cancer The interest of the Aurora inhibitor for the treatment of.In normal cell, Aurora-A inhibition causes to delay but and non-blacked mitosis Into the centerbody separation defect of, monopole mitotic spindle and cytokinesis failure (Marumoto T, et al., J.Biol.Chem.,2003,278:51786-51795).The encouraging antitumous effect of Aurora-A inhibitor is shown in three kinds Human pancreatic cancer cell is in (Panc- Ι, MIA PaCa-2dnSU.86.86), wherein having growth suppression in cell culture System and tumorigenicity in murine xenogralt it is intimate all eliminate (Hata T, et al., Cancer Res., 2005,65:2899-2905)。
Aurora-B inhibits to cause abnormal centromere-micro-pipe attachment, the biology orientation that cannot achieve chromosome, cytokinesis Failure (Goto H, et al., J.Biol.Chem., 2003,278:8526-8530；Severson AF,et al., Curr.Biol.,2000,10:1162-1171).The repetitive cycling of the abnormal mitosis including cytokinesis causes huge Polyploidy and eventually lead to Apoptosis (Hauf S, et al., J.Cell Biol., 2003,161:281-94； Ditchfield C,et al.,J.Cell Biol.,2003,161:267-80；Giet R, et al., J.Cell Biol., 2001；152:669-82；Murata-Hori M,Curr.Biol.,2002,12:894-899；Kallio M J,et al., Curr.Biol.,2002,12:900-905)。
Inhibit Aurora-A or Aurora-B activity that Chromosomal arrangement is caused to damage in tumour cell, Mitotic checkpoint Abolishment, polyploidy and subsequent cell death.These in vitro effects are in the cell of conversion than in non-transformed or undifferentiated Cell in it is more preferable (Ditchfield C, et al., J.Cell Biol., 2003,161:267-280), to target The internal selectivity to cancer may be implemented in Aurora.Although it is foreseen that may be to the quick of hemopoietic system and gastrointestinal system to it Noble cells has certain toxicity, but the activity in xenograft models still shows that rational treatment refers to clinical tolerability Number.Under the premise of preclinical antitumor activity and tumor-selective potentiality, several Aurora As have been developed at present and have been inhibited Agent.
FLT3 (Flt3, FMS- relevant tyrosine kinase 3), also referred to as FLK-2 (fetal livers kinases 2) and the STK-I (mankind Stem cell kinases 1), belong to receptor tyrosine kinase (RTK-III) family member (Gtirewalt DL et al., Nat.Rev.Cancer,2003,3:650-665；Rosnet O,et al.,Genomics,1991,9:380-385；Yarden Y,et al.,Nature,1986；323:226-232；Stanley E R,et al.,J.CellBiochem.,1983,21: 151-159；Yarden Y,et al.,EMBO J.,1987,6:3341-3351).FLT3 is transmembrane protein, by four structures Domain forms, and includes extracellular ligand-binding domain of five immunoglobulin class structure compositions, the domain cross-film (TM), nearly film (JM) domain With the domain cytoplasm C- terminal tyrosines kinases (TK).(Agnes F,et al.Gene,l994,145:283-288；Scheijen B,et al.,Oncogene,2002,21:3314-3333)。
The ligand of FLT3 was cloned in 1993, studies show that, it includes marrow that it, which is Hematopoietic marrow microenvironment cell, Expressed in fibroblast and other cells type I transmembrane proteins (Lyman SD, et al., Cell, 1993,75, 1157-1167).Film combines the tyrosine kinase activity with the equal energy activated receptor of soluble form and stimulates the ancestral in marrow and blood Cell growth.The zygotic induction receptor dimer of ligand-receptor, and activated protein kinase domain；Then it its autophosphorylation and is catalyzed each The substrate protein phosphorylation of kind signal transduction pathway, for example transcribe 5 signal transducer and activator (STAT5), RAS/ mitogens Protein kinase (RAS/MAPK), phosphoinositide 3-kinase (PI3K), the Src of original activation be of the same race and glue protogene (SHC), contains Inositol -5- the phosphatases (SHIP) of SH2 and the cytoplasmic tyrosine phosphoric acid with 2 Src- homologys 2 (SH2) domains (SHP2) Enzyme, play a significant role in cell Proliferation, differentiation and existence (Dosil M., et al., Mol.Cell Biol., 1993, 13:6572-6585.Zhang S,Biochem.Biophys.Res.Commun.,l999,254:440-445).In addition to hematopoiesis is thin Except born of the same parents, FLT3 genes also in placenta, sexual gland and brain expression (Maroc N, et al., Oncogene, 1993,8:909- 918) and in immune response play a significant role (deLapeyriere O.et al., Leukemia, 1995,9:1212- 1218)。
FLT3 also with the hemopoietic system dysfunction before malignant proliferative lesion, such as piastrenemia, true property blood platelet Bone is obtained before increase disease, myelofibrosis (MF), chronic idiopathic myelofibrosis (IMF), polycythemia (PV), canceration Marrow hyperplasia exception syndrome, hematologic malignancies include, but are not limited to leukaemia, (non-Hodgkin lymphoma), lymphogranulomatosis (also known as Hodgkin lymphoma) and myeloma, for example, acute lymphatic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophil leukemia (CNL), it is closely related.Acute myeloid leukaemias (AML) of the FLT3 in 70-100% In, and in the acute lymphoblastic leukemia (ALL) of high percentage with it is each it is horizontal be overexpressed (GriffinJD, et al., Haematol J.,2004,5:188-190).In primitive cell crisis, also in the smaller of chronic myelogenous leukemia (CML) It is overexpressed in hypotype.Research has been displayed B pedigree leukaemia cells ALL and AML and continually co-expresses FL, and FLT3 composing types is caused to be lived The autocrine or paracrine signal transduction of change recycle (Zheng R, et.al.Blood., 2004,103:267-274).In addition, FLT3 ligand is in langerhans cell histiocytosis and Patients with SLE cell serum with high-level table It reaches, the dendritic cells Signal Regulation for further displaying FLT3 and autoimmune disease is extremely closely related.
More and more evidences show that a plurality of types of leukaemia and myeloproliferative syndrome have the prominent of tyrosine kinase Become.FLT3 mutation are one of most frequent body changes in AML, are happened in about 1/3 patient.It is described in leukaemic Two kinds of FLT3 Activating mutations.These include a series of in the internal series-connection occurred from the nearly film domain of inhibition duplication (ITD)(Nakao M,et al.,Leukemia,1996,10:1911-1918；Thiede C et al.,Blood,2002, 99:4326-4335) it is mutated with activation cycle comprising Asp835Tyr (D835Y), Asp835Val (D835V), Asp835His (D835H), Asp835Glu (D835E), Asp835Ala (D835A), Asp835Asn (D835N), Asp835 are lacked The Ile836 that becomes estranged lacks (Yamamoto Y, et al., Blood, 2001,97:2434-2439；Abu-Duhier FM,et al.,Br.J.Haematol.,2001,113:983-988).Internal series-connection in the domains JM, which replicates (ITD) mutation, to be contributed in AML The FLT3 Activating mutations of about 17-34%.FLT3-ITD is also able to detection (MDS) with low frequency in myelodysplastic syndrome (Yokota S.,et al.,Leukemia,l997,11:1605-1609；Horiike S,et al.,Leukemia,1997, 11:1442-1446).ITDs is confined to the domains JM always in frame.However, in different patients, there are change in length and position Change.These repetitive routines can be used for destroying the domains JM from inhibitory activity, cause FLT3 composing types to activate.FLT3-ITD and FLT3-Asp835 mutation it is related with the phosphorylation of FLT3 autophosphorylations and downstream targets (Mizuki M, et al., Blood, 2000,96:3907-3914；Mizuki M,et al.,Blood,2003,101:3164-3173；Hayakawa F,et al., Oncogene,2000,19:624-631)。
Currently, the FLT3 inhibitor ground as some or all with the FLT3 recurrences being mutated or obstinate AML patient Monotherapy have reached clinical test.Generally, these are statistics indicate that FLT3 is to be used for AML and other related diseases for developing The attractive therapeutic targets of the kinase inhibitor of disease.
Janus kinases (JAK) is an intracellular non-receptor tyrosine kinase family, logical by turning JAK-STAT Road, the signal that the transducer cell factor mediates.The proliferation that JAK families rely in cell factor adjusts and is related to the cell of immune response It plays an important role in function.Cell factor is combined with their receptor, is caused receptor dimerization, can be promoted JAKs phases in this way Mutual phosphorylation can also promote cytokine receptor internal specific tyrosine motif phosphorylation.Identify these phosphorylation motifs STATs is focused on receptor, is then activated during the tyrosine phosphorylation that JAK is relied on.Due to activation, STATs with Receptor dissociates, dimerization, and is displaced to nucleus, is combined with the specific sites DNA, and change transcription.
Mammal JAK family members known to being currently, there are four kinds：(Janus swashs by JAK1 (Janus kinases -1), JAK2 Enzyme -2), JAK3 (Janus kinases, leucocyte；JAKL；L-JAK and Janus kinases -3) and TYK2 (protein tyrosine kinase 2). JAK1, JAK2 and TYK2 are general expression, and JAK3 is reported and is preferentially expressed in natural kill (NK) cell, without other T cell in express (" Biology and significance of the JAK/STAT signaling pathways. " Growth Factors,April 2012；30(2):88).
JAK1 is necessary the signal transduction of certain I types and II cytokines.The γ of it and I cytokines receptors Public chain (γ c) interaction, induces IL-2 receptor families, IL-4 receptor families, gp130 receptor families to send out signal.It is to I The signal of type (IFN-α/β) and II types (IFN-γ) interferon, and the IL-10 family members by II cytokines receptors Signal transduction it is also critically important.Heredity and biological study show, JAK1 functionally and physiologically with I types interferon (for example, IFNalpha), II types interferon (for example, IFNgamma), IL-2 to IL-6 cytokine receptor complex are related.Further It is logical in IFN, IL-IO, IL-2/IL-4 and IL-6 to demonstrate the kinases to the characterization of the tissue from JAK1 knock-out mices for ground Key effect in road.
JAK1 expression in cancer cell can promote individual cells atrophy, potentially them is made to flee from tumour, be transferred to body Other positions of body.By the cell factor of JAK1 transduction signals, horizontal raising involves a large amount of immune and inflammation disease Disease.JAK1 or JAK family kinase inhibitors can be used for adjusting or treat these diseases (Kisseleva et al., 2002, Gene 285:1-24；Levy et al.,2005,Nat.Rev.Mol.Cell Biol.,3:651-662).Target the people of IL-6 accesses Resource monoclonal antibody (Torr pearl monoclonal antibody Tocilizumab) is ratified to close for treating moderate to severe rheumatoid by EU Committee Save inflammation (Scheinecker et al., 2009, Nat.Rev.Drug Discov., 8:273-274).
JAK2 and II cytokines receptor family (such as interferon receptors), GM-CSF receptor families, gp130 receptors man The signal transduction of family member is relevant.JAK2 signals are activated in the downstream of hprl receptor.Research shows that in myeloproliferative In disease disease such as polycythemia vera, primary thrombocytosis and idiopathic myelofibrosis, generally deposit It is mutated (JAK2V617F) in the JAK2 of acquired activation.The JAK2 albumen of mutation can be the case where no cell factor stimulates Lower activation downstream signal leads to spontaneous growth and/or the hypersensitivity to cell factor, is considered the process to these diseases Play a part of promotion.The more multimutation of JAK2 functional disturbances or transposition is caused to be found in the description to other malignant tumours (Ihle J.N.and Gilliland D.G.,Curr.Opin.Genet.Dev.,2007,17:8；Sayyah J.and Sayeski P.P.,Curr.Oncol.Rep.,2009,11:117).JAK2 inhibitor has described as to proliferative diseases There are effect (Santos et al, Blood, 2010,115:1131；Barosi G.and Rosti.V., Curr.Opin.Hematol,2009,16:129,Atallah E.and Versotvsek S.,Exp.Rev.Anticancer Ther.,2009,9:663)。
JAK3 only be present in IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokine receptor complex Public gamma cells factor acceptor chain is related.JAK3 is mainly expressed in immunocyte, and the tyrosine phosphorus for passing through interleukin-2-receptor Acidification activation, transduction signal.Since JAK3 is limited to express in candidate stem cell more, relative to other JAKs, it is in cell factor Effect in signal transduction is stringenter.The mutation of JAK3 can lead to severe combined immunodeficiency (SCID) (O'Shea et al.,2002,Cell,109(suppl.):S121-S131).Effect based on it in adjusting lymphocyte, targeting JAK3 and The access that JAK3 is mediated has been used for treating immunosupress indication (for example, graft rejection and rheumatoid arthritis) (Baslund et al.,2005,Arthritis&Rheumatism 52:2686-2692；Changelian et al., 2003,Science 302:875-878)。
TYK2 and IFN-α, IL-6, IL-10 to IL-12 signal transductions are related.Biochemical research and knock out mice Disclose TYK2 immunology important function.TYK2 deficient mice energy growth and breedings, but panimmunity defect is shown, it is main If to infection, there are hypersensitivities and the existing defects in terms of oncological surveillance.It is opposite, inhibit TYK2 can be improved resist allergy, The ability of autoimmunity and inflammatory disease.Particularly, targeting TYK2 seems to become treatment IL-12-, IL-23- or I types IFN- Jie The innovative strategy for the disease led.The disease includes but not limited to rheumatoid arthritis, multiple sclerosis, lupus, silver bits Disease, psoriasis arthropathica, inflammatory bowel disease, uveitis, sarcoidosis and cancer (Shaw, M.et al., Proc.Natl.Acad.Sci.,USA,2003,100,11594-11599；Ortmann,R.A.,and Shevach, E.M.Clin.Immunol,2001,98,109-118；Watford et al,Immunol.Rev.,2004,202:139). [“Janus Kinase(JAK)Inhibitors in Rheumatoid Arthritis.”Current Rheumatology Reviews,2011,7,306-312]。
European commission has been recently approved the complete people source of the shared p40 subunits of targeting IL-12 and IL-23 cell factors Monoclonal antibody (Ustekinumab), for treat moderate to severe plaque psoriasis (Krueger et al., 2007, N.Engl.J.Med.,356:580-92；Reich et al.,2009,Nat.Rev.Drug Discov.,8:355-356).This Outside, targeting IL-12 and IL-23 accesses antibody carried out for treat Crohn disease clinical test (Mannon et al., N.Engl.J.Med.,2004,351:2069-79)。
When adjusting not normal, the response that JAK- is mediated can positively or negatively influence cell, cause overactivity to be disliked respectively Property tumour, or immune and hematopoietic defect, which imply the practicabilities of jak kinase inhibitor.JAK/STAT signal paths involve To many proliferation and cancer associated processes, including cell cycle progression, apoptosis, angiogenesis, infiltration, transfer and immune system are escaped Keep away (Haura et al., Nature Clinical Practice Oncology, 2005,2 (6), 315-324；Verna et al.,Cancer and Metastasis Reviews,2003,22,423-434).In addition, JAK/STAT signal paths are to making The generation and differentiation of hemocytoblast, proinflammatory and anti-inflammatory dual regulation and immune response play an important role (O'Sullivan et al.,Molecular Immunology,2007,44:2497)。
Therefore, all four members of JAK/STAT accesses, especially JAK families, are considered in asthma reaction, chronic resistance It works in the pathogenesis of plug property tuberculosis, bronchitis and other relevant lower respiratory tract inflammatory diseases.JAK/STAT is logical Road equally (includes, but are not limited to iritis, uvea in ocular inflammatory disease (diseases)/disease (conditions) Inflammation, sclerotitis, conjunctivitis) and chronic anaphylaxis reaction in work.Since cell factor swashs using various various forms of JAK Enzyme (O'Sullivan et al., Mol.Immunol, 2007,44:2497；Murray J.,Immunol,2007,178: 2623), different selective jak kinases in antagonism family are logical to treat the relevant disease of the specific cells factor or JAK/STAT Variability or the relevant disease of polymorphism may be useful in road.
Rheumatoid arthritis (RA) is a kind of autoimmune disease characterized by chronic joint inflammation.Take JAK suppressions The patient with rheumatoid arthritis of preparation shows the inhibition of the JAK1 and JAK3 module by signal caused to cytokine profiles, it To lymphocyte function, including proleulzin (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21 are critically important [Fleischmann,R.et al.,“Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis.”N.Engl.J.Med.,2012,367,495-507].It is assumed that directly making specific JAK sub- The micromolecular inhibitor of type inactivation can not only mitigate the clinical symptoms of RA, those can also be inhibited to promote being permitted for RA disease progressions Excessive adjusting (" the Inhibitors of JAK for the treatment of rheumatoid of more proinflammatory cytokines arthritis:rationale and clinical data.”Clin.Invest.,2012,2(1),39-47)。
The sustained activation of STAT3 or STAT5 has been proved to be present in many entity human tumours, including lacteal tumor, pancreas Tumor, prostate tumor, ovarioncus and liver cancer, while existing in a large amount of blood tumor, including lymthoma and leukaemia.In this side Face, the inactivation proliferation capable of inhibiting cell and/or inducing cell apoptosis of the JAK/STAT signals in neoplastic hematologic disorder.Although tumour cell In STAT3 can still be counted as most important upstream activat person by many kinase activations, JAK2, it can be activated derived from each STAT3 (Mohamad Bassam Sonbol, Belal Firwana, Ahmad in the human tumor cell line of kind entity tumor Zarzour,Mohammad Morad,Vishal Rana and Ramon V.Tiu “Comprehensive review of JAK inhibitors in myeloproliferative neoplasms.”Therapeutic Advances in Hematology 2013,4(1),15-35；Hedvat M,Huszar D,Herrmann A,Gozgit J M,Schroeder A,Sheehy A,et al.“The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors.”Cancer Cell 2009,16(6):487-97).Therefore, inhibit JAK Kinases plays beneficial effect to the treatment of these diseases.
It knows clearly, kinases inhibitor is poly- as new immunosupress, anti-inflammatory double action medicine and anticancer medicine Numerous concerns are collected.Therefore, inhibit the protein kinase such as novel agent of Aurora A, FLT3 kinases and jak kinase or improve examination Agent is needed for a long time, it can be used as the immunosuppressor of organ transplant, antitumor agent, it can also be used to prevent and treat autoimmunity Disease is (for example, multiple sclerosis, psoriasis, rheumatoid arthritis, asthma, type-1 diabetes mellitus, inflammatory bowel disease, Crow grace Disease, polycythemia vera, primary thrombocytosis, myelofibrosis, autoimmune thyroid disease, the seas A Erzi Silent disease), it is related to the disease (for example, eczema) of overactivity inflammatory reaction, allergy, chronic obstructive pulmonary disease, bronchitis, cancer (for example, prostate cancer, acute myelocytic leukemia, chronic granulocytic leukemia, acute lymphoblastic leukemia, white blood Disease, Huppert's disease) and other treatment caused by immune response (for example, fash, contact dermatitis or diarrhea), etc..This Compound, composition and the method for invention description directly correspond to these needs and other purposes.
Invention content
The present invention provides one kind to inhibit, adjusts and/or regulate and control one or more protein kinases, as jak kinase, FLT3 swash Enzyme and the active compound of Aurora A, for treating proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease Disease, graft rejection and their complication.Present invention provides the methods for preparing these compounds, use these compounds The method for treating the above-mentioned disease of mammal, the especially mankind, and the pharmaceutical composition comprising these compounds.And have Similar compound compare, the compound of the present invention have better pharmacological activity, specifically, the compounds of this invention is to target Kinases shows the Kinase Selectivity of preferable inhibitory activity and optimization.In addition, the compounds of this invention also has excellent permeable membrane Property and dissolution properties, therefore, the compounds of this invention have preferable development prospect.
Specifically：
On the one hand, the present invention relates to the alloisomerisms of one kind compound as shown in formula (I) compound represented or formula (I) Body, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein, Z, Z1、A、U1、U2、U3And R1With meaning as described in the present invention.
In some embodiments, Z C7-C12Spiral shell bicyclic alkyl, C7-C12Condensed-bicyclic alkyl, 7-12 atom composition The miscellaneous bicyclic group of spiral shell or 7-12 former molecular condense miscellaneous bicyclic group, wherein each C7-C12Spiral shell bicyclic alkyl, C7-C12It is thick Close bicyclic alkyl, the 7-12 former molecular miscellaneous bicyclic group of spiral shell and 7-12 former molecular condensed miscellaneous bicyclic group individually optionally By 1,2,3,4 or 5 R2Group is replaced；Or Z is C3-C7Monocyclic cycloalkyl or 3-7 former molecular monocyclic heterocycles base, In, each C3-C7Monocyclic cycloalkyl and 3-7 former molecular monocyclic heterocycles base are individually optionally by 1,2,3,4 or 5 R3 Group is replaced；
Z1For H, C1-C12Alkyl, C3-C12Naphthenic base or 3-12 former molecular heterocycle, wherein each C1-C12 Alkyl, C3-C12Naphthenic base and 3-12 former molecular heterocycle are individually optionally by 1,2,3,4 or 5 R3Group is replaced；
Work as U1For N when, U2For CH, U3For N；
Work as U1For C when, U2For NH, U3For N or CH；
Respectively --- -- independently is a singly-bound or a double bond；
A is pyrazolyl, optionally by 1,2 or 3 R4Group is replaced；
R1For H, F, Cl, Br, I, N3、CN、NO2、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl or-(CR6R7)nC (= O)NRaRb, wherein each C1-C12Alkyl, C2-C12Alkenyl and C2-C12Alkynyl is individually optionally by 1,2,3,4 or 5 R8Base Group is replaced；
Each R2It independently is F, Cl, Br, I, NO2、N3, CN, oxo (=O), C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynes Base, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl, 5-12 former molecular heteroaryl ,-C (= O)CH2CN、-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb,-C (=NRd)NRaRb、-N(Rd) C (=O) NRaRb、-N(Rd) S (=O)mR5 Or-S (=O)2NRaRbOr two R2, and together with the atom that they are connected, form C3-C12Naphthenic base, C6-C12Aryl, 3- The molecular heterocycle of 12 originals or 5-12 former molecular heteroaryl groups, wherein each C1-C12Alkyl, C2-C12Alkene Base, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl and 5-12 original are molecular miscellaneous Aryl is individually optionally by 1,2,3,4 or 5 R8Group is replaced；
R3For F, Cl, CN, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6- C12Aryl, 5-12 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (= O)2NRaRb, wherein each C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6- C12Aryl and 5-12 former molecular heteroaryl are individually optionally by 1,2,3,4 or 5 R8Group is replaced；
R4For F, Cl, CN, C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 atom composition Heterocycle, C6-C12Aryl, 5-12 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRb, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 Former molecular heterocycle, C6-C12Aryl and 5-12 former molecular heteroaryl are individually optionally by 1,2,3,4 or 5 R8 Group is replaced；
Each R5It independently is C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Alkoxy, C1-C12Alkylamino, C3- C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl, 5-12 former molecular heteroaryl ,-(C1-C4Alkylene Base)-(C3-C12Naphthenic base) ,-(C1-C4Alkylidene)-(3-12 former molecular heterocycle) ,-(C1-C4Alkylidene)-(C6- C12Aryl) or-(C1-C4Alkylidene)-(5-12 former molecular heteroaryl), wherein above-mentioned each group individually optional ground quilt 1,2,3,4 or 5 R8Group is replaced；
Each R6And R7It is separately H, F, Cl, Br, I, NO2、N3、CN、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynes Base, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Virtue or 5-12 former molecular heteroaryl, alternatively, R6、R7C is formed together with the carbon atom being connected with them3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl Or 5-12 former molecular heteroaryl, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, 3-12 former molecular heterocycle, C6-C12The former molecular heteroaryl of aryl and 5-12 individually optionally by 1,2,3, 4 or 5 R8Group is replaced；
Each R8It independently is F, Cl, Br, I, CN, NO2、N3、OH、NH2、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Halogenated alkyl, C3-C12Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle, 5-12 original are molecular miscellaneous Aryl, C1-C12Aminoalkyl, C1-C12Alkylamino, C1-C12Alkoxy, C1-C12Hydroxy alkyl ,-NH (C0-C4Alkylidene)-(C3- C12Naphthenic base) ,-NH (C0-C4Alkylidene)-(C6-C12Aryl) ,-NH (C0-C4Alkylidene)-(3-12 former molecular heterocycle Base) ,-NH (C0-C4Alkylidene)-(5-12 former molecular heteroaryl) ,-N [(C0-C4Alkylidene)-(C3-C12Naphthenic base) ]2、-N[(C0-C4Alkylidene)-(C6-C12Aryl)]2、-N[(C0-C4Alkylidene)-(3-12 former molecular heterocycle)]2、- N[(C0-C4Alkylidene)-(5-12 former molecular heteroaryl)]2、-O(C0-C4Alkylidene)-(C3-C12Naphthenic base) ,-O (C0- C4Alkylidene)-(C6-C12Aryl) ,-O (C0-C4Alkylidene)-(3-12 former molecular heterocycle) or-O (C0-C4Alkylene Base)-(5-12 former molecular heteroaryl)；
Each Ra、Rb、RcAnd RdIt is separately H, C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl, 5-12 former molecular heteroaryl ,-(C1-C4Alkylidene)-(C3-C12 Naphthenic base) ,-(C1-C4Alkylidene)-(3-12 former molecular heterocycle) ,-(C1-C4Alkylidene)-(C6-C12Aryl) or- (C1-C4Alkylidene)-(5-12 former molecular heteroaryl) or Ra、Rb3- is formed together with the nitrogen-atoms being connected with them 12 molecular heterocycles of original, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3- The molecular heterocycle of 12 originals, C6-C12Aryl, 5-12 former molecular heteroaryl ,-(C1-C4Alkylidene)-(C3-C12Ring Alkyl) ,-(C1-C4Alkylidene)-(3-12 former molecular heterocycle) ,-(C1-C4Alkylidene)-(C6-C12Aryl) and-(C1- C4Alkylidene)-(5-12 former molecular heteroaryl) optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N3、 NO2、OH、NH2、C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Hydroxy alkyl, C1-C6Aminoalkyl or C1-C6 The substituent group of alkyl amino is replaced；
Each m independently is 1 or 2；With
Each n independently is 0,1,2,3 or 4.
In other embodiments, Z is：
Or their stereoisomer, wherein each X and X1It is separately-CH2,-NH- ,-S- or-O-；X2For- NH- ,-S- or-O-；Each minor structure or its stereoisomer shown in formula (Z-1)~(Z-54) individually optionally by 1,2,3,4 or 5 R2Group is replaced；(Z-55) each minor structure or its stereoisomer are individually optionally by 1,2,3,4 shown in~(Z-59) Or 5 R3Group is replaced.
Also in some embodiments, Z is:
Or their stereoisomer, wherein formula (Z-61)~ (Z-79) each minor structure or its stereoisomer shown in are individually optionally by 1,2,3,4 or 5 R2Group is replaced；Formula (Z- 80) each minor structure or its stereoisomer shown in~(Z-95) are individually optionally by 1,2,3,4 or 5 R3Group is replaced.
In some embodiments, Z1For H, C1-C4Alkyl, C3-C6Naphthenic base or 4-7 former molecular heterocycle, In, each C1-C4Alkyl, C3-C6Naphthenic base and 4-7 former molecular heterocycle are individually optionally by 1,2 or 3 R3Group Replaced.
In another embodiment, Z1For H, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.
In some embodiments, A is：
Wherein, each minor structure shown in formula (A-1)~(A-3) is individually optional Ground is by 1,2 or 3 R4Group is replaced.
In some embodiments, R1For H, F, Cl, Br, I, N3、CN、NO2、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl Or-(CR6R7)nC (=O) NRaRb, wherein each C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl individually optionally by 1,2 or 3 R8Group is replaced.
In some embodiments, each R2It independently is F, Cl, Br, I, NO2、N3, CN, oxo (=O), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl Base ,-C (=O) CH2CN、-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) C (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRb, wherein each C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 original are molecular The former molecular heteroaryl of heterocycle, phenyl and 5-6 is individually optionally by 1,2 or 3 R8Group is replaced.
In other embodiments, each R2It independently is F, Cl, Br, CN, oxo (=O), C1-C4Alkyl, C2-C4Alkene Base, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, furyl, imidazole radicals, isoxazolyl, oxazolyl, pyrroles Base, pyridyl group, pyriconyl, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, thiazolyl, isothiazolyl, tetrazole base, triazol radical, Thienyl, pyrazolyl, oxadiazolyls, thiadiazolyl group, pyrazinyl, triazine radical ,-C (=O) CH2CN、-(CR6R7)n-ORc、- (CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRb, wherein each C1-C4Alkyl, C2-C4Alkenyl, C3-C6Cycloalkanes Base, 4-7 former molecular heterocycle, phenyl, furyl, imidazole radicals, isoxazolyl, oxazolyl, pyrrole radicals, pyridyl group, pyrrole Pyridine ketone group, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, thiazolyl, isothiazolyl, tetrazole base, triazol radical, thienyl, pyrazoles Ji, oxadiazolyls, thiadiazolyl group, pyrazinyl and triazine radical are individually optionally by 1,2 or 3 R8Group is replaced.
In some embodiments, R3For F, Cl, CN, C2-C4Alkenyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle Base, phenyl, 5-6 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (= O)2NRaRb, wherein each C1-C4Alkyl, C2-C4Alkenyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl and 5-6 former molecular heteroaryl is individually optionally by 1,2 or 3 R8Group is replaced；
R4For F, Cl, CN, C1-C4Alkyl, C2-C4Alkenyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd)C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRb, In, each C1-C4Alkyl, C2-C4Alkenyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl and 5-6 atom The heteroaryl of composition is individually optionally by 1,2 or 3 R8Group is replaced.
In other embodiments, R3For F, Cl, CN, cyclopropyl, phenyl, 4-7 former molecular heterocycle or 5-6 A molecular heteroaryl of original, wherein each cyclopropyl, phenyl, 4-7 former molecular heterocycle and 5-6 atom group At heteroaryl it is individually optional by 1,2 or 3 R8Group is replaced；
R4For F, Cl, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, 4-7 former molecular heterocycle Or 5-6 former molecular heteroaryl, wherein each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, 4-7 Former molecular heterocycle and 5-6 former molecular heteroaryl are individually optionally by 1,2 or 3 R8Group is replaced.
Also in other embodiments, R3For F, Cl, CN, cyclopropyl, phenyl, 4-7 former molecular heterocycle, furan It mutters base, imidazole radicals, isoxazolyl, oxazolyl, pyrrole radicals, pyridyl group, pyriconyl, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, thiophene Oxazolyl, isothiazolyl, tetrazole base, triazol radical, thienyl, pyrazolyl, oxadiazolyls, thiadiazolyl group, pyrazinyl or triazine Base, wherein each cyclopropyl, phenyl, 4-7 former molecular heterocycle, furyl, imidazole radicals, isoxazolyl, oxazole Base, pyrrole radicals, pyridyl group, pyriconyl, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, thiazolyl, isothiazolyl, tetrazole base, three Nitrogen oxazolyl, thienyl, pyrazolyl, oxadiazolyls, thiadiazolyl group, pyrazinyl and triazine radical are individually optionally by 1,2 or 3 R8Base Group is replaced；
R4For F, Cl, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, 4-7 former molecular heterocycle Or 5-6 former molecular heteroaryl, wherein each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, 4-7 Former molecular heterocycle and 5-6 former molecular heteroaryl are individually optionally by 1,2 or 3 R8Group is replaced.
In some embodiments, each R5It independently is C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Alkoxy, C1-C4Alkylamino, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C1- C2Alkylidene)-(C3-C6Naphthenic base) ,-(C1-C2Alkylidene)-(4-7 former molecular heterocycle) ,-(C1-C2Alkylidene)- Phenyl or-(C1-C2Alkylidene)-(5-6 former molecular heteroaryl), wherein above-mentioned each group is individually optionally by 1,2 or 3 A R8Group is replaced.
In other embodiments, each R5It independently is methyl, ethyl, n-propyl, isopropyl, C2-C4Alkenyl, C2-C4 Alkynyl, C1-C4Alkoxy, C1-C4Alkylamino, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 atom group At heteroaryl ,-(C1-C2Alkylidene)-(C3-C6Naphthenic base) ,-(C1-C2Alkylidene)-(4-7 former molecular heterocycle Base) ,-(C1-C2Alkylidene)-phenyl or-(C1-C2Alkylidene)-(5-6 former molecular heteroaryl), wherein above-mentioned each base Group is individually optionally by 1,2 or 3 R8Group is replaced.
In some embodiments, each R6And R7It is separately H, F, Cl, Br, CN, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl or 5-6 former molecular heteroaryl, wherein Each C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl and 5-6 A molecular heteroaryl of original is individually optionally by 1,2 or 3 R8Group is replaced.
In some embodiments, each R8It independently is F, Cl, Br, CN, NO2、OH、NH2、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C3-C6Naphthenic base, phenyl, 4-7 former molecular heterocycle, 5-6 original are molecular Heteroaryl, C1-C6Aminoalkyl, C1-C6Alkylamino, C1-C6Alkoxy, C1-C6Hydroxy alkyl ,-NH (C0-C2Alkylidene)-(C3- C6Naphthenic base) ,-NH (C0-C2Alkylidene)-phenyl ,-NH (C0-C2Alkylidene)-(4-7 former molecular heterocycle) ,-NH (C0-C2Alkylidene)-(5-6 former molecular heteroaryl) ,-N [(C0-C2Alkylidene)-(C3-C6Naphthenic base)]2、-N[(C0-C2 Alkylidene)-phenyl]2、-N[(C0-C2Alkylidene)-(4-7 former molecular heterocycle)]2、-N[(C0-C2Alkylidene)-(5-6 A molecular heteroaryl of original)]2、-O(C0-C2Alkylidene)-(C3-C6Naphthenic base) ,-O (C0-C2Alkylidene)-(4-7 atom The heterocycle of composition) or-O (C0-C2Alkylidene)-(5-6 former molecular heteroaryl).
In some embodiments, wherein each Ra、Rb、RcAnd RdIt is separately H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C1-C2 Alkylidene)-(C3-C6Naphthenic base) ,-(C1-C2Alkylidene)-(4-7 former molecular heterocycle) ,-(C1-C2Alkylidene)-benzene Base or-(C1-C2Alkylidene)-(5-6 former molecular heteroaryl), wherein above-mentioned each C1-C6Alkyl, C2-C6Alkenyl, C2-C6 Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C1-C2Alkylene Base)-(C3-C6Naphthenic base) ,-(C1-C2Alkylidene)-(4-7 former molecular heterocycle) ,-(C1-C2Alkylidene)-phenyl and- (C1-C2Alkylidene)-(5-6 former molecular heteroaryl) optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N3、 OH、NH2、C1-C3Alkyl, C1-C3Halogenated alkyl, C1-C3Alkoxy, C1-C3Hydroxy alkyl, C1-C3Aminoalkyl or C1-C3Alkane ammonia The substituent group of base is replaced.
On the other hand, the present invention relates to a kind of pharmaceutical compositions, and it includes compounds disclosed by the invention.
In one embodiment, pharmaceutical composition of the present invention further includes pharmaceutically acceptable auxiliary material.
In other embodiments, pharmaceutical composition of the present invention, wherein further include therapeutic agent, it is described Therapeutic agent is selected from chemotherapeutics, antiproliferative, phosphodiesterase 4 (PDE4) inhibitor, beta-2-adrenoreceptor agonists, cortex Steroids, nonsteroidal GR agonists, anticholinergic drug, antihistamine, anti-inflammatory reagent, immunosuppressor, immunomodulator, For treating the drug of atherosclerosis, drug and combination thereof for treating pulmonary fibrosis.
On the other hand, the purposes the present invention relates to compound disclosed by the invention or pharmaceutical composition in medicine preparation, The drug is for preventing, handling, treating or mitigating the protein kinase mediated disease of patient.
In some embodiments, protein kinase mediated disease of the present invention is JAK-, FLT3- or Aurora- The disease of mediation.
In other embodiments, protein kinase mediated disease of the present invention is proliferative diseases, exempts from self Epidemic disease, anaphylactia, inflammatory disease or graft rejection.
In other embodiments, protein kinase mediated disease of the present invention is cancer, polycythemia vera Disease, primary thrombocytosis, it is acute myelocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, acute Myelocytic leukemia chronic granulocytic leukemia, acute lymphoblastic leukemia, Chronic Obstructive Pulmonary Disease, asthma, is System property lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren syndrome, psoriasis, type-1 diabetes mellitus, is exhaled at skin lupus erythematosus Inhale road anaphylactia, nasosinusitis, eczema, measles, food hypersenstivity, insect venom allergies, inflammatory bowel disease, Crohn disease, class wind Wet arthritis, juvenile arthritis, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or cell transplantation row Reprimand.
On the other hand, the purposes the present invention relates to compound disclosed by the invention or pharmaceutical composition in medicine preparation, The drug is used to reconcile the activity of protein kinase.
In some embodiments, protein kinase of the present invention be jak kinase, FLT3 kinases, Aurora A or Combination thereof.
On the other hand, the method for preparation, separation and the purifying of the compound for being included the present invention relates to formula (I).
Biological results show that compound provided by the invention can be used as preferable kinases inhibitor.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted for other realities The technical characteristic in scheme is applied, as long as they are not in contradiction.
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 make more specific complete description below.
Detailed description of the invention
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and the similar material that are combined Or more 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 subject to the application.
It will further be appreciated that certain features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also in combination be provided in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with any suitable deformation in single embodiment.
Unless otherwise stated, 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 identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise stated, following definition used herein should be applied.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.In addition, organic chemistry General Principle can join It examines " 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:2007, in description, entire contents are incorporated herein by reference.
There is apparent conflict unless otherwise indicated or in context, article " one " used herein, " one (kind) " " 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 embodiment of the embodiment and use or use.
Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right As, such as also refer to primate (such as 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 by It is people to try object.
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, that is, includes the content specified by the present invention, but be not precluded otherwise Content.
" stereoisomer " refers to having identical chemical constitution, but atom or the group spatially different change of arrangement mode Close object.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be with its mirror image cannot be overlapped property molecule；And " achirality " refer to can be overlapped with its mirror image Molecule.
" enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.
" diastereoisomer " refer to there are two or multiple 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 Such as electrophoresis and chromatography, such as HPLC can be operated by high resolution analysis to detach by closing object.
Stereochemical definitions used in the present invention and rule generally 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, which have, makes the plane of linearly polarized light rotate Ability.When describing optically active compound, indicate molecule about 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 rotated for linearly polarized light caused by appointed compound, Wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.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 in the process without stereoselectivity or stereospecificity when, It may occur in which such case.
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 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 one in possible isomers or they Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits .Chiral synthon or chiral reagent can be used to prepare for optically active (R)-or (S)-isomers, or be torn open using routine techniques Point.If compound contains, there are one double bonds, and substituent group may be E or Z configurations；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or 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.
Can the racemic modification of any gained final product or intermediate be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is detached by its diastereoisomeric salt to acquisition.Racemic production Object can also be detached by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is can refer 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 " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example 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.Another tautomeric 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 tautomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, such as General formula compound above, or as special example inside embodiment, subclass, and a kind of compound that the present invention is included.
It should be appreciated that this term can exchange use to " optionally replacing " this term with " substituted or non-substituted ".Generally For, " substituted " expression of term is replaced to one or more of structure hydrogen atom by specific substituent group." optionally " Unless otherwise indicated, an optional substituent group can be replaced at various substitutable position of that group.When being given More than one position can be replaced by one or more substituent groups selected from specific group in the structural formula gone out, then substituent group can With identical or different replace at various locations.
Term " optional " either " optionally " mean event described later or environment can with but need not occur, should Illustrate to include the thing occasion that either environment occurs or do not occur.For example, " optionally by alkyl-substituted heterocyclic group " anticipates Taste alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted scene and heterocyclic group not by alkyl Substituted scene.
Term " optionally by ... replace " can exchange use, i.e., with term " unsubstituted or by ... replace " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group of the present invention Include, but are not limited to D, F, Cl, Br, I, N3、CN、NO2、OH、SH、NH2, oxo (=O), alkyl, halogenated alkyl, alkenyl, alkynes Base, alkoxy, hydroxy alkyl, alkylthio group, alkyl amino, aminoalkyl, naphthenic base, heterocycle, aryl, heteroaryl ,-C (=O) CH2CN、-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb,-C (=NRd)NRaRb、-N(Rd) C (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRb, etc..Wherein, R5、R6、R7、Ra、Rb、Rc、Rd, m and n there is meaning as described in the present invention.
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, It is not influenced mutually between the same symbol between expressed specific option either refer among the different groups, can also table Show in the same group, is not influenced mutually between expressed specific option between the same symbol.
It is disclosed according to radical species or range in the substituent group of each section of this specification, disclosed compound of present invention.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-C6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl；" 4-7 former for term Molecular heterocycle " refers to the molecular heterocycle of independent disclosed 4 originals, the molecular heterocycle of 5 originals, 6 originals Molecular heterocycle or 7 molecular heterocycles of original.
In each section of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl ", " heterocycle " or " aryl ", then it should be understood that should " alkyl ", " heterocycle Base " or " aryl " respectively represent the alkylidene group, sub- heterocyclyl groups or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1 to 20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Substitution.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1- 12 carbon atoms；In another embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group Contain 1-4 carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The alkyl group can be optional The substituent group that ground is described by the present invention is replaced.
The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr、-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,- CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tertiary butyl (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyls (- CH (CH3)CH2CH2CH3), 3- amyls (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1s-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3) CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyls (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyls (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyls (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyls (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Term " alkylidene " indicates to remove two obtained saturations of hydrogen atom from the linear chain or branched chain alkyl of saturation Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In some embodiments, sub- Alkyl group contains 1-6 carbon atom；In another embodiment, alkylidene group contains 1-4 carbon atom；In other realities It applies in scheme, alkylidene group contains 0-4 carbon atom；Also in some embodiments, it is former to contain 0-3 carbon for alkylidene group Son；Also in other embodiments, alkylidene group contains 0-2 carbon atom.It refers to alkylene that alkylidene, which contains 0 carbon atom, Base is not present, and is directly a singly-bound.The example of alkylidene includes, but are not limited to methylene (- CH2), ethylidene (- CH2CH2), isopropylidene (- CH (CH3)CH2) etc..
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, i.e., there are one carbon-to-carbon sp2Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention The substituent group stated is replaced comprising the positioning of " cis " and " trans ", or " E " and " Z " positioning.In an embodiment In, alkenyl group includes 2-8 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；In another reality It applies in scheme, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH= CH2), allyl (- CH2CH=CH2) etc..
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, i.e., there are one tri- keys of carbon-to-carbon sp.In one embodiment, alkynyl group includes 2-8 carbon atom；In another implementation In scheme, alkynyl group includes 2-6 carbon atom；In yet another embodiment, alkynyl group includes 2-4 carbon atom.Alkynyl The example of group includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), propinyl (- C ≡ C-CH3) etc. Deng.The alkynyl group can optionally be replaced by one or more substituent groups described in the invention.
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom； In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more The substituent group that the present invention describes is replaced.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, positive propoxy ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, isopropoxy ,-OCH (CH3)2), 1- butoxy (n-BuO, n-butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, isobutyl oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, sec-butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, tert-butoxy ,-OC (CH3)3), 1- amoxys (n-pentyloxy ,-OCH2CH2CH2CH2CH3), 2- amoxys (- OCH (CH3) CH2CH2CH3), 3- amoxys (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourths Oxygroup (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " halogenated alkyl ", " halogenated alkenyl " or " halogenated alkoxy " indicate alkyl, and alkenyl or alkoxy base are by one A or multiple halogen atoms are replaced, and such example includes, but is not limited to, trifluoromethyl (- CF3), trifluoromethoxy (- OCF3), bis-fluoro ethyls (- CH2CHF2,-CF2CH3,-CHFCH2F), trifluoroethyl (- CH2CF3,-CF2CH2F,-CFHCHF2) etc..
Term " hydroxy alkyl " and " hydroxy alkoxy base " indicate alkyl or alkoxy, depend on the circumstances, one or more Hydroxyl group is replaced, wherein " hydroxy alkyl " can exchange use with " hydroxyalkyl ", and such example includes, but and unlimited In methylol (- CH2OH), 2- ethoxys (- CH2CH2OH), 1- ethoxys (- CH (OH) CH3), 2- hydroxyl propyl- 2- bases (- COH (CH3)2), 2- hydroxy-2-methyl propyl (- CH2COH(CH3)2), 3- hydroxypropyls (- CH2CH2CH2OH), 2- hydroxypropyls (- CH2CH(OH)CH3), hydroxymethoxy (- OCH2OH) etc..
Term " carbocylic radical " or " carbocyclic ring " indicate containing 3-12 carbon atom, monovalent or multivalence nonaromatic saturation Or the unsaturated monocycle in part, bicyclic or three-ring system.Carbon bicyclic group includes spiral shell carbon bicyclic group and condensed carbon bicyclic group, suitably Carbocylic radical group includes, but is not limited to, naphthenic base, cycloalkenyl group and cycloalkynyl radical.The example of carbocylic radical group further comprises, but Be not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -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, ring are pungent Base, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..
Term " naphthenic base " indicates containing 3-12 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies System.Bicyclic cycloalkyl includes spiral shell bicyclic alkyl, condensed-bicyclic alkyl and bridge bicyclic alkyl.In some embodiments, naphthenic base Including 3-12 carbon atom；In other embodiments, naphthenic base includes 3-7 carbon atom；In other embodiments, Naphthenic base includes 3-6 carbon atom；Also in some embodiments, naphthenic base C7-C12Naphthenic base, it includes C7-C12Monocycle Alkyl, C7-C12Bicyclic alkyl (such as C7-C12Spiral shell bicyclic alkyl, C7-C12Condensed-bicyclic alkyl and C7-C12Bridge bicyclic alkyl) or C7- C12Tricyclic alkyl.The group of naphthene base can be independently unsubstituted or by one or more substituent group described in the invention Replaced.Term " monocyclic cycloalkyl " or " monocycle alkyl " indicate the naphthenic base of single ring systems, wherein the naphthenic base has such as The preceding definition, the monocyclic cycloalkyl group can be independently unsubstituted or by one or more described in the invention Substituent group is replaced.
Term " heterocycle " and " heterocycle " are used interchangeably here, and it includes 3-12 annular atom all to refer to, it is monovalent or Multivalence, saturation or part it is undersaturated, nonaromatic monocyclic, bicyclic or tricyclic, wherein at least one annular atom be selected from nitrogen, Sulphur and oxygen atom.Unless otherwise stated, heterocycle can be carbon-based or nitrogen base, and-CH2Group can optionally by-C (= O)-substitute, the sulphur atom of ring can optionally be oxidized to S- oxides, and the nitrogen-atoms of ring can optionally be oxidized to N- oxygen Compound.Heterocycle includes the undersaturated heterocycle of heterocycle (Heterocyclylalkyl) and part of saturation.The heterocycle has One or more tie points are connected with the rest part of molecule.The example of heterocycle includes, but are not limited to：Oxyranyle, nitrogen Heterocycle butyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, Imidazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxies cyclopenta, two sulphur rings penta It is base, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl, morpholinyl, thio Quinoline base, piperazinyl, alkyl dioxin, dithianyl, thioalkyl, high piperazine base, homopiperidinyl, oxepane alkyl, thia ring Heptane base, nitrogen list trioxepane, oxygen azepineBase (e.g., Isosorbide-5-Nitrae-oxygen azepineBase, 1,2- oxygen azepinesBase), diazaBase (e.g., Isosorbide-5-Nitrae-diazaBase, 1,2- diazasBase), dioxaBase (e.g., Isosorbide-5-Nitrae-dioxaBase, 1,2- dioxas Base), sulphur azepineBase (such as 1,4- sulphur azepineBase, 1,2- sulphur azepinesBase), indoline base, 1,2,3,4- tetrahydro isoquinolyls, 1,3- Ben Bing bis- Evil cyclopentadienyls, 2- oxa- -5- azabicyclos [2.2.1] hept- 5- bases, 2- azaspiros [4.4] nonyl, 1,6- dioxies Miscellaneous spiral shell [4.4] nonyl, 2- azaspiros [4.5] decyl, 8- azaspiros [4.5] decyl, 7- azaspiros [4.5] decyl, 3- azaspiros [5.5] undecyl, 2- azaspiros [5.5] undecyl, octahydro -1H- isoindolyls, octahydro pentamethylene are simultaneously [c] Pyrrole radicals, indolinyl, 1,2,3,4- tetrahydro isoquinolyls, hexahydro furyl simultaneously [3,2-b] furyl and ten dihydro-isoquinolines Base, etc..- CH in heterocycle2Group includes, but are not limited to 2- oxo-pyrrolidines base, oxo-by-C (=the O)-examples substituted 1,3- thiazolidinyls, 2- piperidone bases and 3,5- dioxy piperazine piperidinyls.The example that sulphur atom is aoxidized in heterocycle includes, but not It is limited to, sulfolane base, 1,1- dioxothiomorpholinyls.The heterocyclyl groups can be optionally by this one or more hair Bright described substituent group is replaced.Term " monocyclic heterocycles base " or " monocyclic heterocycles " indicate the heterocycle of single ring systems, wherein There is the heterocycle foregoing definition, the monocyclic heterocycles base group can be independently unsubstituted or by one or more A substituent group described in the invention is replaced.
Also in one embodiment, heterocycle is 4-7 former molecular heterocycle, and it includes 4-7 annular atom to refer to Unit price or multivalence, saturation or part undersaturated nonaromatic monocycle or bicyclic, wherein at least one annular atom be selected from nitrogen, Sulphur and oxygen atom.Unless otherwise stated, 4-7 former molecular heterocycle can be carbon-based or nitrogen base, and-CH2Group can be with Optionally substituted by-C (=O)-.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can be optional Ground is oxidized to N- oxygen compounds.Described 4-7 former molecular heterocycle has its of one or more tie points and molecule Remaining part split-phase connects.Wherein, the example of 4-7 former molecular monocyclic heterocycles base includes, but are not limited to：Azetidinyl, oxygen Azetidinyl, Thietane base, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidine Base, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyrans Base, 4H- pyranoses, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxins, dithianyl, thiophene Oxane base, 1,2- oxazinyls, 1,2- thiazinyls, hexahydro-pyridazine base, high piperazine base, homopiperidinyl, oxepane alkyl, thia ring Heptane base, oxygen azepineBase (1,4- oxygen azepinesBase, 1,2- oxygen azepinesBase), diazaBase (1,4- diazasBase, 1, 2- diazasBase) and sulphur azepineBase (1,4- sulphur azepinesBase, 1,2- sulphur azepinesBase) etc.；4-7 former molecular bicyclic The example of heterocycle includes, but are not limited to：Bicyclic [3,2,0] heptane of 3- azabicyclos [3,2,0] heptane, 3- oxos etc.；4-7 - CH in former molecular heterocycle2Group by-C (=O)-substitute example include, but are not limited to 2- oxo-pyrrolidines base, Oxo -1,3- thiazolidinyls, 2- piperidone bases and 3,5- dioxy piperazine piperidinyls；Sulphur atom in 4-7 former molecular heterocycle The example aoxidized includes, but are not limited to sulfolane base, 1,1- dioxotetrahydros thiophene, 1,1- dioxotetrahydros thiapyran, 1,1- Dioxothiomorpholinyl.The former molecular heterocyclyl groups of described 4-7 can be optionally by one or more present invention Described substituent group is replaced.
Term " condensed-bicyclic " and " condensed-bicyclic base " are used interchangeably here, all refer to unit price or multivalence saturation or Part is unsaturated but nonaromatic member ring systems, and two rings in the member ring systems share a key.Such system can wrap Containing independent or conjugation unsaturated system, but its nuclear structure does not include aromatic rings or hetero-aromatic ring, but aromatic group can Using as substituent group thereon.
Term " spiral shell bicyclic group " and " spiral shell is bicyclic " are used interchangeably here, refer to unit price or multivalence saturation or part not Saturated ring system, one of ring is originating from specific ring carbon atom on another ring, and two rings only share this original Son.For example, as described in following formula a, the member ring systems (ring U and U ') of a saturation are referred to as " condensed-bicyclic ", and ring V and ring U shares a carbon atom, is referred to as " spiral shell is bicyclic ".Each ring in condensed-bicyclic base and spiral shell bicyclic group can be carbocylic radical or Heterocycle, and each ring is optionally replaced by one or more substituent groups described in the invention.
Term " Heterocyclylalkyl " refers to saturation monocycle, the bicyclic or tricyclic of the unit price containing 3-12 annular atom or multivalence System, wherein at least one annular atom are selected from nitrogen, sulphur or oxygen atom.Unless otherwise stated, Heterocyclylalkyl can be carbon-based or nitrogen Base, and-CH2Group can be substituted optionally by-C (=O)-, and the sulphur atom of ring can optionally be oxidized to S- oxides, The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.The Heterocyclylalkyl can be optionally by one or more sheets The described substituent group of invention is replaced.
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 the molecular carbocylic radical group of 10 originals.
Contain one or more degrees of unsaturation in " undersaturated " the expression group of term as used in the present invention.
Term " hetero atom " refers to O, S, N, P and Si, includes the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (NR in the pyrrolidinyl replaced as N-).
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " azido " or " N3" indicate a nitrine structure.This group can be connected with other groups, for example, It can be connected to form triazonmethane (MeN with a methyl3), or it is connected to form phenylazide (PhN with a phenyl3)。
Term " aryl " indicates to contain 6-14 annular atom or the monocycle of 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring and tricyclic, wherein at least one member ring systems are aromatic, and wherein each member ring systems includes 3-7 former Molecular ring, and there are one or multiple tie points be connected with the rest part of molecule.Term " aryl " can be with term " fragrance Ring ", which exchanges, to be used.The example of aryl group may include phenyl, naphthalene and anthryl.The aryl group can individually optionally Replaced by one or more substituent groups described in the invention.
Term " heteroaryl " indicate containing 5-12 annular atom or the monocycle of 5-10 annular atom or 5-6 annular atom, Bicyclic and three-ring system, wherein at least one ring is aromatic, and at least one aromatic rings includes one or more hetero atoms, Wherein each member ring systems includes 5-7 former molecular ring, and there are one or multiple tie points be connected with molecule rest part. Term " heteroaryl " can exchange use with term " hetero-aromatic ring " or " heteroaromatics ".In one embodiment, heteroaryl To include 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-12.In another implementation case In, heteroaryl is comprising 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-10.Another In one embodiment, heteroaryl is former molecular miscellaneous comprising 1,2,3 or 4 be independently selected from O, S and N heteroatomic 5-6 Aryl.The heteroaryl groups are optionally replaced by one or more substituent groups described in the invention.
The example of 5-12 former molecular heteroaryl groups includes, but is not limited to these following bicyclic heteroaryls： Benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyls, 3- indyls, 4- indyls, 5- indoles Base, 6- indyls, 7- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls), isoquinolyl (such as 1- isoquinolyls, 3- isoquinolyls or 4- isoquinolyls), indazolyl (such as 3- indazolyls, 4- indazolyls, 5- indazolyls, 6- indazoles Base, 7- indazolyls), imidazo [1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, pyrazolo [4,3-c] pyridyl group, pyrazoles And [3,4-b] pyridyl group, 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] pyridyl group, etc..5-12 atom The example of the heteroaryl groups of composition further includes 5-6 former molecular single ring heteroaryl group, and the example includes, but and unlimited In monocycle below, furyl (such as 2- furyls, 3- furyls), imidazole radicals (such as 1- imidazole radicals, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals), isoxazolyls (such as 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyl), oxazolyl (such as 2- oxazolyls, 4- Evil Oxazolyl, 5- oxazolyls), pyrrole radicals (such as 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals), pyridyl group (such as 2- pyridyl groups, 3- pyridines Base, 4- pyridyl groups), pyriconyl, pyrimidine radicals (such as 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals), pyrimidine ketone group, hybar X Base, pyridazinyl (such as 3- pyridazinyls, 4- pyridazinyls), pyrazinyl (such as 2- pyrazinyls, 3- pyrazinyls), thiazolyl (such as 2- thiazolyls, 4- thiazolyls, 5- thiazolyls), tetrazole radical (such as 5- tetrazole radicals), triazolyl (such as 2- triazolyls and 5- triazolyls), thienyl (such as 2- thienyls, 3- thienyls), pyrazolyl (such as 1- pyrazolyls, 3- pyrazolyls, 4- pyrazolyls, 5- pyrazolyls), pyrazoline ketone group, Isothiazolyl, 1,2,3- oxadiazolyls, 1,2,5- oxadiazolyls, 1,2,4- oxadiazolyls, 1,2,3- triazolyls, 1,2,3- are thio Di azoly, 1,3,4- thio biphospholes base, 1,2,5- thio biphospholes base, pyrazinyl and cyanuro 1,3,5 etc..
Term " alkyl amino " or " alkylamino " are used interchangeably here, including " N- alkyl aminos " and " N, N- dioxane Base amino ", wherein amino group is separately replaced by one or two alkyl group.Wherein, some embodiments It is that alkylamino is one or two C1-C12Alkyl is connected to the alkylamino group of the lower level formed on nitrogen-atoms.Another In a little embodiments, alkylamino is one or two C1-C6Alkyl is connected to the alkyl amino base of the lower level formed on nitrogen-atoms Group.In other embodiments, alkylamino is one or two C1-C4Alkyl is connected to the lower level formed on nitrogen-atoms Alkylamino group.Also in other embodiments, alkylamino is one or two C1-C3Alkyl is connected on nitrogen-atoms The alkylamino group of the lower level of formation.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, alkane The example of amino includes, but is not limited to, N- methylaminos (- NHCH3), N- ethylaminos, N, N- dimethylaminos (- NH (CH3)2), N, N- lignocaines, N- ethyl propyl -2- amino etc..
Term " fragrant amino " indicates that amino group is replaced by one or two aryl group, and such example includes, but It is not limited to N- phenylaminos.Some of embodiments are that the aromatic ring in fragrant amino can be further substituted.
Term " aminoalkyl " includes the C replaced by one or more amino1-C12Linear or branched alkyl group group. In some embodiments, aminoalkyl is the C replaced by one or more amino groups1-C12Alkyl；In other embodiment party In case, aminoalkyl is the C replaced by one or more amino groups1-C6" aminoalkyl of lower level ", in other realities It applies in scheme, aminoalkyl is the C replaced by one or more amino groups1-C4Alkyl；Also in other embodiments, Aminoalkyl is the C replaced by one or more amino groups1-C3Alkyl.The example of aminoalkyl includes, but is not limited to, Aminomethyl (- CH2NH2), aminoethyl (- CH2CH2NH2,-CH(NH2)CH3), aminopropyl, ammonia butyl and ammonia hexyl.
As described in the invention, it draws a key and substituent group is connected to the member ring systems of ring being centrally formed (such as formula b institutes Show) it represents substituent group any commutable position in the member ring systems and can replace.For example, formula b represent substituent group can be Any possible substituted position on pyrazole ring, as shown in formula c~formula f.
As described in the invention, two connect member ring systems (as shown in the formula h) generation for being keyed to and being formed on the center of ring Two connecting keys of table can be connected any attachable position in member ring systems with molecule rest part, and two connecting pins Point K and K ' can be exchanged with each other.The positions that formula h represents two any possible connections on W rings can be with molecule rest part It is connected.
Such as shown in following formula i, one connects the center for being keyed to piperidine ring, and representing this connecting key can be in piperidines The position that can be arbitrarily connected on ring is connected with the rest part of molecule.Formula i indicates that piperidine ring can be in the position that can be connected It is connected with molecule rest part, as shown in formula j~m.
Term " blocking group " or " PG " refer to when other functional groups react in compound, for blocking or The specific functional substituent group of protection.It is connected with amino group for example, " blocking group of amino " refers to a substituent group Include acetyl group, trifluoroacetyl group, tertiary fourth to block or protect the functionality of amino in compound, suitable amido protecting group Oxygen carbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " Refer to that the substituent group of hydroxyl is used for blocking or protecting the functionality of hydroxyl, suitable blocking group includes acetyl group and monosilane Base." carboxy protective group " refers to that the substituent group of carboxyl is used for blocking or protecting the functionality of carboxyl, general carboxyl-protecting group Including-CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..It is right Document is can refer in the general description of blocking group：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups, Thieme,Stuttgart,2005.
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed by pro-drug or is influenced for precursor structure through enzymatic conversion in blood or tissue in blood.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.It is completely begged for about pro-drug By following documents can be referred to：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of 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。
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change Closing the metabolite of object can be identified by technology well-known in the art, and activity can be retouched by such as the present invention It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, being restored, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. recorded.The salt that pharmaceutically acceptable nontoxic acid is formed includes, 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 recorded in books, literature Other methods such as ion-exchanges 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 alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to that one or more solvent molecules are formed by association with the compound of the present invention Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (development for slowing down or prevent or mitigate disease or 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 (such as stablizing perceptible symptom) or physiologically (such as stablizes body Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease Breaking-out, generation or the deterioration of disease.
" inflammatory disease " used in the present invention refers to the excessive inflammation caused by excessive or out of control inflammatory responses Property symptom, host tissue damage or function of organization any disease for losing, disorderly or symptom." inflammatory disease " also refers to by leucocyte The pathologic state that inflow and/or Neutrophil chemotaxis mediate.
" inflammation " used in the present invention refers to by tissue damaged or topical protective response caused by destroying, it is for breaking Tissue that is bad, diluting or separate (isolation) harmful substance and be damaged.Inflammation is flowed into leucocyte and/or neutrophil cell becomes The property changed has significant contact.Inflammation can result from the infection of pathogenic organism and virus and non-infectious mode, such as heart Wound after muscle infarction or apoplexy or Reperfu- sion, to the immune response and autoimmune response of exotic antigen.Therefore, this can be used Disclosure of the invention compound treatment inflammatory disease include：It is reacted with specific system of defense and non-specific defense system reacts Relevant disease.
" specific system of defense " refers to that the component of immune system reacts to the presence of specific antigen.Result from specificity The example of the inflammation of system of defense reaction includes classical response, autoimmune disease and the delayed type hypersensitivity, DTH to exotic antigen Response (cell-mediated by T-).The repulsion of chronic inflammatory disease, transplanting solid tissue and organ is (such as kidney and bone-marrow transplantation Repel) and graft versus host disease (GVHD) be other examples of specific system of defense inflammatory reaction.
" autoimmune disease " used in the present invention refers to and body fluid or cell-mediated to body itself component response The set of the arbitrary disease of relevant tissue damage.
" allergy " used in the present invention refers to that the arbitrary symptom for generating allergy, histologic lesion or function of organization lose.Such as " arthritis disease " used in the present invention refers to arbitrary characterized by being attributable to various etiologic etiological arthritis damages Disease." dermatitis " refers to the skin disease characterized by being attributable to various etiologic etiological scytitis as used in the present invention Large family in any one." graft rejection " refers to the funeral of the function of transplanting or surrounding tissue as used in the present invention Tissue is transplanted in the confrontation that mistake, pain, swelling, leukocytosis and decrease of platelet are characterized, such as organ or cell (such as marrow) Arbitrary immune response.The therapy of the present invention includes for treating and the method for the relevant disease of inflammatory cell activation.
Term " cancer " and " cancer " refer to or description patient in physiology usually characterized by cell growth out of control Illness." tumour " includes one or more cancer cells.The example of cancer includes but 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 Small Cell Lung Cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of lung and lung carcinoma squamosum), peritoneal cancer, hepatocellular carcinoma (hepatocellular cancer), gastric 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 Uterine cancer, 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 the compound of the present invention
The invention discloses a kind of novel compounds, can be used as protein kinase activity, especially jak kinase, FLT3 swashs Enzyme and the active inhibitor of Aurora A.Compound as kinases inhibitor can be used for treating and unsuitable albumen Kinase activity, is especially unsuitable jak kinase, FLT3 kinases and the relevant disease of Aurora A activity, for example, treatment and Prevent to be related to the disease that the jak kinase, FLT3 kinases and Aurora A of signal path mediate.Such disease includes proliferative Disease, autoimmune disease, anaphylactia, inflammatory disease, graft rejection and their complication.Particularly, of the invention Compound can be used for treating following disease, such as cancer, polycythemia vera, primary thrombocytosis, marrow Fibrosis, property myelocytic leukemia, acute lymphoblastic leukemia, chronic granulocytic leukemia (CML), chronic obstructive Lung disease (COPD), asthma, systemic loupus erythematosus, skin lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren syndrome, Psoriasis, type-1 diabetes mellitus, respiratory anaphylactic disease, nasosinusitis, eczema, measles, food hypersenstivity, insect venom allergies, inflammatory Enteropathy, Crohn disease, rheumatoid arthritis, juvenile arthritis, psoriasis arthropathica, organ-graft refection, tissue move Plant repulsion, cell transplant rejection, etc..
In one embodiment, disclosed compound of present invention can be shown shows stronger suppression to one or more protein kinases System activity.
On the one hand, the present invention relates to the alloisomerisms of one kind compound as shown in formula (I) compound represented or formula (I) Body, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein, Z, Z1、A、U1、U2、U3And R1With meaning as described in the present invention.
In some embodiments, Z C7-C12Spiral shell bicyclic alkyl, C7-C12Condensed-bicyclic alkyl, 7-12 atom composition The miscellaneous bicyclic group of spiral shell or 7-12 former molecular condense miscellaneous bicyclic group, wherein each C7-C12Spiral shell bicyclic alkyl, C7-C12It is thick Close bicyclic alkyl, the 7-12 former molecular miscellaneous bicyclic group of spiral shell and 7-12 former molecular condensed miscellaneous bicyclic group individually optionally By 1,2,3,4 or 5 R2Group is replaced；Or Z is C3-C7Monocyclic cycloalkyl or 3-7 former molecular monocyclic heterocycles base, In, each C3-C7Monocyclic cycloalkyl and 3-7 former molecular monocyclic heterocycles base are individually optionally by 1,2,3,4 or 5 R3 Group is replaced；
Z1For H, C1-C12Alkyl, C3-C12Naphthenic base or 3-12 former molecular heterocycle, wherein each C1-C12 Alkyl, C3-C12Naphthenic base and 3-12 former molecular heterocycle are individually optionally by 1,2,3,4 or 5 R3Group is replaced；
Work as U1For N when, U2For CH, U3For N；
Work as U1For C, U2For NH, U3For N or CH；
Respectively --- -- independently is a singly-bound or a double bond；
A is pyrazolyl, optionally by 1,2 or 3 R4Group is replaced；
R1For H, F, Cl, Br, I, N3、CN、NO2、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl or-(CR6R7)nC (= O)NRaRb, wherein each C1-C12Alkyl, C2-C12Alkenyl and C2-C12Alkynyl is individually optionally by 1,2,3,4 or 5 R8Base Group is replaced；
Each R2It independently is F, Cl, Br, I, NO2、N3, CN, oxo (=O), C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynes Base, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl, 5-12 former molecular heteroaryl ,-C (= O)CH2CN、-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb,-C (=NRd)NRaRb、-N(Rd) C (=O) NRaRb、-N(Rd) S (=O)mR5 Or-S (=O)2NRaRbOr two R2, and together with the atom that they are connected, form C3-C12Naphthenic base, C6-C12Aryl, 3- The molecular heterocycle of 12 originals or 5-12 former molecular heteroaryl groups, wherein each C1-C12Alkyl, C2-C12Alkene Base, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl and 5-12 original are molecular miscellaneous Aryl is individually optionally by 1,2,3,4 or 5 R8Group is replaced；
R3For F, Cl, CN, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6- C12Aryl, 5-12 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (= O)2NRaRb, wherein each C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6- C12Aryl and 5-12 former molecular heteroaryl are individually optionally by 1,2,3,4 or 5 R8Group is replaced；
R4For F, Cl, CN, C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 atom composition Heterocycle, C6-C12Aryl, 5-12 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRb, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 Former molecular heterocycle, C6-C12Aryl and 5-12 former molecular heteroaryl are individually optionally by 1,2,3,4 or 5 R8 Group is replaced；
Each R5It independently is C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Alkoxy, C1-C12Alkylamino, C3- C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl, 5-12 former molecular heteroaryl ,-(C1-C4Alkylene Base)-(C3-C12Naphthenic base) ,-(C1-C4Alkylidene)-(3-12 former molecular heterocycle) ,-(C1-C4Alkylidene)-(C6- C12Aryl) or-(C1-C4Alkylidene)-(5-12 former molecular heteroaryl), wherein above-mentioned each group individually optional ground quilt 1,2,3,4 or 5 R8Group is replaced；
Each R6And R7It is separately H, F, Cl, Br, I, NO2、N3、CN、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynes Base, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Virtue or 5-12 former molecular heteroaryl, alternatively, R6、R7C is formed together with the carbon atom being connected with them3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl Or 5-12 former molecular heteroaryl, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, 3-12 former molecular heterocycle, C6-C12The former molecular heteroaryl of aryl and 5-12 individually optionally by 1,2,3, 4 or 5 R8Group is replaced；
Each R8It independently is F, Cl, Br, I, CN, NO2、N3、OH、NH2、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Halogenated alkyl, C3-C12Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle, 5-12 original are molecular miscellaneous Aryl, C1-C12Aminoalkyl, C1-C12Alkylamino, C1-C12Alkoxy, C1-C12Hydroxy alkyl ,-NH (C0-C4Alkylidene)-(C3- C12Naphthenic base) ,-NH (C0-C4Alkylidene)-(C6-C12Aryl) ,-NH (C0-C4Alkylidene)-(3-12 former molecular heterocycle Base) ,-NH (C0-C4Alkylidene)-(5-12 former molecular heteroaryl) ,-N [(C0-C4Alkylidene)-(C3-C12Naphthenic base) ]2、-N[(C0-C4Alkylidene)-(C6-C12Aryl)]2、-N[(C0-C4Alkylidene)-(3-12 former molecular heterocycle)]2、- N[(C0-C4Alkylidene)-(5-12 former molecular heteroaryl)]2、-O(C0-C4Alkylidene)-(C3-C12Naphthenic base) ,-O (C0- C4Alkylidene)-(C6-C12Aryl) ,-O (C0-C4Alkylidene)-(3-12 former molecular heterocycle) or-O (C0-C4Alkylene Base)-(5-12 former molecular heteroaryl)；
Each Ra、Rb、RcAnd RdIt is separately H, C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl, 5-12 former molecular heteroaryl ,-(C1-C4Alkylidene)-(C3-C12 Naphthenic base) ,-(C1-C4Alkylidene)-(3-12 former molecular heterocycle) ,-(C1-C4Alkylidene)-(C6-C12Aryl) or- (C1-C4Alkylidene)-(5-12 former molecular heteroaryl) or Ra、Rb3- is formed together with the nitrogen-atoms being connected with them 12 molecular heterocycles of original, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3- The molecular heterocycle of 12 originals, C6-C12Aryl, 5-12 former molecular heteroaryl ,-(C1-C4Alkylidene)-(C3-C12Ring Alkyl) ,-(C1-C4Alkylidene)-(3-12 former molecular heterocycle) ,-(C1-C4Alkylidene)-(C6-C12Aryl) and-(C1- C4Alkylidene)-(5-12 former molecular heteroaryl) optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N3、 NO2、OH、NH2、C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Hydroxy alkyl, C1-C6Aminoalkyl or C1-C6 The substituent group of alkyl amino is replaced；
Each m independently is 1 or 2；With
Each n independently is 0,1,2,3 or 4.
In other embodiments, Z is：
Or they Stereoisomer, wherein each X and X1It is separately-CH2,-NH- ,-S- or-O-；X2For-NH- ,-S- or-O-；Formula (Z-1) each minor structure or its stereoisomer shown in~(Z-54) are individually optionally by 1,2,3,4 or 5 R2Group is taken Generation；(Z-55) each minor structure or its stereoisomer shown in~(Z-59) are individually optionally by 1,2,3,4 or 5 R3Group institute Substitution.
Also in some embodiments, Z is:
Or their stereoisomer, wherein formula (Z-61)~ (Z-79) each minor structure or its stereoisomer shown in are individually optionally by 1,2,3,4 or 5 R2Group is replaced；Formula (Z- 80) each minor structure or its stereoisomer shown in~(Z-95) are individually optionally by 1,2,3,4 or 5 R3Group is replaced.
In some embodiments, Z1For H, C1-C4Alkyl, C3-C6Naphthenic base or 4-7 former molecular heterocycle, In, each C1-C4Alkyl, C3-C6Naphthenic base and 4-7 former molecular heterocycle are individually optionally by 1,2 or 3 R3Group Replaced.
In another embodiment, Z1For H, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.
In some embodiments, A is：
Wherein, each minor structure shown in formula (A-1)~(A-3) is individually optional Ground is by 1,2 or 3 R4Group is replaced.
In some embodiments, R1For H, F, Cl, Br, I, N3、CN、NO2、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl Or-(CR6R7)nC (=O) NRaRb, wherein each C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl individually optionally by 1,2 or 3 R8Group is replaced.
In some embodiments, each R2It independently is F, Cl, Br, I, NO2、N3, CN, oxo (=O), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl Base ,-C (=O) CH2CN、-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) C (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRb, wherein each C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 original are molecular The former molecular heteroaryl of heterocycle, phenyl and 5-6 is individually optionally by 1,2 or 3 R8Group is replaced.
In other embodiments, each R2It independently is F, Cl, Br, CN, oxo (=O), C1-C4Alkyl, C2-C4Alkene Base, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, furyl, imidazole radicals, isoxazolyl, oxazolyl, pyrroles Base, pyridyl group, pyriconyl, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, thiazolyl, isothiazolyl, tetrazole base, triazol radical, Thienyl, pyrazolyl, oxadiazolyls, thiadiazolyl group, pyrazinyl, triazine radical ,-C (=O) CH2CN、-(CR6R7)n-ORc、- (CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRb, wherein each C1-C4Alkyl, C2-C4Alkenyl, C3-C6Cycloalkanes Base, 4-7 former molecular heterocycle, phenyl, furyl, imidazole radicals, isoxazolyl, oxazolyl, pyrrole radicals, pyridyl group, pyrrole Pyridine ketone group, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, thiazolyl, isothiazolyl, tetrazole base, triazol radical, thienyl, pyrazoles Ji, oxadiazolyls, thiadiazolyl group, pyrazinyl and triazine radical are individually optionally by 1,2 or 3 R8Group is replaced.
In some embodiments, R3For F, Cl, CN, C2-C4Alkenyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle Base, phenyl, 5-6 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (= O)2NRaRb, wherein each C1-C4Alkyl, C2-C4Alkenyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl and 5-6 former molecular heteroaryl is individually optionally by 1,2 or 3 R8Group is replaced；
R4For F, Cl, CN, C1-C4Alkyl, C2-C4Alkenyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd)C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRb, In, each C1-C4Alkyl, C2-C4Alkenyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl and 5-6 atom The heteroaryl of composition is individually optionally by 1,2 or 3 R8Group is replaced.
In other embodiments, R3For F, Cl, CN, cyclopropyl, phenyl, 4-7 former molecular heterocycle or 5-6 A molecular heteroaryl of original, wherein each cyclopropyl, phenyl, 4-7 former molecular heterocycle and 5-6 atom group At heteroaryl it is individually optional by 1,2 or 3 R8Group is replaced；
R4For F, Cl, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, 4-7 former molecular heterocycle Or 5-6 former molecular heteroaryl, wherein each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, 4-7 Former molecular heterocycle and 5-6 former molecular heteroaryl are individually optionally by 1,2 or 3 R8Group is replaced.
Also in other embodiments, R3For F, Cl, CN, cyclopropyl, phenyl, 4-7 former molecular heterocycle, furan It mutters base, imidazole radicals, isoxazolyl, oxazolyl, pyrrole radicals, pyridyl group, pyriconyl, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, thiophene Oxazolyl, isothiazolyl, tetrazole base, triazol radical, thienyl, pyrazolyl, oxadiazolyls, thiadiazolyl group, pyrazinyl or triazine Base, wherein each cyclopropyl, phenyl, 4-7 former molecular heterocycle, furyl, imidazole radicals, isoxazolyl, oxazole Base, pyrrole radicals, pyridyl group, pyriconyl, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, thiazolyl, isothiazolyl, tetrazole base, three Nitrogen oxazolyl, thienyl, pyrazolyl, oxadiazolyls, thiadiazolyl group, pyrazinyl and triazine radical are individually optionally by 1,2 or 3 R8Base Group is replaced；
R4For F, Cl, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, 4-7 former molecular heterocycle Or 5-6 former molecular heteroaryl, wherein each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, 4-7 Former molecular heterocycle and 5-6 former molecular heteroaryl are individually optionally by 1,2 or 3 R8Group is replaced.
In some embodiments, each R5It independently is C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Alkoxy, C1-C4Alkylamino, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C1- C2Alkylidene)-(C3-C6Naphthenic base) ,-(C1-C2Alkylidene)-(4-7 former molecular heterocycle) ,-(C1-C2Alkylidene)- Phenyl or-(C1-C2Alkylidene)-(5-6 former molecular heteroaryl), wherein above-mentioned each group is individually optionally by 1,2 or 3 A R8Group is replaced.
In other embodiments, each R5It independently is methyl, ethyl, n-propyl, isopropyl, C2-C4Alkenyl, C2-C4 Alkynyl, C1-C4Alkoxy, C1-C4Alkylamino, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 atom group At heteroaryl ,-(C1-C2Alkylidene)-(C3-C6Naphthenic base) ,-(C1-C2Alkylidene)-(4-7 former molecular heterocycle Base) ,-(C1-C2Alkylidene)-phenyl or-(C1-C2Alkylidene)-(5-6 former molecular heteroaryl), wherein above-mentioned each base Group is individually optionally by 1,2 or 3 R8Group is replaced.
In some embodiments, each R6And R7It is separately H, F, Cl, Br, CN, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl or 5-6 former molecular heteroaryl, wherein Each C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl and 5-6 A molecular heteroaryl of original is individually optionally by 1,2 or 3 R8Group is replaced.
In some embodiments, each R8It independently is F, Cl, Br, CN, NO2、OH、NH2、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C3-C6Naphthenic base, phenyl, 4-7 former molecular heterocycle, 5-6 original are molecular Heteroaryl, C1-C6Aminoalkyl, C1-C6Alkylamino, C1-C6Alkoxy, C1-C6Hydroxy alkyl ,-NH (C0-C2Alkylidene)-(C3- C6Naphthenic base) ,-NH (C0-C2Alkylidene)-phenyl ,-NH (C0-C2Alkylidene)-(4-7 former molecular heterocycle) ,-NH (C0-C2Alkylidene)-(5-6 former molecular heteroaryl) ,-N [(C0-C2Alkylidene)-(C3-C6Naphthenic base)]2、-N[(C0-C2 Alkylidene)-phenyl]2、-N[(C0-C2Alkylidene)-(4-7 former molecular heterocycle)]2、-N[(C0-C2Alkylidene)-(5-6 A molecular heteroaryl of original)]2、-O(C0-C2Alkylidene)-(C3-C6Naphthenic base) ,-O (C0-C2Alkylidene)-(4-7 atom The heterocycle of composition) or-O (C0-C2Alkylidene)-(5-6 former molecular heteroaryl).
In some embodiments, wherein each Ra、Rb、RcAnd RdIt is separately H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C1-C2 Alkylidene)-(C3-C6Naphthenic base) ,-(C1-C2Alkylidene)-(4-7 former molecular heterocycle) ,-(C1-C2Alkylidene)-benzene Base or-(C1-C2Alkylidene)-(5-6 former molecular heteroaryl), wherein above-mentioned each C1-C6Alkyl, C2-C6Alkenyl, C2-C6 Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C1-C2Alkylene Base)-(C3-C6Naphthenic base) ,-(C1-C2Alkylidene)-(4-7 former molecular heterocycle) ,-(C1-C2Alkylidene)-phenyl and- (C1-C2Alkylidene)-(5-6 former molecular heteroaryl) optionally by 1,2 or 3 independently selected from F, Cl, Br, CN, N3、 OH、NH2、C1-C3Alkyl, C1-C3Halogenated alkyl, C1-C3Alkoxy, C1-C3Hydroxy alkyl, C1-C3Aminoalkyl or C1-C3Alkane ammonia The substituent group of base is replaced.
Also in some embodiments, the present invention relates to the compound of one of or its stereoisomer, mutually Tautomeric, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, but it is not limited to these Compound：
Unless otherwise mentioned, the stereoisomer, tautomer, solvate of compound shown in formula (I), metabolism production Object, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
Disclosed compound of present invention can contain asymmetric or chiral centre, thus can different stereoisomer forms deposit .The present invention is directed to all stereoisomer forms of compound shown in formula (I), including but not limited to diastereoisomer, Enantiomter, atropisomer and geometry (or conformation) isomers and their mixture such as racemic mixture, become The component part of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.
Compound shown in formula (I) can exist with different tautomeric forms, and all these tautomers, As is described in the claims, it is included within the scope of the present invention.
Compound can exist in a salt form shown in formula (I).In one embodiment, the salt refers to that can pharmaceutically connect The salt received.Term " pharmaceutically acceptable " refer to substance or composition must with other ingredients comprising preparation and/or use it The mammal for the treatment of is compatible chemically and/or in toxicology.In another embodiment, the salt, which is not necessarily, pharmaceutically may be used The salt of receiving can be used to prepare and/or purify compound shown in formula (I) and/or for detaching compound shown in this formula (I) Enantiomer intermediate.
Pharmaceutical acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Object/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 includes such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.
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, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..
Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.
Can obtain the inorganic base of salt by its derivative includes, for example, the I races of ammonium salt and periodic table to XII races metal. In certain embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.
It includes primary amine, secondary amine and tertiary amine that can obtain the organic base of salt by its derivative, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Certain organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.
The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid of metered amount reacts to be prepared.Such reaction usually carries out in water or organic solvent or the mixture of the two. Usually, in appropriate cases, it needs to use non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile. 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) list of the other suitable for salt can be found in.
In addition, compound disclosed by the invention including their salt, in the form of their hydrate or can also include it The form of solvent (such as ethyl alcohol, DMSO, etc.) obtains, and is used for their crystallization.Disclosed compound of present invention can be with pharmacy Upper acceptable solvent (including water) forms solvate inherently or by design；Therefore, the present invention is intended to include solvations And unsolvated form.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is 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、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there are radioactive isotopes, such as3H、14C and18Those of F compounds, or wherein there is non radioactive isotope, such as2H and13C.The compound of such isotope enrichment can be used for being metabolized research and (use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.18The compound of F enrichments to PET or It is especially desirable for SPECT researchs.Compound can be ripe by those skilled in the art shown in the formula (I) of isotope enrichment Embodiment and preparation process in the routine techniques or the present invention known is described former using suitable isotope labeling reagent replacement Carry out used unmarked reagent to prepare.
In addition, higher isotope especially deuterium (that is,2H or D) substitution certain treatment advantages can be provided, these advantages are It is brought by metabolic stability higher.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is counted as the substituent group of compound shown in formula (I).Isotope enrichment factor can be used To define the concentration of such higher isotope especially 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 substituent group of the compounds of this invention is designated as deuterium, The compound at least 3500 (52.5% deuterium incorporation at each specified D-atom), at least for each specified D-atom 4000 (60% deuterium incorporations), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7 The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) The factor.The pharmaceutical solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution2O, acetone-d6、 DMSO-d6Those of solvate.
On the other hand, the present invention relates to the intermediates for preparing compound shown in formula (I).
On the other hand, the present invention relates to the methods of preparation, separation and the purifying of compound shown in formula (I).
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or combination thereof.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.
On the other hand, the present invention relates to one or more protein kinases are treated, such as jak kinase, FLT3 kinases and Aurora The method of disease or disorder that kinases is adjusted, the therapy include giving the of the invention of mammalian effective amount to disclose chemical combination Object or pharmaceutical composition.In some embodiments, the disease or disorderly selected from proliferative diseases, autoimmune disease, mistake Quick property disease, inflammatory disease or graft rejection.
On the other hand, the present invention relates to use the compounds of this invention or medicine composite for curing disease disclosed by the invention or Disorder, the disease or disorderly selected from proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease or transplanting row Reprimand.
On the other hand, the present invention relates to compounds disclosed by the invention or pharmaceutical composition to prepare treatment disease or disorder Drug purposes, the disease be selected from proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease or transplanting row Reprimand.
On the other hand, the purposes of drug, institute are prepared the present invention relates to compound disclosed by the invention or pharmaceutical composition State activity of the drug for regulatory protein kinases.
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, and it includes listed compounds in disclosed compound of present invention or embodiment； With pharmaceutically acceptable auxiliary material, excipient, carrier, solvent or combination thereof.Change in pharmaceutical composition disclosed by the invention The amount for closing object refers to that can effectively detect the amount for inhibiting biological sample or patient's body protein kinase.
It will also be appreciated that certain compounds of the present invention can exist for treating in a free form, or if it is appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
Drug pharmaceutical compositions disclosed by the invention can prepare and be packaged as (bulk) form in bulk, wherein extractable safety A effective amount of formula (I) compound represented, then gives patient with powder or syrup form.Alternatively, drug disclosed by the invention Composition can prepare and be packaged as unit dosage forms, wherein each physically discrete unit contains formula (I) institute of safe and effective amount The compound shown.When being prepared with unit dosage forms, pharmaceutical composition disclosed by the invention can usually contain, for example, 0.5mg to 1g, Or the compound disclosed by the invention of 1mg to 700mg or 5mg to 100mg.
" pharmaceutically acceptable auxiliary material " used in the present invention means relevant with form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Each auxiliary material must be other at split-phase with pharmaceutical composition in mixing Hold, interaction the effect of to avoid disclosed compound of present invention can be substantially reduced when administering to a patient and can cause not being medicine The interaction of acceptable pharmaceutical composition on.In addition, each auxiliary material must be pharmaceutically acceptable, for example, having Sufficiently high purity.
Suitable pharmaceutically acceptable auxiliary material can be different according to selected specific dosage form.In addition, can combined according to them Specific function in object selects pharmaceutically acceptable auxiliary material.For example, may be selected to can help to produce the certain of equal one dosage type low temperature Pharmaceutically acceptable auxiliary material.The certain pharmaceutically acceptable auxiliary materials that can help to produce stabilizer type may be selected.It may be selected Contribute to carry or transport disclosed compound of present invention when administering to a patient from an organ of body or partly to the another of body One organ or partial certain pharmaceutically acceptable auxiliary materials.The certain pharmaceutically acceptable of enhancing patient compliance may be selected Auxiliary material.
Suitable pharmaceutically acceptable auxiliary material includes following kind of auxiliary material：Diluent, filler, adhesive, disintegration Agent, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, flavoring Agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilizer, Surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable auxiliary materials can provide more than one function, And alternative function is provided, this is depended in preparation in the presence of there are which other auxiliary materials in how much auxiliary materials and preparation.
Technical staff grasps the knowledge and skills of this field, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable auxiliary material.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Auxiliary material, and for selecting suitable pharmaceutically acceptable auxiliary material.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
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 and J.C.Boylan,1988-1999,Marcel The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Known technology, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object acts on, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of open compound, pays close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to the technique for preparing pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable auxiliary material, excipient, carrier, solvent or combination thereof, the technique include that mixing is each Kind ingredient.Include the pharmaceutical composition of disclosed compound of present invention, can be mixed under such as environment temperature and atmospheric pressure to make It is standby.
Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes the dosage form that those are suitable for following administration route：(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the substance packet for being resistant to hydrochloric acid in gastric juice effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, to prevent the acidic environment of active ingredient contacts stomach.Enteric coating includes, but are not limited to aliphatic acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds Piece can be conducive to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of substance.Film coating includes, but are not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses general characteristic identical with sweet tablet.It is multiple Tabletting is the compressed tablets by being prepared more than a press cycles, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by one kind that powder, crystallization or granular active constituent are individual or are described with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colorant.Fumet and sweetener are particularly useful when forming chewable tablets and pastille.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section It fills in another section, therefore encloses active constituent completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is plasticized by the way that glycerine, sorbierite or similar polyalcohol is added.Soft gelatin shell can include the pre- preventing microorganism life of preservative It is long.Suitable preservative be as described in the present invention those, including methyl hydroxybenzoate and propylben and sorbic acid.This Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution in propene carbonate, vegetable oil or triglycerides and suspension.Including the capsule of such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active constituent.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in pellet form in another liquid, It can be oil-in-water type or water-in-oil type.Emulsion may include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifier and Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions may include pharmaceutically may be used The acetal of receiving, for example, low alkyl group aldehyde two (low alkyl group) acetals, such as acetaldehyde diethyl acetal；With tool there are one or it is more The water-soluble solvent of a hydroxyl, such as propylene glycol and ethyl alcohol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and can also include preservative.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.
Other useful liquid and semisolid dosage form include, but are not limited to include active constituent provided by the invention and two level Change those of mono- or poly- alkylene glycol dosage form, described mono- or poly- alkylene glycol includes：1,2- dimethoxymethane, diethylene glycol (DEG) Dimethyl ether, triglyme, tetraethylene glycol dimethyl ether, polyethylene glycol -350- dimethyl ether, polyethylene glycol -550- dimethyl ether, poly- second The approximate average molecular weight of glycol -750- dimethyl ether, wherein 350,550,750 finger polyethylene glycol.These preparations can be further Including one or more antioxidant, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propylgallate, vitamin E, hydrogen Quinone, Hydroxycoumarin, ethanol amine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, coke Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.
Where appropriate, can be by the dosage unit preparations microencapsulation of oral medication.It can also be prepared into extending or tie up Hold the composition of release, such as by being coated by microparticle material or be embedded in polymer, wax or the like.
Combination of oral medication provided by the invention can also be carried in the form of liposome, micella, microballoon or nanometer system For.Micella dosage form can be prepared with the method that U.S.Pat.No.6,350,458 is described.
Pharmaceutical composition provided by the invention can be provided with the granule and pulvis of non-effervesce or effervesce, to be reconstructed into Liquid dosage form.The pharmaceutically acceptable carrier and excipient used in non-effervescent or pulvis may include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier and excipient used in effervescent or pulvis can wrap Include organic acid and carbon dioxide source.
Colorant and flavoring agent can be used in all above-mentioned dosage forms.
Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.It is such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl asparagus fern acyl Amine phenol or the oxide polylysine of palmitoyl residues substitution.In addition, compound disclosed in this invention can in reality A kind of Biodegradable polymeric used in the control release of existing drug combines, for example, polylactic acid, poly-epsilon-caprolactone, poly- Hydroxybutyric acid, polyorthoester, polyacetals, poly- dihydropyran, the crosslinking of polybutylcyanoacrylate and hydrogel or amphiphilic block are total Polymers.
Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect Prepare, or with the substance co-formulation that is acted on expected from supplement.
Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body is administered.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such dosage form can according to conventional method known to the technical staff in pharmaceutical science field come prepare (referring to Remington:The Science and Practice of Pharmacy, ibid).
The pharmaceutical composition for being intended for parenteral administration may include one or more pharmaceutically acceptable carriers and Excipient includes, but are not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and the dispersion of object growth Agent, wetting agent or emulsifier, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.
Suitably include, but are not limited to containing transporter：Water, brine, physiological saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers injections, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers injections.Non- transporter includes, but are not limited to fixed oil, castor oil, corn oil, the cottonseed of plant origin The middle chain of oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil Triglycerides and palm seed oil.Water miscibility carrier includes, but are not limited to the poly- second of ethyl alcohol, 1,3-BDO, liquid two Alcohol (such as Liquid Macrogol and polyethylene glycol 400), propylene glycol, glycerine, n-methyl-2-pyrrolidone, N, N- dimethylacetamides Amine and dimethyl sulfoxide.
Suitable antimicrobial or preservative include, but are not limited to phenol, cresols, mercurial, benzyl alcohol, chlorobutanol, Methyl p-hydroxybenzoate and propylparaben, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl hydroxybenzoate and Propylben and sorbic acid.Suitable isotonic agent includes, but are not limited to sodium chloride, glycerine and glucose.Suitable buffer Include, but are not limited to phosphate and citrate.Suitable antioxidant is such as those of present invention description, including sulfurous acid Hydrogen salt and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to procaine hydrochloride.Suitable suspending agent and point Powder is such as those of present invention description, including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitable emulsifier includes those of present invention description, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene is de- Water sorbitol monooleate 80 and triethanolamine oleate ester.Suitable sequestering agent or chelating agent include, but are not limited to EDTA. Suitable pH adjusting agent includes, but are not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitable complexing agent includes, but unlimited In cyclodextrin, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-β-cyclodextrin, Sulfobutylether-beta-cyclodextrin and sulfobutyl group Ether 7- beta-cyclodextrins (CyDex,Lenexa,KS)。
Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multi-dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art and practice.
In one embodiment, pharmaceutical composition is provided with instant sterile solution.In another embodiment, drug Composition is provided with sterile dried soluble product, including freeze-dried powder and hypodermic tablet, and carrier is used before use Reconstruct.In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In yet another embodiment, medicine Compositions are formulated into the sterile dry insolubility product reconstructed with carrier before use.Also in one embodiment, Pharmaceutical composition is formulated into instant without bacterial emulsion.
Pharmaceutical composition disclosed in this invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, Pulse-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition can be configured to suspension, solid, semisolid or thixotropic liquid, be used as the reservoir administration of implantation. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, be insoluble to body fluid but The external polymeric membrane that the active constituent in pharmaceutical composition diffuses through is allowed to be surrounded.
Suitable internal matrix include polymethyl methacrylate, poly- butyl methacrylate, plasticising or it is unplasticizied Polyvinyl chloride, the nylon of plasticising, the polyethylene terephthalate of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly- diformazan silica Alkane, silicone carbonate copolymer, the hydrogel of ester of hydrophilic polymer such as acrylic acid and methacrylic acid, collagen, crosslinking The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and coach.
Suitable external polymeric membrane includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Object, ethylene/vinyl acetate copolymer, silicone rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second Alkene, the copolymer of ethlyene dichloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer are poly- to benzene two Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.
On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable for any dose to patient's inhalation Type, such as dry powder doses, aerosol, suspension or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention Object can be configured to be suitable for the dosage form with dry powder doses to patient's inhalation.In yet another embodiment, disclosed in this invention Pharmaceutical composition can be configured to be suitable for the dosage form by sprayer to patient's inhalation.Pass through the dry powder of inhalation delivery to lung Composition generally comprise fine powdered compound disclosed in this invention and it is one or more it is fine powdered pharmaceutically Acceptable excipient.Pharmaceutically acceptable excipient be especially suitable for dry powder doses is known to those skilled in the art Dawn comprising lactose, starch, mannitol and mono-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding preparation It obtains.In general, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value is (for example, with swashing What optical diffraction method measured) it defines.
Aerosol can be prepared by the way that compound disclosed in this invention to be suspended or dissolved in liquefied propellant.It is suitble to Propellant include chlorohydrocarbon, hydro carbons and other liquid gas.Representative propellant includes：Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1- difluoros Ethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, Perfluorinated butane, perflenapent, butane, iso-butane and pentane.Including the aerosol of compound disclosed in this invention usually passes through Metered dose inhaler (MDI) administers to a patient.Such device dawn known to those skilled in the art
Aerosol may include pharmaceutically acceptable excipient that is additional, being used by MDIs, such as surface-active Agent, lubricant, cosolvent and other excipient, with improve preparation physical stability, improve valve characteristic, improve dissolubility, Or improve taste.
Discontinuous patch agent can be prepared by being suitable for the pharmaceutical composition of cutaneous penetration, it is intended that be kept with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.For example, ointment, cream and gelling agent can use water or oil Matrix, and suitable thickener and/or gelling agent and/or solvent configure.Such matrix may include water, and/or oily example Such as liquid-liquid paraffin and vegetable oil (such as peanut oil or castor oil) or solvent such as polyethylene glycol.Made according to medium property Thickener and gelling agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, poly- carboxylic second Alkene and cellulose derivative and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.
Lotion can use water or oil matrix to prepare, and generally also contain one or more emulsifying agents, stabilizer, dispersion Agent, suspending agent or thickener.
Externally-applied powder can be molded in the presence of any suitable powder matrix such as talcum powder, lactose or starch.Drops It can be formulated with the water comprising one or more dispersing agents, solubilizer, suspending agent or preservative or non-aqueous matrix.
Topical formulations can be by being administered using one or many daily in affected part；The impermeable plastic wound dressing for covering skin is preferential It is used.Adhesiveness store system can realize continuous or extended administration.
When treating eyes or other organs such as face and skin, the combination as topical ointment or cream can be applied Object.When being formulated as ointment, compound disclosed in this invention can be used together with paraffin or water-soluble ointment matrix.Or Person, compound disclosed in this invention can be configured to cream together with Oil-in-water emulsifiable paste agent matrix or oil-in-water base.
The purposes of the compounds of this invention and composition
The present invention, which provides, uses compound disclosed in this invention and medicine composite for curing, prevention, or improves by one kind Or multiple protein kinases, such as jak kinase (including JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (also referred to as FLK-2) or The disease or disorderly that Aurora A (including Aurora-A, Aurora-B and Aurora C) behavior is mediated or otherwise influenced Disorderly or by one or more protein kinases, such as jak kinase (including JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (also referred to as FLK-2) or Aurora A (including Aurora-A, Aurora-B and Aurora C) behavior mediate or otherwise The method of the disease of influence or one or more symptoms of disorder.
Jak kinase can be wild type and/or the mutation of JAK1, JAK2, JAK3 or TYK2 kinases.
In one embodiment, the present invention provides a kind of compound disclosed in this invention or includes presently disclosedization The pharmaceutical composition for closing object, for treating, preventing or improves by unsuitable JAK1 kinases behavior mediation or otherwise shadow Loud disease or disorder or mediated by unsuitable JAK1 kinases behavior or otherwise influenced the one of disease or disorder Kind or a variety of symptoms.In another embodiment, the disease, disorder or disease or one or more symptoms of disorder with not JAK2 kinases behavior appropriate is related.Also in one embodiment, the disease, disorder or disease or one kind or more of disorder Kind symptom is related to unsuitable JAK3 kinases behavior.
In some embodiments, the present invention provides a kind of compound disclosed in this invention or comprising presently disclosed The pharmaceutical composition of compound, for treating, preventing or improve by unsuitable FLT3 kinases behavior mediation or otherwise The disease of influence or disorder are mediated or the disease that otherwise influences or disorder by unsuitable FLT3 kinases behavior One or more symptoms.
In some embodiments, the present invention provides a kind of compound disclosed in this invention or comprising presently disclosed The pharmaceutical composition of compound is mediated or with other for treating, preventing or improve by unsuitable Aurora-A kinases behavior Disease that mode influences or disorder or the disease for being mediated by unsuitable Aurora-A kinases behavior or otherwise being influenced Or disorderly one or more symptoms.In other embodiments, one kind of the disease, disorder or disease or disorder or A variety of symptoms are related to unsuitable Aurora-B kinases behavior.Also in some embodiments, the disease, disorder or disease Disease or disorderly one or more symptoms are related to unsuitable Aurora C kinases behaviors.
" unsuitable jak kinase behavior " refers to being happened to deviate the JAK of normal jak kinase behavior with particular patient and swash Enzyme behavior.Unsuitable jak kinase behavior can show as example active abnormal growth or jak kinase time of the act point With the form of the deviation in control.This unsuitable kinases behavior is derived from, for example, the overexpression or mutation of protein kinase and Caused inappropriate or uncontrolled behavior.Therefore, the present invention, which provides, treats these diseases and disorderly method.
Consistent with above description, such disease or disorder include but not limited to：Bone marrow proliferative diseases, such as very Property polycythemia (PCV), essential thrombocythemia, idiopathic myelofibrosis (IMF)；Leukaemia, such as medullary system Leukaemia includes chronic myelogenous leukemia (CML), the CML forms of resistance to Imatinib, acute myeloid leukemia (AML) and AML Hypotype, acute megakaryoblastic leukemia (AMKL)；Lymphoproliferative disease, for example, acute lymphoblastic leukemia (ALL) and Myeloma etc.；Cancer includes incidence cancer, prostate cancer breast cancer, oophoroma, melanoma, lung cancer, brain tumor, cancer of pancreas and kidney Cancer；Diseases associated with inflammation related with immunologic function disorder, immune deficiency, immunological regulation or disorder, autoimmune disease, group Knit graft rejection, graft versus host disease(GVH disease), wound healing, nephrosis, multiple sclerosis, thyroiditis, type-1 diabetes mellitus, sarcoidosis, Psoriasis, allergic rhinitis, inflammatory bowel disease include Crohn disease and ulcerative colitis (UC), systemic loupus erythematosus (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD) and Dry eye syndrome (or keratoconjunctivitis sicca (KCS)).
On the one hand, the present invention provides a kind of compound disclosed in this invention or includes the medicine of presently disclosed compound Compositions, proliferative diseases, autoimmune disease, anaphylaxis for preventing and/or treating mammal (including mankind) Disease, inflammatory disease or graft rejection.
On the other hand, the present invention provides a kind for the treatment of and suffers from or the risky mammal for suffering from disease disclosed herein Method, the method includes give effectively treatment illness amount or effectively prevent illness amount one or more medicines disclosed herein Compositions or compound.
On the other hand, it suffers from provided herein is a kind for the treatment of or risky suffers from proliferative diseases, autoimmune disease, mistake The method of the mammal of quick property disease, inflammatory disease or graft rejection.
In a kind of method in terms for the treatment of, the present invention provides treatment and/or prevents to be susceptible or suffering from proliferative diseases The method of mammal, the method includes giving one or more medicines disclosed herein of effective therapeutic dose or effective preventive dose Compositions or compound.
On the other hand, provided herein is a kind of compounds disclosed herein, for treating and/or preventing proliferative diseases.
On the other hand, provided herein is a kind of compounds disclosed herein, or include the pharmaceutical composition of compound disclosed herein Object is used to prepare the drug for treating or preventing proliferative diseases.
In particular instances, proliferative diseases are selected from cancer (for example, solid tumor such as leiomyosarcoma of uterus or prostate Cancer), polycythemia vera, primary thrombocytosis, myelofibrosis, leukaemia (for example, AML, CML, ALL or ) and Huppert's disease CLL.
On the other hand, provided herein is treatment and/or the sides for preventing to be susceptible or suffering from the mammal of autoimmune disease Method, the method includes giving one or more pharmaceutical compositions disclosed herein of effective therapeutic dose or effective preventive dose or change Close object..
On the other hand, provided herein is a kind of compounds disclosed herein, for treating and/or preventing autoimmune disease.
On the other hand, provided herein is a kind of compounds disclosed herein, or include the pharmaceutical composition of compound disclosed herein Object is used to prepare the drug for treating or preventing autoimmune disease.
In certain embodiments, autoimmune disease is selected from COPD, and asthma, systemic loupus erythematosus, skin-type is red Yabbi sore, lupus nephritis, dermatomyositis, Sjogren syndrome, psoriasis, type-1 diabetes mellitus and inflammatory bowel disease.
On the other hand, the method that the mammal of anaphylactia is susceptible or suffering from provided herein is treatment and/or prevention, The method includes giving the one or more pharmaceutical compositions disclosed herein or chemical combination of effective therapeutic dose or effective preventive dose Object.In certain embodiments, anaphylactia is selected from respiratory anaphylactic disease, nasosinusitis, eczema and measles, food mistake Quick and insect venom allergies.
On the other hand, provided herein is a kind of compounds disclosed herein, for treating and/or preventing anaphylactia.
On the other hand, provided herein is a kind of compounds disclosed herein, or include the pharmaceutical composition of compound disclosed herein Object is used to prepare the drug for treating or preventing anaphylactia.
In certain embodiments, anaphylactia is selected from respiratory anaphylactic disease, nasosinusitis, eczema and measles, Food hypersenstivity and insect venom allergies.
On the other hand, provided herein is treatment and/or the method for preventing to be susceptible or suffering from the mammal of inflammatory disease, institutes The method of stating includes giving the one or more pharmaceutical compositions disclosed herein or compound of effective therapeutic dose or effective preventive dose.
On the other hand, provided herein is a kind of compounds disclosed herein, for treating and/or preventing inflammatory disease.
On the other hand, provided herein is a kind of compounds disclosed herein, or include the pharmaceutical composition of compound disclosed herein Object is used to prepare the drug for treating or preventing inflammatory disease.
In certain embodiments, inflammatory disease is selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, childhood Type arthritis and psoriasis arthropathica.
On the other hand, provided herein is treatment and/or the method for preventing to be susceptible or suffering from the mammal of graft rejection, institutes The method of stating includes giving the one or more pharmaceutical compositions disclosed herein or compound of effective therapeutic dose or effective preventive dose.
On the other hand, provided herein is a kind of compounds disclosed herein, for treating and/or preventing graft rejection.
On the other hand, provided herein is a kind of compounds disclosed herein, or include the pharmaceutical composition of compound disclosed herein Object is used to prepare the drug for treating or preventing graft rejection.
In particular instances, graft rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.
On the other hand, provided herein is one kind is especially used as treating and/or preventing disease medicament noted earlier as drug Compound disclosed herein.It is also provided with compound manufacture treatment disclosed herein and/or prevents the medicine of disease noted earlier Object.
One special projects of this method include giving a effective amount of present invention of study subject with inflammation to disclose chemical combination For a period of time, the time is enough to reduce the level of inflammation of study subject object, and preferably terminates the process of the inflammation.The party The special embodiment of method includes giving a effective amount of present invention public affairs of tested patients for suffering from or being susceptible to suffer from bone rheumatoid arthritis Open compound for a period of time, the time is enough to reduce or prevent the arthritis of the patient respectively, and preferably terminates institute State the process of inflammation.
Another special projects of this method include giving a effective amount of present invention of study subject with proliferative diseases For a period of time, the hyperplasia that the time is enough to reduce study subject is horizontal, and preferably terminates the increasing for open compound The process of growing property disease.The special embodiment of this method include give the tested patients with cancer it is a effective amount of be disclosed herein For a period of time, the time is enough to reduce or prevent the cancer symptom of the patient respectively compound, and preferably described in termination The process of cancer.
Combination therapy
The compounds of this invention can be used as individual active agent to be administered, or can be administered with other therapeutic agents, Including being determined as safe and efficient other compounds with same or similar therapeutic activity and for such administering drug combinations.
On the one hand, the present invention provides treatment, prevents or improve the method for disease or illness, including gives safe and effective amount Include the combination medicine of disclosed compound of present invention and one or more therapeutically active agents.In one embodiment, combination medicine Including one or two kinds of other therapeutic agents.
The example of other therapeutic agents includes including but not limited to：Anticancer agent, including chemotherapeutics and antiproliferative；Anti-inflammatory agent； With immunity regulatin remedy agent or immunosuppressor.
On the other hand, present invention offer includes the product of the compounds of this invention and at least one other therapeutic agent, can be prepared At the combination simultaneously, separately or sequentially applied in the treatment.In some embodiments, treatment is for by one or more eggs White kinases, such as the treatment of disease or symptom that jak kinase, FLT3 kinases or Aurora A activity mediate.Prepared by joint provides Product include be present in same pharmaceutical composition comprising be disclosed herein compound and other therapeutic agents composition, or with Compound and other therapeutic agents are disclosed herein existing for different form, for example, medicine box.
On the other hand, the present invention provides a kind of comprising compound disclosed herein and the drug of another or a variety of therapeutic agents Composition.In one embodiment, pharmaceutical composition can include pharmaceutically acceptable auxiliary material as described above.
On the other hand, the present invention provides the medicine box for including two kinds or more of single pharmaceutical composition, wherein at least one Pharmaceutical composition includes disclosed compound of present invention.In one embodiment, medicine box includes the work for individually keeping the composition Tool, such as container, separated bottle or separated foil box.The example of this kind of medicine box is blister package, be commonly used for package troche, Capsule etc..
Purposes in disease or symptom that the present invention also provides the compounds of this invention to mediate in treatment albumen kinase activity, Wherein patient previously treated with other therapeutic agents by (such as in 24 hours).The present invention also provides other treatments Purposes of the agent in treatment albumen kinases, the disease and symptom that are mediated such as jak kinase, FLT3 kinases and Aurora A activity, Wherein patient previously treated with the compounds of this invention by (such as in 24 hours).
Compound disclosed herein can be used as single-activity component application or as such as adjuvant, common with other therapeutic agents Using.
In some embodiments, other therapeutic agents include chemotherapeutics and/or antiproliferative.Known chemotherapeutic Object includes, but is not limited to, other therapies or anticancer drug, operation, radiotherapy that can be used in combination with the compounds of this invention (such as γ radiation of a little example, neutron beam radiotherapy, electron beam evaporation therapy, proton therapy, brachytherapy and system Isotope therapy), endocrinotherapy, taxanes (taxol (taxol), Docetaxel (taxotere) etc.), Platinum derivatives (cis-platinum (cisplatin), carboplatin (carboplatin)), biological response modifiers (interferon, between leucocyte Element), tumor necrosis factor (TNF, TRAIL receptor target object), overheat and cold therapy, the reagent for mitigating any adverse reaction (such as antiemetic) and other approved chemotherapeutics include but is not limited to, alkylating drug (mustargen (mechlorethamine), Chlorambucil (chlorambucil), cyclophosphamide (cyclophosphamide), melphalan (melphalan), ifosfamide (ifosfamide)), antimetabolite (methotrexate (MTX) (methotrexate), pemetrexed (pemetrexed) etc.), (6-MP (6-mercaptopurine), 5- fluorine urine are phonetic for purine antagonist and Pyrimidine antagonists Pyridine (5-fluorouracil), cytarabine (cytarabile), gemcitabine (gemcitabine)), spindle poison (vincaleukoblastinum (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine)), podophyllotoxin (according to Support pool glycosides (etoposide), Irinotecan (irinotecan), Hycamtin (topotecan)), antibiotic (Doxorubicin (doxorubicin), bleomycin (bleomycin), mitomycin (mitomycin)), nitroso ureas (Carmustine (carmustine), lomustine (lomustine)), (KSP passes through mitotic kinesins to cell division cycle inhibitor Inhibitor, CENP-E and CDK inhibitor), enzyme (asparaginase (asparaginase)), hormone (tamoxifen (tamoxifen), Leuprorelin (leuprolide), Flutamide (flutamide), megestrol acetate (megestrol), fill in rice Loose (dexamethasone) etc.).Anti-angiogenesis reagent (Avastin (avastin) etc.).Monoclonal antibody (Baily monoclonal antibody (belimumab), brentuximab, Cetuximab (cetuximab), WAY-CMA 676 (gemtuzumab), her monoclonal antibody (ipilimumab), ofatumumab, Victibix (panitumumab), Lucentis (ranibizumab), rituximab list Anti- (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab)).Kinase inhibitor (she Imatinib (imatinib), Sutent (sunitinib), Sorafenib (sorafenib), Tarceva (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), nilotinib (nilotinib), Lapatinib (lapatinib), gram Zhuo for Buddhist nun (crizotinib), ruxolitinib, vemurafenib, vandetanib, Pazopanib, etc.).Drug inhibition or activate cancer approach such as mTOR, HIF (hypoxia inducible factor) approach and other.Cancer Disease is treated wide forum and is seenhttp://www.nci.nih.gov/, FDA approve oncologic inventory seehttp:// www.fda.gov/cder/cancer/druglist-rame.htmAnd Merck Manual, the 18th edition .2006, all contents All as the bibliography of the application.
Also in other embodiments, the compound of the present invention can be with binding signal transduction inhibitor.Signal 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 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), posupini (bosutinib), brivanib, canertinib, cabozantinib, Si Dinibu (cediranib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, Ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, replaces husky Buddhist nun (motesanib), linatinib (neratinib), niraparib, Oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, saracatinib (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..
In some embodiments, compound disclosed herein can also be co-administered with other medicines.The other medicines Including, immunosuppressor, immunomodulator, other anti-inflammatory agents, such as treating or preventing allogeneic-or xenograft Acute or chronic repulsion, inflammatory, autoimmune disease drug；Or chemotherapeutics, such as malignant cell antiproliferative.For example, Disclosed compound of present invention can combine with following active component：The plain inhibitor of calcium nerve, such as cyclosporin A or FK506； MTOR inhibitors, for example, rapamycin, 40-O- (2- hydroxyethyls)-rapamycin, CCI779, ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9；Ascosin with immunosuppressive properties, such as ABT-281, ASM981 Deng；Corticosteroid；Cyclophosphamide；Imuran；Methotrexate (MTX)；Leflunomide；Mizoribine；Mycophenolic Acid or salt；Wheat Examine phenolic acid mofetil ester；15- deoxyspergualins or its immunosupress homologue, analog or derivative；Pkc inhibitor, such as Described in WO 02/38561 or WO 03/82859, for example, embodiment 56 or 70 compound；Immunosupress monoclonal antibody, Such as the monoclonal antibody of leukocyte receptors, for example, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or its ligand；Other immunomodulatory compounds, such as at least partly extracellular domain with CTLA4 Recombination binding molecule or its mutant, such as at least extracellular portion of CTLA4 being connected with non-CTLA4 protein sequences or its Mutant, such as CTLA4Ig (such as being named as ATCC 68629) or its mutant, such as LEA29Y；Adhesion molecule inhibitor, Such as LFA-1 antagonists, the antagonists of ICAM-1 or -3, VCAM-4 antagonists or VLA-4 antagonists；Or chemotherapeutics, such as Japanese yew Alcohol, gemcitabine, cis-platinum, Doxorubicin or 5 FU 5 fluorouracil；Or anti-infective.
In disclosed compound of present invention and other immunotherapeutic agent/immunomodulators, anti-inflammatory agent, chemotherapy or anti-infective In the case for the treatment of administering drug combinations, immunosuppressor, immunomodulator, anti-inflammatory agent, chemotherapeutant or the anti-sense of administering drug combinations The dosage for contaminating compound certainly can be according to the type of combination medicine used, such as whether it is that steroidal or calcineurin inhibit Agent, specific drug used, illness to be treated etc. and change.
On the one hand, it includes disclosed compound of present invention and β that the present invention, which provides a kind of,2The connection of adrenoceptor agonists It closes.β2The example of adrenoceptor agonists includes salmeterol, salbutamol, Formoterol, salmefamol, Fei Nuote Sieve, Yi Tanteluo, naminterol, Clenbuterol, pirbuterol, Flerobuterol, reproterol, promulgates special sieve, indenes at carmoterol Da Teluo, Terbutaline and their salt, such as the xinafoate (1- hydroxy-2-naphthoic acids salt) of salmeterol, husky butylamine The sulfate or free alkali of alcohol or the fumarate of Formoterol.In one embodiment, long-acting beta2Adrenocepter swashs Dynamic agent, such as preferably, it is to provide effective bronchiectasis up to 12 hours or the compound of longer time.
β2Adrenoceptor agonists can be with the form of pharmaceutically acceptable sour forming salt.It is described pharmaceutically The acid of receiving is selected from sulfuric acid, hydrochloric acid, fumaric acid, carbonaphthoic acid (such as 1- or 3- hydroxy-2-naphthoic acids), cinnamic acid, substituted meat Cinnamic acid, triphenylacetic acid, sulfamic acid, p-aminobenzene sulfonic acid, 3- (1- naphthalenes) acrylic acid, benzoic acid, 4- methoxy benzoic acids, 2- or 4-HBA, 4- chlorobenzoic acids and 4- Phenylbenzoic acids.
On the other hand, the present invention provides a kind of joint including disclosed compound of present invention and corticosteroid.Suitably Corticosteroid refers to those oral and sucking corticosteroids, and its has the prodrug of anti-inflammatory activity.Example includes that methyl sprinkles Ni Songlong, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), -17 α of -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-[(4- methyl-1,3-thiazoles - 5- carbonyls) oxygroup] -17 β of -3- oxo-androst -1,4- diene-thiocarboxylic acid S- fluorine methyl esters, 6 α, fluoro- 17 α-[(the 2- furans of 9 α-two Mutter carbonyl) oxygroup]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-thiocarboxylic acid S- fluorine methyl esters (furancarboxylic acids Fluticasone) ,-16-17 α of Alpha-Methyl-3- oxos of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-- 17 β of propionyloxy-androsta-1,4- diene- Thiocarboxylic acid S- (2- oXo-tetrahydro furans -3S- bases) ester, -17 α of -16 Alpha-Methyl -3- oxos of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy - (2,2,3,3- tetramethyls cyclopropyl carbonyl) oxygroup--17 β of androstane -1,4- diene-thiocarboxylic acid S- cyano methyl esters and 6 α, 9 α-two Fluoro- -17 β of -17 α of -16 Alpha-Methyl of 11 beta-hydroxy-(1- ethyls cyclopropyl carbonyl) oxygroup -3- oxo-androst -1,4- diene-is thio Carboxylic acid S- methyl fluorides ester, beclomethasone ester (such as 17- propionic esters or 17,21- dipropionic acids fat), budesonide (budesonide), Flunisolide (flunisolide), Mometasone ester (such as momestasone furoate), Triamcinolone acetonide (triamcinolone Acetonide), ([[(R)-cyclohexyl is sub- by 16 α, 17- for sieve fluoronaphthalene moral (rofleponide), ciclesonide (ciclesonide) Methyl] bis- (oxygroups)] -11 β, 21- dihydroxy-pregnant steroid -1,4- diene -3,20- diketone), butixocort propionate (butixocort Propionate), RPR-106541 and ST-126.Preferred corticosteroid includes fluticasone propionate (fluticasone Propionate), -17 α of -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-[(4- methyl-1,3-thiazole -5- carbonyls) oxygroup] - - 17 β of 3- oxo-androst -1,4- diene-thiocarboxylic acid S- methyl fluorides ester, 6 α, fluoro- 17 α-of 9 α-two [(2- furanylcarbonyls) oxygen Base]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-thiocarboxylic acid S- methyl fluorides ester, 6 α, 9 α-two are fluoro- - 17 α of -16 Alpha-Methyl -3- oxos of 11 beta-hydroxy-(2,2,3,3- tetramethyls cyclopropyl carbonyl) oxygroup-androstane -1,4- diene -17 - 17 α of β-thiocarboxylic acid S- cyano methyl esters and -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-(1- methylcyclopropyl groups carbonyl) oxygen - 17 β of base -3- oxo-androst -1,4- diene-thiocarboxylic acid S- fluorine methyl esters.In some embodiments, corticosteroid is 6 α, - 16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of fluoro- 17 α-of 9 α-two [(2- furanylcarbonyls) oxygroup]-11 beta-hydroxy-sulphur For carboxylic acid S- methyl fluoride esters.
On the other hand, the present invention provides a kind of joint including disclosed compound of present invention and nonsteroidal GR agonists. To Transcription inhibition with selectivity (compared with transcriptional activation), can be used for combination therapy with glucocorticoid agonist activity Nonsteroidal compound includes the compound that those covered in following patent：WO 03/082827、WO 98/54159、WO 04/005229、WO 04/009017、WO 04/018429、WO 03/104195、WO 03/082787、WO 03/082280、WO 03/059899、WO 03/101932、WO 02/02565、WO 01/16128、WO 00/66590、WO 03/086294、WO 04/026248, WO 03/061651 and WO 03/08277.More nonsteroidal compounds are in WO 2006/000401, WO It is included in 2006/000398 and WO 2006/015870.
On the other hand, it includes disclosed compound of present invention and nonsteroidal anti-inflammatory drug (NSAID's) that the present invention, which provides a kind of, Joint.The example of NSAID's includes nasmil, sodium nedocromil (nedocromil sodium), phosphodiesterase (PDE) inhibitor (such as theophylline, PDE4 inhibitor or mixed type PDE3/PDE4 inhibitor), leukotriene antagonist, leukotriene close At inhibitor (such as montelukast), iNOS inhibitor, trypsase and elastatinal, Beta 2 integrin antagonist With adenosine receptor agonist or antagonist (e.g., adenosine 2a receptor stimulating agents), (such as chemokine receptors is short of money for cytokine antagonist Anti-agent, including CCR3 antagonists), cytokine synthesis inhibitor or 5-LO inhibitor.Wherein, iNOS (inductivities one Nitric oxide synthase) inhibitor is preferably administered orally.The example of iNOS inhibitor includes those in WO93/13055, WO 98/ 30537, compound disclosed in WO 02/50021, WO 95/34534 and WO 99/62875.CCR3 inhibitor include those Compound disclosed in WO 02/26722.
In one embodiment, the present invention relates to disclosed compound of present invention with phosphodiesterase 4 (PDE4) inhibitor Joint in application, the application especially in inhalant dosage form.PDE4 specific inhibitors for this aspect of the present invention can To be known inhibition PDE4 enzymes or be found any compound as PDE4 inhibitor, they are only PDE4 inhibitor, It is not to inhibit other members in PDE families, such as the compound of PDE3 and PDE5.Compound includes cis- -4- cyano -4- (3- rings Amyl oxygroup -4- methoxyphenyls) hexamethylene -1- carboxylic acids, 2- carbomethoxy -4- cyano -4- (3- cyclo propyl methoxy -4- difluoros Methoxyphenyl) hexamethylene -1- ketone and cis--[4- cyano -4- (3- cyclo propyl methoxy -4- difluoro-methoxies phenyl) hexamethylene Alkane -1- alcohol]；Also include cis- -4- cyano -4- [3- (ring propoxyl group) -4- methoxyphenyls] hexamethylene -1- carboxylic acids (also referred to as west Lip river department) and its salt, ester, prodrug or physical form, in 09 month 1996 No. 03 United States Patent (USP) US 5,552,438 authorized Open, this patent and its disclosed compound are incorporated herein by reference in their entirety.
On the other hand, the present invention provides a kind of joint including disclosed compound of present invention and anticholinergic agent.Cholinolytic Can agent example be those be used as muscarinic receptor antagonist compounds, especially those as M1 or M3 receptor antagonists, M1/M3Or M2/M3Receptor dual antagonist or M1/M2/M3The compound of the general antagonist of receptor.The example compound packet of inhalation Include ipratropium (for example, as bromide, CAS22254-24-6, withSold for trade name), Oxygen support ammonium (for example, as bromide, CAS 30286-75-0) and tiotropium (for example, as bromide, CAS 136310-93- 5, withIt is sold for trade name)；Be also interested in also have Revatropate (for example, as hydrobromate, CAS 262586-79-8) and the LAS-34273 disclosed in WO01/04118.The example compound of oral medication includes piperazine logical sequence Xiping (CAS 28797-61-7), darifenacin (CAS 133099-04-4 or its hydrobromate CAS133099-07-7, withSold for trade name), oxybutynin (CAS 5633-20-5, withIt is sold for trade name Sell), terodiline (CAS 15793-40-5), Tolterodine (CAS 124937-51-5 or its tartrate CAS 124937- 52-6, withSold for trade name), Austria for ammonium (for example, as bromide, CAS 26095-59-0, withSold for trade name), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, Or its succinate CAS242478-38-2, i.e. compound YM-905, withIt is sold for trade name).
On the other hand, the present invention provides a kind of joint including disclosed compound of present invention and H1 antagonists.H1 antagonists Example include, but are not limited to Amlexanox (amelexanox), western this imidazoles (astemizole), azatadine (azatadine), azelastine (azelastine), Acrivastine (acrivastine), Brompheniramine (brompheniramine), cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine), chloropheniramine (chlorpheniramine), clemastine (clemastine), marezine (cyclizine), Carebastine (carebastine), cyproheptadine (cyproheptadine), carbinoxamine (carbinoxamine), descarboethoxyloratadine (descarboethoxyloratadine), doxylamine (doxylamine), diformazan indenes (dimethindene), Ebastine (ebastine), epinastine (epinastine), second Fluorine profit piperazine (efletirizine), fexofenadine (fexofenadine), hydroxyzine (hydroxyzine), Ketotifen (ketotifen), Loratadine (loratadine), levocabastine (levocabastine), Mizolastine (mizolastine), mequitazine (mequitazine), Mianserin (mianserin), the primary sting of promise (noberastine), meclizine (meclizine), Tecastemizole (norastemizole), olopatadine (olopatadine), piperacetazine (picumast), than Lamine (pyrilamine), phenergan (promethazine), special Fei Nading (terfenadine), Tripelennamine (tripelennamine), temelastine (temelastine), nedeltran (trimeprazine) and triprolidine (triprolidine), preferably cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine) and fexofenadine (fexofenadine).In another implementation In scheme, the present invention provides the joint that one kind including disclosed compound of present invention and H3 antagonists (and/or inverse agonist).H3 is short of money The example of anti-agent includes those compounds disclosed in WO 2004/035556 and WO2006/045416.It can be used for and this hair Other histamine receptor antagonists that bright open chemical combination Internet of Things are closed include H4 receptor antagonists (and/or inverse agonist), such as Jablonowski et al.,J.Med.Chem.,2003,46:Compound disclosed in 3957-3960.
Another aspect, it includes disclosed compound of present invention that the present invention, which provides a kind of, with PDE4 inhibitor and β2Adrenaline The joint of receptor stimulating agent.
Also on the one hand, it includes disclosed compound of present invention that the present invention, which provides a kind of, is inhibited with anticholinergic drug and PDE-4 The joint of agent.
Above-described joint can easily be prepared into pharmaceutical composition to use, therefore, including defined above group It closes and represents another aspect of the present invention with the pharmaceutical composition of pharmaceutically acceptable excipient or carrier.
These united each compounds with alone or in combination pharmaceutical dosage form order of administration or can be administered simultaneously. In one embodiment, each compound component is administered simultaneously with the pharmaceutical dosage form of combination.Known treatment agent is suitble to Dosage is easy to be understood by the person skilled in the art.
Therefore, on the other hand, the present invention provides a kind of pharmaceutical composition, including compound disclosed by the invention is controlled with other Treat the joint of activating agent.
In some embodiments, pharmaceutical composition provided by the invention includes disclosed compound of present invention and chemotherapeutics Joint.
In some embodiments, pharmaceutical composition provided by the invention includes disclosed compound of present invention and antiproliferative Joint.
In one embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and phosphodiesterase The joint of 4 (PDE4) inhibitor.
In another embodiment, pharmaceutical composition provided by the invention includes on disclosed compound of present invention and β 2- kidneys The joint of adrenoceptor agonist.
In another embodiment, pharmaceutical composition provided by the invention includes that disclosed compound of present invention and cortex class are solid The joint of alcohol.
In another embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and nonsteroidal The joint of GR agonists.
In another embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and anticholinergic The joint of medicine.
In yet another embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and antihistamine Joint.
In other embodiment, pharmaceutical composition provided by the invention includes disclosed compound of present invention and anti-inflammatory examination The joint of agent.
In other embodiment, pharmaceutical composition provided by the invention includes that disclosed compound of present invention is adjusted with immune Save the joint of agent.
In other embodiment, pharmaceutical composition provided by the invention include disclosed compound of present invention be used for move The joint of the drug of pulse atherosclerosis.
In other embodiment, pharmaceutical composition provided by the invention include disclosed compound of present invention be used for control Treat the joint of the drug of pulmonary fibrosis.
In internal medicine oncology, combine that carry out treating cancer patient be conventional means using different form of therapy.Inside In section's oncology, being added to one or more other co-therapies forms of the present composition can be, for example, performing the operation, putting Treatment, chemotherapy, single transduction inhibitor or conditioning agent (for example, kinase inhibitor or conditioning agent) and/or monoclonal antibody.
Disclosed compound of present invention can also be advantageously utilised in the combination with other compounds, or and other therapeutic agents, especially It is in the combination of antiproliferative.Such antiproliferative includes, but are not limited to aromatase inhibitor；Antiestrogenic；Topology is different Structure enzyme I inhibitor；Topoisomerase II inhibitors；Microtubule active agent；Alkylating agent；Histon deacetylase (HDAC) inhibitor；Induction The compound of cell differentiation procedure；Cyclooxygenase-2 inhibitors；MMP inhibitor；MTOR inhibitors；Antitumor antimetabolite；Platinum Close object；The compound of the compound and other anti-angiogenesis of targeting/reduction albumen or lipid kinase activity；Targeting, reduce or Inhibit the compound of albumen or lipid phosphate esterase active；Gonadorelin excitomotor；Antiandrogen；Methionine aminopeptidase inhibits Agent；Diphosphonate；Biological response modifiers；Antiproliferation antibodies；Heparanase inhibitors；The carcinogenic hypotype inhibitor of Ras；Telomere Enzyme inhibitor；Proteasome inhibitor；Treat the medicament of neoplastic hematologic disorder；Targeting reduces or inhibits the active compounds of Flt-3； Hsp90 inhibitor；TemozolomideAnd Calciumlevofolinate.
Term used herein " aromatase inhibitor " refers to the compound inhibited estrogen production, that is, inhibits substrate male Alkene diketone and testosterone are converted to the compound of oestrone and estradiol respectively.The term includes, but are not limited to：Steroid, especially It is atamestane (atamestane), Exemestane (exemestane) and formestane (formestane)；And especially Non-steroids, especially aminoglutethimide (aminoglutethimide), Rogletimide (roglethimide), pyrrole Rumi Special (pyridoglutethimide), Trilostane (trilostane), Testolactone (testolactone), ketoconazole (ketoconazole), fluorine chlorazol (vorozole), Fadrozole (fadrozole), Anastrozole (anastrozole) and come it is bent Azoles (letrozole).Exemestane can be with commercially available, as trade mark isForm administration.Fu Mei Smooth (formestane) can be with commercially available, as trade mark isForm administration.Fadrozole It (fadrozole) can be with commercially available, as trade mark isForm administration.Anastrozole (anastrozole) can be with It is commercially available, as trade mark is Form administration.Letrozole (letrozole) can be with commercially available, such as Trade mark isOrForm administration.Aminoglutethimide (aminoglutethimide) can be with city It sells, as trade mark isForm administration.The present invention includes the combination of aromatase inhibitor chemotherapeutic It is particularly useful for the treatment of the tumour that hormone receptor is positive, such as tumor of breast.
Term used herein " antiestrogenic " refers to the compound in Estrogen Receptor antagonising oestrogen effectiveness. The term includes, but are not limited to tamoxifen (tamoxifen), fulvestrant (fulvestrant), Raloxifene (raloxifene) and raloxifene hydrochloride (raloxifene hydrochloride).Tamoxifen (tamoxifen) can With with commercially available, as trade mark isForm administration.Raloxifene hydrochloride (raloxifene It hydrochloride) can be with commercially available, as trade mark isForm administration.Fulvestrant It (fulvestrant) can be with dosage form disclosed in United States Patent (USP) US 4,659,516 or commercially available, as trade mark isForm administration.The present invention includes that the combination of antiestrogenic chemotherapeutic is particularly useful for the treatment of estrogen receptor in sun The tumour of property, such as tumor of breast.
Term used herein " antiandrogen " refers to any substance that can inhibit male sex hormone biological action, it is wrapped It includes, but is not limited to, Bicalutamide (bicalutamide, trade name), dosage form can be according to United States Patent (USP) US 4,636,505 prepare.
Term used herein " Gonadorelin excitomotor " includes, but are not limited to abarelix (abarelix), Ge She Rayleigh (goserelin) and goserelin acetate.Goserelin is disclosed in United States Patent (USP) US 4,100,274, can be with city It sells, as trade mark is Form administration.Abarelix (abarelix) can be according to United States Patent (USP) Method disclosed in US 5,843,901 prepares dosage form.
Term used herein " topoisomerase I inhibitor " includes, but are not limited to topotecan (topotecan), Ji Horse is for health (gimatecan), Irinotecan (irinotecan), camptothecine (camptothecian) and the like, 9- nitros Camptothecine (9-nitrocamptothecin) and macromolecular camptothecin conjugated compound PNU-166148 are (in WO 99/17804 Compound A1).Irinotecan can be with commercially available, as trade mark isForm administration.Topology is replaced Health can be with commercially available, as trade mark isForm administration.
Term used herein " Topoisomerase II inhibitors " includes, but are not limited to anthracycline compound, such as how soft ratio Star (doxorubicin), its Lipidosome, trade nameDaunomycin (daunorubicin)； Epirubicin (epirubicin)；Idarubicin (idarubicin)；The not soft pyrrole star (nemorubicin) of naphthalene；Anthraquinones rice support Anthraquinone (mitoxantrone) and Losoxantrone (losoxantrone)；It podophillotoxines etoposide (etoposide) and replaces Buddhist nun moors glycosides (teniposide).Etoposide can be with commercially available, as trade mark isForm give Medicine.Teniposide can be with commercially available, if trade mark is VM 26-Form administration.Doxorubicin can be with commercially available , as trade mark isOr Form administration.Table It is soft can be with commercially available, as trade mark is than starForm administration.Idarubicin can be with It is commercially available, as trade mark isForm administration.Mitoxantrone can be with commercially available, as trade mark isForm administration.
Term " microtubule active agent " refers to microtubule stabilizer, microwave destabiliser and microtubule polymerization inhibitor.It includes, but not It is limited to taxanes, such as taxol (paclitaxel) and Docetaxel (docetaxel)；Vinca alkaloids, such as Changchun Alkali (vinblastine), especially vinblastine sulfate, vincristine, especially vincristine sulphate and vinorelbine (vinorelbine)；discodermolides；Colchicin；And Epothilones and its derivative, such as epothilone B or D Or derivatives thereof.Taxol can be with commercially available, as trade mark isForm administration.Docetaxel can be with With commercially available, as trade mark isForm administration.Vinblastine sulfate can be with commercially available, such as trade mark For VINBLASTINForm administration.Vincristine sulphate can be with commercially available, as trade mark isForm Administration.Discodermolide can be obtained according to method disclosed in United States Patent (USP) US 5,010,099.Further include in WO 98/10121, United States Patent (USP) 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653,98/22461 and of WO Epothilones analog derivative disclosed in WO 00/31247, particularly preferred ebomycin A and/or B.
Term used herein " alkylating agent " includes, but are not limited to cyclophosphamide (cyclophosphamide), different ring phosphorus Amide (ifosfamide), melphalan (melphalan) or Nitrosourea (nitrosourea, such as BCNU or carmustine).Ring phosphinylidyne Amine can be with commercially available, as trade mark is Form administration.Ifosfamide can with commercially available, As trade mark isForm administration.
Term " histon deacetylase (HDAC) inhibitor " or " hdac inhibitor " they refer to inhibition of histone deacetylase, and Compound with antiproliferative activity.It is included in compound disclosed in WO 02/22577, especially N- hydroxyls -3- [4- [[(2- ethoxys) [2- (1H- indol-3-yls) ethyl]-amino] methyl] phenyl] -2E-2- acrylamides, N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- bases)-ethyl]-amino] methyl] phenyl] it -2E-2- acrylamides and its can pharmaceutically connect The salt received.It especially include Vorinostat (SAHA).
Term " antitumor antimetabolite " includes, but are not limited to 5-fluor-uracil (5-fluorouracil) or 5-FU； Capecitabine (capecitabine)；Gemcitabine (gemcitabine)；DNA demethylation reagents, such as U-18496 (5- ) and Decitabine (decitabine) azacytidine；Methotrexate (MTX) (methotrexate) and Edatrexate (edatrexate)；And antifol, such as pemetrexed (pemetrexed).Capecitabine can be with commercially available, such as trade mark ForForm administration.Gemcitabine can be with commercially available, as trade mark is 's Form is administered.This term further includes monoclonal antibody Herceptin (trastuzumab), can be with commercially available, as trade mark isForm administration.
Term used herein " platinum compounds " includes, but are not limited to carboplatin (carboplatin), cDDP (cis- Platin), cis-platinum (cisplatinum) and oxaliplatin (oxaliplatin).Carboplatin can be with commercially available, as trade mark isForm administration.Oxaliplatin can be with commercially available, as trade mark isForm Administration.
Term used herein " targeting/reduction albumen or lipid kinase activity or albumen or lipid phosphatase activeization Close the compound of object or other anti-angiogenesis " include, but are not limited to protein tyrosine kinase and/or serine and/or Threonine inhibitor or lipid kinase inhibitors, such as
A) it targets, reduces or inhibit platelet derived growth factor receptor (PDGFR) active compound；Targeting reduces Or inhibit the active compounds of PDGFR, it includes N- phenyl-2-pyrimidine-amine derivatives especially to inhibit the compound of pdgf receptor, Such as Imatinib (imatinib), SU101, SU6668, GFB-111 etc.；
B) target, reduce or inhibit fibroblast growth factor acceptor (FGFR) active compound；
C) target, reduce or inhibit insulin-like growth factor receptor -1 (IGF-1R) active compound；Targeting reduces Or inhibit the active compounds of IGF-1R, it includes those in patent WO 02/ especially to inhibit the compound of IGF-1 receptor actives Compound disclosed in 092599；
D) targeting, reduction or the compound for inhibiting Trk receptor tyrosine kinase family actives；
E) targeting, reduction or the compound for inhibiting Axl Receptor Tyrosine Kinase family active；
F) targeting, reduction or the compound for inhibiting c-Met receptor actives；
G) targeting, reduction or the compound for inhibiting Kit/SCFR receptor tyrosine kinase activities；
H) target, reduce or inhibit C-kit receptor tyrosine kinases (part in PDGFR families) active chemical combination Object；Targeting, the compound for reducing or inhibiting C-kit receptor tyrosine kinase family actives, especially inhibit the change of c-Kit receptors Close object, including Imatinib (imatinib) etc.；
I) it targets, reduce or inhibit c-Abl families and their gene fusion products, such as the change of BCR-Abl kinase activities Close object；Targeting, reduction or the compound of inhibition c-Abl family members and their Gene Fusion objects include N- phenyl -2- pyrimidines - Amine derivative, such as Imatinib, PD180970, AG957, NSC 680410, from the PD173955 of ParkeDavis
J) it targets, Raf family members in reduction or inhibition protein kinase C (PKC) and serine/threonine kinases, MEK, SRC, JAK, FAK, PDK and Ras/MAPK family member, Pl (3) kinase families member or Pl (3) kinases associated kinase family at The compound of member and/or cell cycle protein dependent kinase family (CDK) member activity；Especially those are in United States Patent (USP) Staurosporine derivatives disclosed in US 5,093,330, such as midostaurin (midostaurin)；More examples of compounds Further include UCN-01；Safingol (safingol)；BAY 43-9006；Bryostatin 1；Piperazine Li Fuxin (Perifosine)；She Mo Fuxin (llmofosine)；RO 318220 and RO 320432；GO 6976；Isis 3521；LY333531/LY379196； Isoquinoline compound, such as in WO 00/09495 those disclosed；FTIs；PD184352；Or a kind of QAN697 (P13K suppressions Preparation)；
K) target, reduce or inhibit the active compound of protein tyrosine kinase inhibitor；Targeting reduces or inhibits The active compound of protein tyrosine kinase inhibitor includes GleevecOr tyrosine phosphorylation Inhibitor；Preferred low molecular weight (the Mr of tyrphostin<1500) compound or its pharmaceutically acceptable salt, especially It is selected from the compound of the third two eyeball class of two eyeball class of benzyl allyl or S- aryl sheet or Double bottom object quinolines, is further selected from tyrosine Phosphorylation inhibitor A23/RG-50810, AG 99, tyrphostin AG213, tyrphostin AG 1748, tyrphostin AG 490, tyrphostin B44, tyrphostin B44 (+) Enantiomer, tyrphostin AG 555, AG 494, tyrphostin AG 556, AG957 and Adaphostin (4- { [(2,5- dihydroxy phenyls) methyl] amino }-benzoic acid Buddha's warrior attendant alkyl ester, NSC 680410, adaphostin)；With
I) target, reduce or inhibit receptor tyrosine kinase epidermal growth factor receptor family (EGFR, ErbB2, The equal or heterodimer of ErbB3, ErbB4) active compound；Targeting reduces or inhibits Epidermal Growth Factor Receptor Family Compound refer in particular to inhibit EGF receptor family member (such as EGF receptor, ErbB2, ErbB3, ErbB4, or can with EGF or The substance that EGF associated ligands combine) compound, albumen or antibody, is especially summarized in the following documents or it is specific openly Compound, albumen or monoclonal antibody：WO 97/02266 (such as embodiment 39), EP 0 564 409, WO 99/03854, EP 0520722、EP 0 566 226、EP 0 787 722、EP 0 837 063、US 5,747,498、WO 98/10767、WO 97/30034, WO 97/49688 and WO 97/38983, WO 96/30347 (such as CP 358774), WO96/33980 (such as chemical combination Object ZD 1839), WO 95/03283 (such as compound ZM105180), Herceptin (Trastuzumab), Cetuximab, Yi Rui Sand, Erlotinib, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, E7.6.3, and 7H- pyrrolo-es-[2,3-d] pyrimidine derivatives for being disclosed in WO 03/013541.
In addition, anti-angiogenic compounds include having other active mechanisms (for example, inhibiting not with albumen or lipid kinase It is related) compound, such as ThalidomideAnd TNP-470.
Targeting, reduction or the compound of inhibition albumen or lipid kinase activity are -1 inhibitor of phosphatase, phosphatase 2A suppressions Preparation, PTEN inhibitor or CDC25 inhibitor, such as okadaic acid or derivatives thereof.
The compound of Cell differentiation inducing activity process is vitamin A acid, α-, γ-or Delta-Tocopherol, α-, γ-or δ-fertility triolefin Phenol.
Term used herein " cyclooxygenase-2 inhibitors " includes, but are not limited to Cox-2 inhibitor, and 5- is alkyl-substituted 2- fragrant aminos phenylacetic acid and its derivative, such as celecoxibRofecoxibEtoricoxib is cut down Former times or 5- alkyl -2- fragrant amino phenylacetic acids are examined in ground, such as 5- methyl -2- (the chloro- 6'- fluoroanilinos of 2'-) phenylacetic acids or reed rice Examine former times
Term used herein " diphosphonate " includes, but are not limited to Etidronic Acid, Clodronate, Tiludronic Acid, pa rice phosphine Acid, alendronic acid, ibandronic acid, Risedronic Acid and zoledronic acid.Etidronic Acid can be with commercially available, such as trade nameForm administration.Clodronate can be with commercially available, such as trade nameForm Administration.Tiludronic Acid can be with commercially available, such as trade nameForm administration；Pamidronic acid (Pamidronic acid) It can be with commercially available, such as trade name ArediaTM(AREDIATM) form administration；Alendronic acid can be with commercially available, such as trade name ForForm administration；Ibandronic acid can be with commercially available, such as trade name Form administration；Risedronic Acid can be with commercially available, such as trade name Form administration；Azoles carrys out phosphine Acid can be with commercially available, such as trade nameForm administration.
Term " mTOR inhibitors " refers to inhibiting mammal rapamycin (mTOR) target protein, with antiproliferative activity Compound, such as sirolimus (sirolimus,), everolimus (CERTICANTM), CCI-779 and ABT578。
Term used herein " heparanase inhibitors " refers to targeting, reduce or inhibiting acetylsulfuric acid depolymerized heparin Compound.This term includes, but unlimited PI-88.
Term used herein " biological response modifiers " refers to lymphokine or interferon, such as interferon gamma.
Term used herein " the carcinogenic hypotypes of Ras (such as H-Ras, K-Ras or N-Ras) inhibitor " refers to targeting, reduces Or inhibit the compound of Ras carcinogenic activities, such as " farnesyl transferase inhibitor ", such as L-744832, DK8G557 or R115777(Zarnestra)。
Term used herein " telomerase inhibitor " refers to the compound targeted, lowered or inhibited telomerase activity.Target To, the compound that reduces or the compound of telomerase activation is inhibited to refer in particular to inhibit telornerase receptor, such as telomere mycin.
Term used herein " methionine aminopeptidase inhibitor " refers to targeting, reduces or inhibit methionine aminopeptidase activity Compound.Targeting, reduction or the inhibition active compound of methionine aminopeptidase include bengamide or derivatives thereof.
Term used herein " proteasome inhibitor " refers to targeting, reduction or the active chemical combination of protease inhibition body Object.Targeting, reduction or the active compound of protease inhibition body include PS-341 and MLN 341.
Term used herein " Matrix Metalloproteinase Inhibitors " or " MMP inhibitor " include, but are not limited to glue Former albumen peptides and non-peptide inhibitor, tetracycline derivant, such as hydroxamic acid peptide inhibitor Batimastat (batimastat) With its equivalent homologue Marimastat (marimastat, BB-2516) of oral bio, prinomastat (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996。
Term used herein includes, but are not limited to FMS- sample tyrosine kinase " for treating the reagent of neoplastic hematologic disorder " Inhibitor.Targeting reduces or inhibits FMS- samples tyrosine kinase receptor (Flt-3R) active compound；Interferon, 1-b-D- Arabinofuranosyl adenin cytimidine (ara-c) and bisulfan；With ALK inhibitor, such as targeting reduces or inhibits anaplastic lymphoma kinase Compound.
Targeting, reduce or inhibit FMS- samples tyrosine kinase receptor (Flt-3R) compound especially inhibit Flt-3 by The compound of body kinase families member, albumen or antibody, such as PKC412, midostaurin (midostaurin), staurosporin Derivative, SU11248 and MLN518.
Term used herein " antiproliferation antibodies " includes, but are not limited to Herceptin (HERCEPTINTM), toltrazuril Monoclonal antibody-DM1, Tarceva (TARCEVATM), bevacizumab (AVASTINTM), Rituximab PR064553 (anti-CD40) and 2C4 antibody.Antibody means complete monoclonal antibody, polyclonal antibody, complete by least two The multi-specificity antibody and antibody fragment (as long as they have desired bioactivity) that whole antibody is formed.It is thin for acute marrow For the treatment of born of the same parents' sample leukaemia (AML), the leukemia therapy of disclosed compound of present invention and standard can be used in combination, especially It is used in combination with the therapy treated for AML.Specifically, disclosed compound of present invention and such as farnesyl- can be turned It moves enzyme inhibitor and/or other is used for drug such as daunorubicin, adriamycin, Ara-C, VP-16, Teniposide, rice that AML is treated Hold in the palm anthraquinone, idarubicin, carboplatin and PKC412 administering drug combinations.
Compound disclosed by the invention can also be advantageously utilised in combination with other compounds or with other therapeutic agents In combination, especially other anti-malarial agents.Such anti-malarial agents include, but are not limited to chloroguanide (proguanil), Chlorproguanil (chlorproguanil), trimethoprim (trimethoprim), chloroquine (chloroquine), Mefloquine (mefloquine), Lumefantrine (lumefantrine), Atovaquone (atovaquone), pyrimethamine-sulfanilamide (SN) (pyrimethamine- Sulfadoxine), pyrimethamine-chlorobenzene (pyrimethamine-dapsone), halofantrine (halofantrine), quinine (quinine), quinindium (quinidine), amodiaquine (amodiaquine), amopyroquine (amopyroquine), sulfanilamide (SN) Class drug, qinghaosu, Arteflene (arteflene), Artemether, Artesunate, primaquine, sucking NO, L-arginine, dipropyl Alkene triamine NONO esters (NO donor), Rosiglitazone (PPARy agonists), activated carbon, hematopoietin, levamisol, And Malaridine.
Compound above-described, being applied in combination with disclosed compound of present invention, can be by people in the art Member prepares and is administered according to above-mentioned method recorded in the literature.
Compound disclosed by the invention can also combine with therapeutic process, improve curative effect.For example, give hormone therapy or Special radiotherapy.Compound disclosed by the invention is used especially as radiosensitizer, it is especially useful in those radiotherapies The oncotherapy of sensibility weak ground.
" joint " indicates the fixing joint in single dose unit form or the medicine box of the part for administering drug combinations, In compound disclosed by the invention and joint companion can be in same time individual application or can be in certain time interval It inside applies respectively, joint companion is especially made to show cooperation, for example act synergistically.Term " co-administered " as used herein Or " administering drug combinations " etc. are intended to include to be applied to selected joint companion and need its single individual (such as patient), and anticipate It is intended to include wherein substance without going through identical administration route or the therapeutic scheme being administered simultaneously.Term " drug as used herein Joint " indicates that more than one active constituents are mixed to or combined obtained product, and had both included the fixed connection of active constituent Close also includes that on-fixed is combined.Term " fixing joint " indicates active constituent compound for example disclosed by the invention, and joint companion It is administered simultaneously in patient in the form of single entities or dosage.Term " on-fixed joint " indicates that the active constituent such as present invention discloses Compound Compound, and joint companion be used as corpus separatum simultaneously, it is common or limit ground successively to patient without specific time Administration, wherein the administering mode provides the treatment effective level of two kinds of compounds in patient's body.The latter applies also for chicken tail Wine therapy, such as using three or more active constituents.
Therapy
In one embodiment, therapy disclosed by the invention includes giving safe and effective amount to patient in need The compounds of this invention or pharmaceutical composition comprising the compounds of this invention.Each embodiment disclosed by the invention includes by having The patient needed gives the disclosed compound of present invention of safe and effective amount or the pharmaceutical composition comprising disclosed compound of present invention, Method to treat disease mentioned above.
In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with It is administered by any suitable administration route, including Formulations for systemic administration and local administration.Formulations for systemic administration includes oral medication, stomach and intestine External administration, cutaneous penetration and rectally.Typical parenteral refer to by injection or administered by infusion, including it is intravenous, Intramuscular and hypodermic injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, sucking and intranasal Administration.In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with It is oral medication.In another embodiment, disclosed compound of present invention or the pharmaceutical composition comprising disclosed compound of present invention Object can be inhalation.In a further embodiment, disclosed compound of present invention or comprising disclosed compound of present invention can be Intranasal administration.
In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with Once daily, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.For example, every It is administered once, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, daily It is administered twice.It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.It is of the invention public Open medicine generation of the appropriate dosage regimen of compound or the pharmaceutical composition comprising disclosed compound of present invention depending on the compound Kinetic property, such as dilution, distribution and half-life period, these can be by determination of technical staff.In addition, disclosed compound of present invention Or the appropriate dosage regimen of the pharmaceutical composition comprising disclosed compound of present invention, including implement the duration of the program, it takes Certainly in treated disease, the severity of disease being treated, the age of patient under consideration and physical condition, patient under consideration The factor within the scope of technical staff's knowledge and experience such as the property of medical history while therapy, desired therapeutic effect.It is such Technical staff should also be understood that the reaction to dosage regimen for individual patient, or individual patient needs to become as time goes by When change it may require that adjust the dosage regimen of matters.
Disclosed compound of present invention can simultaneously, or before it or later be administered with one or more other therapeutic agents. The compounds of this invention can be respectively administered with other therapeutic agents by identical or different administration route, or therewith with with medicine group Solvate form is administered.
For the individual of about 50-70kg, the present invention pharmaceutical composition disclosed and combination can be containing about 1-1000mg, Or the unit dose of about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg active constituents Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination be depending on individual species, weight, the age and Individual instances, treated disease (disorder) or disease (disease) or its severity.Has the doctor of common technical ability Teacher, clinician or animal doctor can be easy to determine to prevent, treat or inhibit disease (disorder) or disease (disease) development The effective quantity of each active constituent needed in the process.
Dose Characteristics cited above using advantageous mammal (such as mouse, rat, dog, monkey) or its from It is confirmed in the external and in vivo studies of body organ, tissue and sample.Disclosed compound of present invention is with solution, such as aqueous solution form Use in vitro, can also such as enteral of suspension or aqueous solution form in vivo, it is parenteral, it is especially intravenous to use.
In one embodiment, the treatment effective dose of disclosed compound of present invention is daily about 0.1mg to about 2, 000mg.Its pharmaceutical composition should provide about 0.1mg to the compound of about 2,000mg dosage.In a particular embodiment In, the pharmaceutical dosage unit forms of preparation can provide about 1mg to about 2,000mg, and about 10mg to about 1,000mg, about 20mg is to about The combination of each main component in 500mg, or the main active of about 25mg to about 250mg or every dosage unit form.One In particular embodiment, the pharmaceutical dosage unit forms of preparation can provide about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg main active.
In addition, compound disclosed by the invention can be administered with prodrug forms.In the present invention, disclosed compound of present invention " prodrug " be that can finally release the functional derivatives of disclosed compound of present invention in vivo when administering to a patient.In the past When medicine form gives compound disclosed by the invention, those skilled in the art can implement one kind or more in following manner：(a) Change the internal onset time of compound；(b) the internal acting duration of compound is changed；(c) change compound is internal Conveying or distribution；(d) the internal solubility of compound is changed；And the side effect for (e) overcoming compound to be faced or other difficult points. The typical functional derivatives of prodrug are used to prepare, including in vivo chemically or the mode of the enzyme compound that cracks Variant.Including preparing these variants of phosphate, amide, ester, monothioester, carbonate and carbaminate to people in the art It is well-known for member.
General synthesis step
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only The method that the practice present invention is provided.
Usually, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment is for being further illustrated this The content of invention.
The professional of fields will be recognized that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods for the preparation of the compounds of the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention It is completed by method of modifying, such as protection interference group appropriate, by using other known reagent in addition to 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 suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1HNMR spectrums are recorded using Bruker 300MHz, 400MHz or 600MHz nuclear magnetic resonance spectrometers.1H H NMR spectroscopies with CDC13、DMSO-d6、CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as Reference standard.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), T (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), brs (broadened Singlet, width unimodal), dd (doublet of doublets, double doublet), dt (doublet of triplets, double three Weight peak).Coupling constant is indicated with hertz (Hz).
The determination condition of Algorithm (MS) data is：6120 level four bars HPLC-M (column models of Agilent： Zorbax SB-C18,2.1 × 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase：5%-95% (contains 0.1% The CH of formic acid3CN) (containing the H of 0.1% formic acid2O the ratio in)), using electron spray ionisation (ESI), at 210nm/254nm, It is detected with UV.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar types Number：NOVASEP 50/80mm DAC), it is detected with UV in 210nm/254nm.
The use of brief word below is through the present invention：
AcOH、HOAc、CH3COOH acetic acid
ACN,MeCN,CH3CN acetonitriles
Boc2O di-tert-butyl dicarbonates
BOC, Boc tert-butoxycarbonyl
The double diphenyl phosphines of BINAP 1,1'- dinaphthalenes -2,2'-
Bu4NBr tetrabutylammonium bromide
N-BuOH n-butanols
Cbz-Cl benzyl chloroformates
CH2Cl2, DCM dichloromethane
CDC13Deuterochloroform
Cs2CO3Cesium carbonate
DIEA、DIPEA、i-Pr2NEt diisopropyl ethyl amines
DMF dimethylformamides
DMAP 4-dimethylaminopyridine
DMSO dimethyl sulfoxide (DMSO)s
EDC, EDCI 1- (3- dimethylamino-propyls) -3- ethyl-carboddiimide hydrochlorides
EDTA ethylenediamine tetra-acetic acids
Et3N, TEA triethylamines
EtOAc, EA ethyl acetate
G grams
H hours
HATU 2- (7- azepine -1H- benzotriazole -1- bases) -1,1,3,3- tetramethylurea hexafluorophosphoric acid esters
HCl hydrochloric acid
HOAT 1- hydroxyl -7- azepine benzotriazole
K2CO3Potassium carbonate
LDA lithium diisopropyl amidos
ML, ml milliliters
Min minutes
MCPBA metachloroperbenzoic acids
MTBE methyl tertiary butyl ether(MTBE)s
NaHCO3Sodium bicarbonate
NH4Cl ammonium chlorides
M mol/L
Na2CO3Sodium carbonate
Na2SO4Sodium sulphate
NaOH sodium hydroxides
NaH sodium hydrides
Na2S2O3Sodium thiosulfate
T-BuONa sodium tert-butoxides
Pd/C palladiums/carbon
Pd(OH)2Palladium dydroxide
Pd(OAc)2Palladium
Pd2(dba)3Three (dibenzylidene indenes acetone) two palladiums
Pd(dppf)2Cl2[bis- (diphenyl is seen) ferrocene of 1,1'-] palladium chloride
PE petroleum ethers (60~90 DEG C)
RT, rt, r.t. room temperature
Rt retention times
TsCl paratoluensulfonyl chlorides
TFA trifluoroacetic acids
THF tetrahydrofurans
The typical synthesis step of disclosed compound of present invention is prepared as shown in following synthetic schemes 1~5.Unless in addition saying It is bright, each Z, Z1、R1、R2、R3And R4With definition as described in the present invention；PG1And PG2It is blocking group；P is 0,1,2 or 3；Q is 0,1,2,3 or 4；D is 0,1,2,3 or 4.
Synthetic schemes 1：
With such as formula(9)Or formula(10)The compounds of this invention of shown structure can be described general by synthetic schemes 1 Synthetic method is prepared, and specific steps can refer to embodiment.In synthetic schemes 1, under alkaline condition, to substituted heteroaryl Compound(1)One blocking group of middle introducing, obtains compound(2).Compound(2)Iodine is obtained by the reaction with LDA and iodine to take The compound in generation(3).Compound(3)With the boron ester derivant of the pyrazoles that optionally replaces (4) in suitable alkali (such as cesium carbonate, carbon Sour potassium, sodium carbonate etc.), and suitable Pd catalyst (such as Pd (OAc)2、Pd(dppf)2Cl2Or Pd2(dba)3Deng) effect Under, occur coupling reaction obtain compound (5).Compound (5) with the heterocyclic compound that optionally replaces(6)Alkali (such as triethylamine, Diisopropyl ethyl amine), alternatively, in suitable alkali (such as cesium carbonate, potassium carbonate, sodium carbonate etc.) and Pd catalyst (such as Pd (OAc)2、Pd(dppf)2Cl2Or Pd2(dba)3Deng) under the action of reaction generate compound(7).Compound(7)First in alkali, such as In the presence of (sodium hydroxide etc.), then at acid condition (ethyl acetate solution of such as trifluoroacetic acid or hydrogen chloride), successively Two blocking groups are removed, kinase inhibitor is obtained(9).Under suitable conditions to compound(9)The middle suitable substitution of introducing Another kinase inhibitor also can be obtained in base(10)。
Synthetic schemes 2:
With such as formula(7)The general synthesis side that the midbody compound of shown structure can also be described by synthetic schemes 2 Method is prepared, and specific steps can refer to embodiment.In synthetic schemes 2, substituted heteroaryl compound (11) by suitable oxygen Agent be oxidized to compound (12), then oxide (12) with tetrabutylammonium bromide be obtained by the reaction bromide (13).In alkaline item Under part, to bromide (13) in introduce a blocking group obtain compound(14), compound(14)With LDA and simple substance Iod R Obtain the compound of iodine substitution(15).Compound(15)With the boron ester derivant of the pyrazoles that optionally replaces (4) in alkali (such as carbonic acid Caesium, potassium carbonate, sodium carbonate etc.), and suitable Pd catalyst (such as Pd (OAc)2、Pd(dppf)2Cl2Or Pd2(dba)3Deng) Under effect, occur coupling reaction obtain compound (16).Compound (16) with the heterocyclic compound that optionally replaces(6)In alkali, such as Triethylamine, diisopropyl ethyl amine, alternatively, being catalyzed at alkali (such as cesium carbonate, potassium carbonate, sodium carbonate etc.), and in suitable Pd Agent (such as Pd (OAc)2、Pd(dppf)2Cl2Or Pd2(dba)3Deng) under the action of reaction generate midbody compound(7)。
Synthetic schemes 3
With such as formula (21) or formula (22) shown in structure the compounds of this invention can be described by synthetic schemes 3 it is general Synthetic method is prepared, and specific steps can refer to embodiment.In synthetic schemes 3, compound (17) with the heterocycle that optionally replaces Compound (6) under the action of alkali (such as triethylamine, diisopropyl ethyl amine) reaction generate compound (18), compound (18) With compound (19) in reducing agent (such as Na2S2O4Deng) effect under and polar solvent (such as EtOH) in compound is obtained by the reaction (20), then at acid condition (ethyl acetate solution of such as trifluoroacetic acid or hydrogen chloride), removing compound (20) protection Group, obtain kinases inhibitor (21).Under suitable conditions to compound(21)The middle suitable substituent group of introducing may be used also Obtain another kinase inhibitor(22)。
Synthetic schemes 4
With such as formula (26) or formula (27) shown in the disclosed compound of present invention of structure can be described by synthetic schemes 4 General synthetic method is prepared, and specific steps can refer to embodiment.In synthetic schemes 4, compound (23) and optionally replace Heterocyclic compound (6) under the action of alkali (such as triethylamine or diisopropyl ethyl amine) reaction generate compound (24), chemical combination Object(24)With the boron ester derivant of the pyrazoles that optionally replaces (4) at suitable alkali (such as cesium carbonate, potassium carbonate or sodium carbonate), with And suitable Pd catalyst (such as Pd (OAc)2、Pd(dppf)2Cl2Or Pd2(dba)3Deng) under the action of, coupling reaction occurs and obtains Compound (25), then at acid condition (ethyl acetate solution of such as trifluoroacetic acid or hydrogen chloride), removing compound (25) Blocking group, obtain kinases inhibitor (26).Under suitable conditions to compound(26)The middle suitable substitution of introducing Another kinases inhibitor also can be obtained in base(27)。
Synthetic schemes 5
With such as formula (31) or formula (32) shown in the disclosed compound of present invention of structure can be described by synthetic schemes 5 General synthetic method is prepared, and specific steps can refer to embodiment.In synthetic schemes 5, compound (16) and optionally replace Heterocyclic compound(28)At alkali (such as cesium carbonate, potassium carbonate, sodium carbonate etc.), and suitable Pd catalyst (such as Pd (OAc)2、Pd (dppf)2Cl2Or Pd2(dba)3) under the action of reaction generate midbody compound(29), compound(29)First in alkali (such as hydrogen-oxygen Change sodium etc.) in the presence of, then at acid condition (ethyl acetate solution of such as trifluoroacetic acid or hydrogen chloride), two are removed successively A blocking group, obtain kinases inhibitor (31).Under suitable conditions to compound(31)It is middle to introduce suitably Another kinases inhibitor also can be obtained in substituent group(32)。
Embodiment
1 4- of embodiment (3- azaspiros [5.5] hendecane -9- bases amino) -2- (1- methyl-1 H- pyrazoles -4- bases) -1H- Pyrrolo- [2,3-b] pyridine -5- formamides
Step 1) 4- chloro- 1- (triisopropylsilyl) -1H- pyrrolo-es [2,3-b] pyridine
At 0 DEG C, to the four of sodium hydride (60% [w/w] mass fraction, be suspended in mineral oil, 2.68g, 67.0mmol) In hydrogen furans (60mL) suspension, the tetrahydrofuran of chloro- 1H- pyrrolo-es [2, the 3-b] pyridines (8.24g, 54.0mmol) of 4- is added dropwise (80mL) solution.After reaction is stirred at room temperature 30 minutes in gained reaction mixture, then by three (isopropyl) chlorosilanes (12.73g, 66.0mmol) is added in above-mentioned system.Reaction system stirs 5 hours at room temperature, is then concentrated under reduced pressure.Gained remains Object is purified through silica gel column chromatography (100%PE), and it is colorless oil (16.68g, yield 100%) to obtain title compound.
MS(ESI,pos.ion)m/z:309.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.16 (d, J=5.1Hz, 1H), 7.35 (d, J=3.5Hz, 1H), 7.08 (d, J=5.1Hz, 1H), 6.68 (d, J=3.5Hz, 1H), 1.88 (dq, J=15.0,7.5Hz, 3H), 1.14 (d, J= 7.6Hz,18H)。
Step 2) 4- chloro- 1- (triisopropylsilyl) -1H- pyrrolo-es [2,3-b] pyridine -5- formamides
At -78 DEG C, to 4- chloro- 1- (triisopropylsilyl) -1H- pyrrolo-es [2,3-b] pyridine (17.55g, Be added dropwise in tetrahydrofuran (120mL) solution 56.81mmol) s-butyl lithium tetrahydrofuran solution (1.3M, 70mL, 91.0mmol).The reaction was continued at -78 DEG C 1 hour for reaction system, then by trimethyl silicane based isocyanate (10.15g, 83.69mmol) it is added in above-mentioned reaction system.After adding, reaction mixture is stirred at room temperature 3.5 hours, then on the rocks Reaction is quenched in acetic acid (11.92g, 198.5mmol) and water (150mL), then ethyl acetate (100mL × 3) is used to extract.Merge Organic phase is washed through saturated salt solution (100mL), and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Gained residue is through silica gel Column chromatography (EtOAc/PE (v/v)=1/8) purifies, and it is white solid (13.43g, yield 67.2%) to obtain title compound.
MS(ESI,pos.ion)m/z:352.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.75 (s, 1H), 7.41 (d, J=3.5Hz, 1H), 6.75 (d, J= 3.5Hz, 1H), 6.52 (br.s, 1H), 5.93 (br.s, 1H), 1.86 (dq, J=15.0,7.5Hz, 3H), 1.13 (d, J= 7.5Hz,18H)。
Chloro- 1H- pyrrolo-es [2,3-b] pyridine -5- formamides of step 3) 4-
To 4- chloro- 1- (triisopropylsilyl) -1H- pyrrolo-es [2,3-b] pyridine -5- formamides (16.53g, Be added dropwise in tetrahydrofuran (100mL) solution 46.96mmol) tetrabutyl ammonium fluoride tetrahydrofuran solution (150mL, 1M, 150mmol).Reaction system is stirred at room temperature 2 hours, and then plus reaction is quenched in water (100mL), and dichloromethane (200mL is used in combination × 9) it extracts.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure into solvent volume residue about 100mL, so After filter.Filter cake is washed with dichloromethane (30mL × 3), filtrate decompression concentration.Gained residue is through silica gel column chromatography (MeOH/ DCM (v/v)=1/100) purifying, obtain white solid, this solid with before filtering obtained by filter cake merge title compound is White solid (7.77g, yield 84.6%)
MS(ESI,pos.ion)m/z:196.0[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):12.09(br.s,1H),8.29(s,1H),7.89(s,1H),7.65 (d, J=3.4Hz, 1H), 7.61 (s, 1H), 6.56 (d, J=3.4Hz, 1H).
Chloro- 1- p-toluenesulfonyls -1H- pyrrolo-es [2,3-b] pyridine -5- formamides of step 4) 4-
At 0 DEG C, to the tetrahydrochysene furan of chloro- 1H- pyrrolo-es [2, the 3-b] pyridine -5- formamides (7.27g, 37.2mmol) of 4- Mutter be added portionwise in (150mL) solution sodium hydride (60% [w/w] mass fraction is suspended in mineral oil, 1.67g, 41.8mmol).After adding, reaction system maintains 0 DEG C to continue stirring 1 hour.By 4- toluene sulfonyl chlorides (7.48g, 39.2mmol) it is added by several times in above-mentioned reaction system.Gained reaction system is stirred at room temperature 1 hour, then adds water (100mL) Reaction is quenched, dichloromethane (250mL × 3) is used in combination to extract.Combined organic phase is washed through saturated salt solution (250mL), anhydrous Sodium sulphate is dried, filtering, and is concentrated under reduced pressure into solvent volume residue about 100mL, is then filtered.Filter cake is with dichloromethane (90mL) Washing, filtrate decompression concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=10/1), obtains white solid, This solid merges with the filter cake of filtering gained before, and it is white solid (12.52g, yield 96.3%) to obtain title compound
MS(ESI,pos.ion)m/z:350.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.41 (s, 1H), 8.09 (d, J=4.0Hz, 1H), 8.01 (d, J= 8.2Hz, 3H), 7.79 (s, 1H), 7.44 (d, J=8.3Hz, 2H), 6.93 (d, J=4.0Hz, 1H), 2.36 (s, 3H).
Iodo- 1- p-toluenesulfonyls -1H- pyrrolo-es [2,3-b] pyridine -5- formamides of the chloro- 2- of step 5) 4-
At -78 DEG C, to chloro- 1- p-toluenesulfonyls -1H- pyrrolo-es [2, the 3-b] pyridine -5- formamides of 4- (1.00g, Be added dropwise in tetrahydrofuran (20mL) solution 2.86mmol) lithium diisopropylamine tetrahydrofuran solution (2M, 5mL, 10mmol).After adding, reaction system continuation is stirred 1 hour at -78 DEG C, then, by elemental iodine (1.11g, 4.37mmol) Tetrahydrofuran (5mL) solution be added dropwise in above-mentioned system.Gained reaction system stirs 2 hours at -78 DEG C, then adds water Reaction is quenched in (30mL), and dichloromethane (100mL × 3) is used in combination to extract.Combined organic phase is washed through saturated salt solution (100mL) It washs, anhydrous sodium sulfate drying, filtering, and is concentrated under reduced pressure into solvent volume residue about 20mL, then filter.Filter cake dichloromethane (20mL × 3) are washed, filtrate decompression concentration.Gained residue is purified through silica gel column chromatography (100%DCM), obtains faint yellow solid, This solid with before filtering gained filter cake merge title compound be faint yellow solid (1.12g, yield 82.4%).MS (ESI,pos.ion)m/z:476.0[M+H]+。
The chloro- 2- of step 6) 4- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] pyrrole Pyridine -5- formamides
To iodo- 1- p-toluenesulfonyls -1H- pyrrolo-es [2,3-b] pyridine -5- formamides of the chloro- 2- of 4- (947.2mg, 1.99mmol) and 1- methyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- bases) pyrazoles (460.2mg, It 2.21mmol) is dissolved in the solution obtained by the in the mixed solvent of 1,4- dioxane (40mL) and water (10mL) and Pd is added (dppf)2Cl2Dichloromethane complex (327.8mg, 0.39mmol) and sodium carbonate (428.1mg, 4.04mmol).Reaction is mixed It closes and is stirred overnight at 100 DEG C of object, then plus reaction is quenched in water (100mL), and dichloromethane (100mL × 3) is used in combination to extract.Merge Organic phase is washed through saturated salt solution (100mL), and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Gained residue is through silica gel Column chromatography (MeOH/DCM (v/v)=1/80) purifies, and it is brown solid (804.6mg, yield 94.0%) to obtain title compound.
MS(ESI,pos.ion)m/z:429.7[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.80 (s, 1H), 7.81 (s, 1H), 7.75 (d, J=8.3Hz, 2H), 7.71 (s, 1H), 7.21 (d, J=8.4Hz, 2H), 6.63 (s, 1H), 6.34 (s, 1H), 5.94 (s, 1H), 4.05 (s, 3H), 2.37(s,3H)。
Step 7) 9- ((5- carbamoyls -2- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrroles And [2,3-b] pyridin-4-yl) amino) -3- azaspiros [5.5] hendecane -3- t-butyl formates
To the chloro- 2- of 4- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo- [2,3-b] pyridines -5- Formamide (2.53g, 5.89mmol) and 3- amino -9- azaspiros [5.5] hendecane -9- t-butyl formates (1.90g, In n-butanol (20mL) solution 7.08mmol), DIPEA (1.57g, 12.20mmol) is added.Gained mixture is warming up to reflux And be stirred overnight, then it is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/40), must be marked Topic compound is brown solid (1.77g, yield 45.4%).
MS(ESI,pos.ion)m/z:661.8[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):9.25 (d, J=7.6Hz, 1H), 8.39 (s, 1H), 7.79 (d, J= 8.2Hz, 2H), 7.70 (s, 1H), 7.61 (s, 1H), 7.21 (d, J=8.1Hz, 2H), 6.48 (s, 1H), 5.70 (brs, 2H), 4.03(s,3H),3.80(m,1H),3.37(m,4H),2.38(s,3H),1.92(m,2H),1.70(m,10H),1.47(s, 9H)。
Step 8) 9- ((5- carbamoyls -2- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridines - 4- yls) amino) -3- azaspiros [5.5] hendecane -3- t-butyl formates
To 9- ((5- carbamoyls -2- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] pyridin-4-yl) amino) -3- azaspiros [5.5] hendecane -3- t-butyl formates (1.77g, 2.67mmol) ethyl alcohol In (50mL) solution, sodium hydrate aqueous solution (1M, 50mL, 50mmol) is added.Reaction system is after 30 DEG C are stirred overnight, with two Chloromethanes (100mL × 3) extracts.Combined organic phase is washed through saturated salt solution (100mL), anhydrous sodium sulfate drying, filtering And it is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/80), and it is shallow brown to obtain title compound Color solid (974.8mg, yield 71.8%).
MS(ESI,pos.ion)m/z:508.4[M+H]+。
Step 9) 4- (3- azaspiros [5.5] hendecane -9- bases amino) -2- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrroles Cough up simultaneously [2,3-b] pyridine -5- formamides
To 9- ((5- carbamoyls -2- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) Amino) -3- azaspiros [5.5] hendecane -3- t-butyl formates (974.8mg, 1.92mmol) DCM (10mL) solution in be added The ethyl acetate solution (10mL, 40mmol) of hydrogen chloride.Reaction system stirs 0.5 hour at room temperature, is then concentrated under reduced pressure.Gained Residue is dissolved in water (30mL), and saturated aqueous sodium carbonate is used in combination to be adjusted to pH=10, then uses dichloromethane (250mL × 3) it extracts.Combined organic phase is washed through saturated salt solution (250mL), and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Gained Residue through silica gel column chromatography (MeOH/DCM (v/v)=1/5) purify, obtain title compound be beige solid (652.7mg, Yield 83.4%).
MS(ESI,pos.ion)m/z:204.7[(M+2H)/2]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):9.05(s,2H),8.39(s,1H),8.24(s,1H),8.00(s, 1H), 6.77 (s, 1H), 4.10 (s, 1H), 3.89 (s, 3H), 3.01 (s, 4H), 2.00 (m, 1H), 1.91 (d, J=3.6Hz, 1H), 1.66 (m, 6H), 1.51 (d, J=8.3Hz, 4H).
2 4- of embodiment ((3- acetyl group -3- azaspiros [5.5] hendecane -9- bases) amino) -2- (1- methyl-1 H- pyrroles Azoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridine -5- formamides
By 4- (3- azaspiros [5.5] hendecane -9- bases amino) -2- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridine -5- formamides (110.1mg, 0.27mmol) and triethylamine (76.4mg, 0.76mmol) are suspended in dichloromethane In (8mL), then into suspending system be added acetic anhydride (34.6mg, 0.34mmol) dichloromethane solution (2mL).Reaction system It is stirred at room temperature 20 minutes, then plus reaction is quenched in water (50mL), and dichloromethane (150mL × 6) is used in combination to extract.What is merged has Machine is mutually washed through saturated salt solution (150mL), and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Gained residue is through silica gel column layer (MeOH/DCM (v/v)=1/5) purifying is analysed, it is beige solid (64.0mg, yield 52.7%) to obtain title compound.
MS(ESI,pos.ion)m/z:449.9[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):9.43(s,1H),8.23(s,1H),7.82(s,1H),7.68(s, 1H), 6.51 (s, 1H), 5.83 (s, 2H), 4.33 (t, J=6.1Hz, 1H), 4.05 (s, 1H), 3.98 (s, 3H), 3.60 (s, 2H),3.43(s,2H),2.11(s,3H),1.76(m,2H),1.63(m,6H),1.45(m,4H)。
3 4- of embodiment ((3- (2- Cyanoacetyls) -3- azaspiros [5.5] hendecane -9- bases) amino) -2- (1- first Base -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridine -5- formamides
To 4- (3- azaspiros [5.5] hendecane -9- bases amino) -2- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridine -5- formamides (0.55g, 1.30mmol) and 2- cyanoacetic acids (171.0mg, 2.01mmol) are dissolved in dichloromethane Alkane (40mL) and DMF (10mL) be formed by solution be added HATU (758.4mg, 2.00mmol) and triethylamine (0.35g, 3.50mmol).Reaction system is stirred at room temperature 10 minutes, and then plus reaction is quenched in water (50mL), and dichloromethane is used in combination (150mL × 3) extract.Combined organic phase is washed through saturated salt solution (150mL), and anhydrous sodium sulfate drying is filtered and depressurized dense Contracting.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/5), and it is beige solid to obtain title compound (54.4mg, yield 8.5%).
MS(ESI,pos.ion)m/z:474.9[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):9.50(s,1H),8.27(s,1H),7.78(s,1H),7.72(s, 1H), 6.50 (s, 1H), 5.82 (s, 2H), 5.36 (s, 1H), 4.06 (s, 1H), 3.99 (s, 3H), 3.64 (dd, J=12.8, 9.1Hz, 2H), 3.51 (s, 2H), 3.45 (dd, J=13.4,8.2Hz, 2H), 2.05 (m, 4H), 1.56 (m, 8H).
The chloro- 2- of 4 5- of embodiment (1- methyl-1 H- pyrazoles -4- bases)-N- (3- azaspiros [5.5] hendecane -9- bases) -1H- Pyrrolo- [2,3-b] pyridine -4- amine
Chloro- 1H- pyrrolo-es [2,3-b] pyridine-N-oxides of step 1) 5-
At 0 DEG C, to the dichloromethane of chloro- 1H- pyrrolo-es [2, the 3-b] pyridines (20.00g, 131.1mmol) of 5- MCPBA (85% [w/w], 67.86g, 393.2mmol) is added in (500mL) solution.Reaction mixture, which moves to, to be stirred at room temperature Then night is concentrated under reduced pressure.Gained residue is dissolved in water (250mL), be used in combination saturated aqueous sodium carbonate be adjusted to pH=8~ 9, then dichloromethane (250mL × 3) is used to extract.Combined organic phase is washed through saturated salt solution (250mL), and anhydrous sodium sulfate is dry It is dry, it filters and is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/50), obtains title compound Object is gray solid (14.00g, yield 63.4%).
MS(ESI,pos.ion)m/z:169.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):12.69 (s, 1H), 8.36 (d, J=1.4Hz, 1H), 7.80 (d, J =1.4Hz, 1H), 7.53 (d, J=2.8Hz, 1H), 6.56 (d, J=3.1Hz, 1H).
Chloro- 1H- pyrrolo-es [2,3-b] pyridines of the bromo- 5- of step 2) 4-
At 0 DEG C, to chloro- 1H- pyrrolo-es [2, the 3-b] pyridine-N-oxides (5.00g, 29.66mmol) of 5- and Bu4NBr In DMF (200mL) solution of (19.12g, 59.31mmol), it is added dropwise to trifluoromethanesulfanhydride anhydride (20.91g, 74.20mmol).Instead It answers mixture to move to room temperature and stirs 2 hours, be then poured into water (500mL).Gained mixture saturated sodium bicarbonate water is molten Liquid is adjusted to pH=8~9, then filter.Filter cake is washed with water (50mL × 3), is collected filter cake, is dried in vacuum overnight at 60 DEG C, It is pale solid (5.83g, yield 84.9%) to obtain title compound.
MS(ESI,pos.ion)m/z:231.0[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):12.24(s,1H),8.30(s,1H),7.68(s,1H),6.45(s, 1H)。
Chloro- 1- p-toluenesulfonyls -1H- pyrrolo-es [2,3-b] pyridines of the bromo- 5- of step 3) 4-
At 0 DEG C, to chloro- 1H- pyrrolo-es [2, the 3-b] pyridines (5.83g, 25.18mmol) of the bromo- 5- of 4- and DMAP Triethylamine (5.10g, 50.40mmol) is added in dichloromethane (250mL) solution of (615.0mg, 5.03mmol) and to toluene Sulfonic acid chloride (7.20g, 37.76mmol).Reaction system moves to room temperature and is stirred overnight, and is then concentrated under reduced pressure.Gained residue passes through Silica gel column chromatography (EtOAc/PE (v/v)=1/50) purifies, and it is white solid (7.23g, yield 74.4%) to obtain title compound.
MS(ESI,pos.ion)m/z:385.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.39 (s, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.82 (d, J= 4.0Hz, 1H), 7.31 (d, J=8.3Hz, 2H), 6.64 (d, J=4.0Hz, 1H), 2.41 (s, 3H).
Iodo- 1- p-toluenesulfonyls -1H- pyrrolo-es [2,3-b] pyridines of the chloro- 2- of the bromo- 5- of step 4) 4-
At -78 DEG C, to chloro- 1- p-toluenesulfonyls -1H- pyrrolo-es [2, the 3-b] pyridines of the bromo- 5- of 4- (2.53g, It is added dropwise to lithium diisopropylamine (5mL, 10mmol) in tetrahydrofuran (20mL) solution 6.56mmol).Reaction mixture is tieed up It holds -78 DEG C to stir 40 minutes, then be added dropwise to tetrahydrofuran (20mL) solution of elemental iodine (2.64g, 10.4mmol) above-mentioned In reaction mixture.After reaction mixture continues stirring 1 hour at -78 DEG C, saturated aqueous sodium thiosulfate is added Reaction is quenched in (60mL).Mixture is extracted with ethyl acetate (100mL × 3).Combined organic phase is dried over anhydrous sodium sulfate, mistake It filters and is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=50/1), and it is light to obtain title compound Yellow solid (1.24g, yield 37%).
MS(ESI,pos.ion)m/z:513.0[M+H]+。
The chloro- 2- of the bromo- 5- of step 5) 4- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3- B] pyridine
To iodo- 1- p-toluenesulfonyls -1H- pyrrolo-es [2,3-b] pyridines of the chloro- 2- of the bromo- 5- of 4-, 1- methyl -4- (4,4,5, 5- tetramethyl -1,3,2- dioxaborolan -2- bases) pyrazoles (491.5mg, 2.362mmol), sodium bicarbonate (402.6mg, 4.792mmol) and Pd (dppf)2Cl2Dichloromethane complex (190.8mg, 0.2337mmol) mixture in 1,4- is added Dioxane (40mL) and water (3mL).Reaction system is warming up to 100 DEG C, stirs 3.5 hours in atmosphere of inert gases, then It is concentrated under reduced pressure.Gained residue adds water (80mL) to dilute, and then ethyl acetate (100mL × 3) is used to extract.Combined organic phase warp Anhydrous sodium sulfate is dried, and is filtered and is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=2/1), It is faint yellow solid (380mg, yield 35%) to obtain title compound
MS(ESI,pos.ion)m/z:465.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.37 (s, 1H), 7.78 (s, 1H), 7.69 (d, J=8.2Hz, 2H), 7.67 (s, 1H), 7.18 (d, J=8.2Hz, 2H), 6.48 (s, 1H), 4.02 (s, 3H), 2.34 (s, 3H).
Step 6) 9- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3- B] pyridin-4-yl) amino) -3- azaspiros [5.5] hendecane -3- t-butyl formates
To the chloro- 2- of the bromo- 5- of 4- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] pyrrole Pyridine (350mg, 0.7514mmol), 3- amino -9- azaspiros [5.5] hendecane -9- t-butyl formates (405.6mg, 1.511mmol), cesium carbonate (735.2mg, 2.256mmol), BINAP (47.3mg, 0.076mmol) and Pd (OAc)2 1,4- dioxane (20mL) is added in the mixture of (16.4mg, 0.0731mmol).Reaction system is warming up to 100 DEG C, inertia It is stirred overnight in atmosphere, then, is concentrated under reduced pressure.Gained residue adds water (40mL) to dilute, and then uses DCM/MeOH (v/v =10/1,60mL × 3) extraction.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Gained residue passes through Silica gel column chromatography (DCM/MeOH (v/v)=125/1) purifies, and it is yellow solid (370mg, yield 75%) to obtain title compound.
MS(ESI,pos.ion)m/z:653.3[M+H]+；
1HNMR(400MHz,CDCl3)δ(ppm):8.09 (s, 1H), 7.74 (d, J=8.3Hz, 2H), 7.70 (s, 1H), 7.60 (s, 1H), 7.17 (d, J=8.1Hz, 2H), 6.40 (s, 1H), 4.88 (d, J=8.3Hz, 1H), 3.99 (s, 3H), 3.77-3.66 (m, 1H), 3.45-3.27 (m, 4H), 2.33 (s, 3H), 1.91 (dd, J=13.6,3.4Hz, 2H), 1.71 (d, J =14.5Hz, 2H), 1.53-1.40 (m, 15H), 1.38-1.32 (m, 2H).
Step 7) 9- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) ammonia Base) -3- azaspiros [5.5] hendecane -3- t-butyl formates
To 9- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] pyrroles Pyridine -4- bases) amino) -3- azaspiros [5.5] hendecane -3- t-butyl formates (370mg, 0.5664mmol) ethyl alcohol (10mL) Sodium hydroxide (10mL, 10mmol, 1M) is added in solution.Reaction system is warming up to 60 DEG C and stirs 5 hours, after reaction, adds Reaction is quenched in water (50mL).Gained mixture is extracted with the mixed solvent (v/v=10/1,80mL × 3) of DCM/MeOH.Merge Organic phase is dried over anhydrous sodium sulfate, filtering, and is concentrated under reduced pressure, and it is yellow solid (290mg) to obtain crude product.Crude product is without pure Change is directly used in next step.
MS(ESI,pos.ion)m/z:499.5[M+H]+。
The chloro- 2- of step 8) 5- (1- methyl-1 H- pyrazoles -4- bases)-N- (3- azaspiros [5.5] hendecane -9- bases) -1H- pyrroles Cough up simultaneously [2,3-b] pyridine -4- amine
To 9- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) amino) -3- Chlorination is added in ethyl acetate (5mL) solution of azaspiro [5.5] hendecane -3- t-butyl formates (290mg, 0.5812mmol) The ethyl acetate solution (10mL, 20mmol, 2M) of hydrogen.Reaction system is stirred at room temperature 1 hour.Reaction mixture water (50mL × 2) are washed, and combined water layer is adjusted to pH=12 with sodium carbonate solid, then gained mixture dichloromethane and methanol Mixed solvent (v/v=10/1,100mL × 4) extraction.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is depressurized dense Contracting.Gained residue is through preparing the thin-layer chromatography (NH of DCM/7M3MeOH solution (v/v)=10/1) purifying, obtain title compound Object is yellow solid (190mg, yield 82%).
MS(ESI,pos.ion)m/z:200.3[(M+2H)/2]+。
5 1-9- of embodiment ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) Amino) -3- azaspiros [5.5] hendecane -3- bases) ethyl ketone
To the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases)-N- (3- azaspiros [5.5] hendecane -9- bases) -1H- pyrrolo-es In dichloromethane (10mL) solution of [2,3-b] pyridine -4- amine (80mg, 0.2006mmol) be added triethylamine (64.5mg, 0.637mmol) and acetic anhydride (21.8mg, 0.214mmol).After gained reaction system stirs 30 minutes at normal temperatures, decompression is dense Contracting.For gained residue through preparing thin-layer chromatography (MeOH/DCM (v/v)=10/1) purifying, it is yellow solid to obtain title compound (73.1mg, yield 82.7%).
MS(ESI,pos.ion)m/z:441.3[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):11.29(s,1H),7.92(s,1H),7.81(s,1H),7.71(s, 1H), 6.44 (s, 1H), 4.96 (d, J=8.4Hz, 1H), 3.98 (m, 4H), 3.59 (dd, J=11.7,7.0Hz, 2H), 3.42 (dd, J=11.5,7.4Hz, 2H), 2.08 (d, J=16.2Hz, 5H), 1.84-1.75 (m, 4H), 1.61-1.53 (m, 4H), 1.50-1.36(m,2H)。
6 3- of embodiment (9- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridine -4- Base) amino) -3- azaspiros [5.5] hendecane -3- bases) -3- oxo propionitriles
To the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases)-N- (3- azaspiros [5.5] hendecane -9- bases) -1H- pyrrolo-es [2,3-b] pyridine -4- amine (100mg, 0.2507mmol), 2- cyanoacetic acids (43.7mg, 0.514mmol), EDCI (96.3mg, 0.502mmol), two are added in the mixture of HOAT (70.4mg, 0.517mmol) and triethylamine (131.9mg, 1.303mmol) Chloromethanes (12mL) and DMF (1mL).Reaction mixture stirs 1 hour at room temperature, and reaction terminates.Mixture adds water (30mL) dilute It releases, gained mixture is extracted with the mixed solvent (v/v=10/1,50mL × 4) of DCM/MeOH.Combined organic phase is through anhydrous sulphur Sour sodium drying, filters and is concentrated under reduced pressure.Gained residue is obtained through preparing thin-layer chromatography (MeOH/DCM (v/v)=1/10) purifying Title compound is yellow solid (80.2mg, yield 68.7%).
MS(ESI,pos.ion)m/z:466.4[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):11.33(s,1H),7.93(s,1H),7.81(s,1H),7.71(s, 1H), 6.43 (s, 1H), 4.96 (d, J=8.4Hz, 1H), 3.99 (m, 4H), 3.62 (dd, J=11.4,6.3Hz, 2H), 3.49 (s, 2H), 3.44 (dd, J=11.6,8.9Hz, 2H), 2.08 (d, J=10.7Hz, 2H), 1.76-1.85 (m, 4H), 1.71- 1.66(m,1H),1.65-1.60(m,1H),1.54-1.59(m,2H),1.53-1.47(m,2H)。
The chloro- 2- of 7 5- of embodiment (1- methyl-1 H- pyrazoles -4- bases)-N- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) -1H- Pyrrolo- [2,3-b] pyridine -4- amine
Step 1) 5- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3- B] pyridin-4-yl) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate
To the chloro- 2- of the bromo- 5- of 4- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] pyrrole Pyridine (596.9mg, 1.28mmol) and 5- amino hexahydros pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate (0.57g, Pd (OAc) is added in 1,4- dioxane (50mL) solution 2.52mmol)2(58.9mg,0.26mmol)、BINAP (188.3mg, 0.29mmol) and Cs2CO3(867.7mg,2.66mmol).Reaction mixture is stirred overnight at 100 DEG C, then It is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (EtOAc/PE (v/v)=2/1), and it is solid for yellow to obtain title compound Body (783.2mg, yield 100%).
MS(ESI,pos.ion)m/z:611.5[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.11 (s, 1H), 7.76 (d, J=8.3Hz, 2H), 7.72 (s, 1H), 7.62 (s, 1H), 7.19 (d, J=8.2Hz, 2H), 6.48 (s, 1H), 5.02 (d, J=8.2Hz, 1H), 4.29 (m, 1H), 4.02 (s, 3H), 3.49 (m, 2H), 3.34 (d, J=9.8Hz, 2H), 2.70 (m, 2H), 2.43 (dt, J=13.3,6.7Hz, 2H), 2.36(s,3H),1.48(s,9H),1.45(m,2H)。
Step 2) 5- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) ammonia Base) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate
To 5- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] pyrroles Pyridine -4- bases) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate (751.8mg, 1.23mmol) ethyl alcohol The aqueous solution (1M, 25mL, 25mmol) of sodium hydroxide is added in (25mL) solution.Reaction system is warming up to 60 DEG C and stirs 3.5 Hour, then it is concentrated under reduced pressure.Gained residue is dissolved in the water in (50mL), then dichloromethane (100mL × 3) is used to extract, Combined organic phase is washed through saturated salt solution (100mL), and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Gained residue passes through Silica gel column chromatography (MeOH/DCM (v/v)=1/50) purifies, and it is faint yellow solid (495.8mg, yield to obtain title compound 88.2%).
MS(ESI,pos.ion)m/z:457.3[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):10.85(s,1H),7.96(s,1H),7.82(s,1H),7.69(s, 1H), 6.52 (s, 1H), 5.05 (d, J=8.3Hz, 1H), 4.56 (m, 1H), 4.01 (s, 3H), 3.54 (m, 2H), 3.40 (brs, 2H),2.78(m,2H),2.56(m,2H),1.55(m,2H),1.50(s,9H)。
The chloro- 2- of step 3) 5- (1- methyl-1 H- pyrazoles -4- bases)-N- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) -1H- pyrroles Cough up simultaneously [2,3-b] pyridine -4- amine
To 5- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) amino) six Hydrogen pentamethylene simultaneously in dichloromethane (10mL) solution of [c] pyrroles -2 (1H)-t-butyl formate (471.7mg, 1.03mmol) plus Enter the ethyl acetate solution (10mL, 40mmol) of hydrogen chloride.Reaction system stirs 1 hour at room temperature, is then concentrated under reduced pressure.Gained Residue is dissolved in water (30mL), and saturated aqueous sodium carbonate is used in combination to be adjusted to pH=10, then uses dichloromethane (250mL × 3) it extracts.Combined organic phase is washed through saturated salt solution (250mL), and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Gained Residue through silica gel column chromatography (MeOH/DCM (v/v)=1/10) purify, obtain title compound be beige solid (324.6mg, Yield 88.1%).
MS(ESI,pos.ion)m/z:357.2[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):11.65(s,1H),8.13(s,1H),7.93(s,1H),7.77(s, 1H), 6.71 (s, 1H), 6.62 (d, J=9.4Hz, 1H), 4.45 (m, 1H), 3.87 (s, 3H), 2.98 (br.s, 1H), 2.69 (d, J=3.0Hz, 4H), 2.61 (m, 2H), 2.25 (dt, J=13.4,6.9Hz, 2H), 1.45 (dt, J=10.6,5.0Hz, 2H)。
8 3- of embodiment (5- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridine -4- Base) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) -3- oxo propionitriles
To the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases)-N- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) -1H- pyrrolo-es The dichloromethane of [2,3-b] pyridine -4- amine (107.4mg, 0.30mmol) and 2- cyanoacetic acids (43.0mg, 0.51mmol) HOAT (87.8mg, 0.64mmol), EDCI (121.5mg, 0.63mmol) and Et are added in (15mL) solution3N(118.5mg, 1.17mmol).Reaction system is stirred at room temperature 0.5 hour, and then plus reaction is quenched in water (30mL), and dichloromethane is used in combination (100mL × 3) extract.Combined organic phase is washed through saturated salt solution (100mL), and anhydrous sodium sulfate drying is filtered and depressurized Concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=1/30), and it is beige solid to obtain title compound (77.6mg, yield 60.8%).
MS(ESI,pos.ion)m/z:424.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):10.66(s,1H),7.97(s,1H),7.82(s,1H),7.70(s, 1H), 6.50 (s, 1H), 4.98 (d, J=8.1Hz, 1H), 4.62 (m, 1H), 4.02 (s, 3H), 3.78 (m, 2H), 3.67 (m, 1H),3.49(m,3H),2.98(m,1H),2.88(m,1H),2.63(m,2H),1.56(m,2H)。
9 1- of embodiment (5- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridine -4- Base) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone
To the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases)-N- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) -1H- pyrrolo-es [2,3-b] pyridine -4- amine (128.0mg, 0.36mmol) and triethylamine (84.8mg, 0.84mmol) are suspended in dichloromethane The dichloromethane solution (5mL) of acetic anhydride (39.6mg, 0.39mmol) is added in the suspending system formed in (10mL).Reactant It ties up to and is stirred to react at room temperature 15 minutes, then plus reaction is quenched in water (30mL).Gained mixture with dichloromethane (100mL × 3) it extracts.Combined organic phase is washed through saturated salt solution (100mL), and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Gained is residual Object is stayed to be purified through silica gel column chromatography (MeOH/DCM (v/v)=1/30), it is beige solid (139.8mg, production to obtain title compound Rate 97.7%).
MS(ESI,pos.ion)m/z:399.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):11.10(s,1H),7.96(s,1H),7.83(s,1H),7.71(s, 1H), 6.51 (s, 1H), 5.01 (d, J=8.2Hz, 1H), 4.60 (m, 1H), 4.01 (s, 3H), 3.67 (m, 3H), 3.44 (dd, J =10.8,3.9Hz, 1H), 2.87 (m, 2H), 2.60 (m, 2H), 2.10 (s, 3H), 1.56 (tt, J=13.0,8.0Hz, 2H).
The chloro- 2- of 10 5- of embodiment (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (3- azaspiros [5.5] hendecane -9- Base) -1H- pyrrolo-es [2,3-b] pyridine -4- amine
Step 1) 1,3- dimethyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) -1H- pyrazoles
To the anhydrous 1,4- dioxane (100.0mL) of the bromo- 1,3- dimethyl -1H- pyrazoles (5.00g, 28.60mmol) of 4- It is added 4,4,4', 4', 5,5,5' in solution, 5'- prestoxs -2,2'- two (1,3,2- dioxaborolans) (8.71g, 34.32mmol), potassium acetate (5.63g, 57.41mmol) and Pd (dppf)2Cl2Dichloromethane complex (2.38g, 2.86mmol).Reaction mixture takes out air to the greatest extent, and it is multiple to be filled with nitrogen, then, is warming up to 100 DEG C and is stirred overnight.Reaction is mixed Object is closed to be concentrated under reduced pressure.After gained mixture adds water (30mL) to dilute, extracted with ethyl acetate (50mL × 3).Combined organic phase It is dried over anhydrous sodium sulfate, filters and is concentrated under reduced pressure.Through silica gel column chromatography, (EtOAc/PE (v/v)=1/20 is arrived gained residue 1/8) it purifies, it is viscous brown shape liquid (3.80g, yield 60%) to obtain title compound.
MS(ESI,pos.ion)m/z:223.3[M+H]+。
The chloro- 2- of the bromo- 5- of step 2) 4- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] pyridine
To iodo- 1- p-toluenesulfonyls -1H- pyrrolo-es [2,3-b] pyridines (2.50g, 4.89mmol) of the chloro- 2- of the bromo- 5- of 4- It is suspended in the suspending system of the mixed solvent formation of 1,4- dioxane (45.0mL) and water (9.0mL) and 1,3- diformazans is added Base -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) -1H- pyrazoles (2.18g, 9.82mmol), sodium carbonate (1.05g, 9.90mmol) and Pd (dppf)2Cl2Dichloromethane complex (0.80g, 0.99mmol).Reaction mixture is taken out to the greatest extent Then air, and it is multiple to be filled with nitrogen is warming up to 100 DEG C and is stirred to react 4 hours, then mixture is concentrated under reduced pressure.Gained remains Object is purified through silica gel column chromatography (100%PE to EtOAc/PE (v/v)=1/4 to 1/2), and it is viscous brown shape to obtain title compound Liquid (0.54g, yield 23%).
MS(ESI,pos.ion)m/z:479.0[M+H]+。
Step 3) 9- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] pyridin-4-yl) amino) -3- azaspiros [5.5] hendecane -3- t-butyl formates
To the chloro- 2- of the bromo- 5- of 4- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3- B] pyridine (0.54g, 1.10mmol) anhydrous 1,4- dioxane (15.0mL) solution in be added 9- amino -3- azaspiros [5.5] undecyl -3- t-butyl formates (0.62g, 2.30mmol), Pd (OAc)2(0.052g,0.23mmol)、BINAP (0.14g, 0.23mmol) and cesium carbonate (0.75g, 2.31mmol).Reaction mixture takes out air to the greatest extent, and it is multiple to be filled with nitrogen, so Afterwards, it is warming up to and flows back and be stirred overnight.Reaction mixture is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/PE (v/ V) it=1/4 to 1/2) purifies, it is yellow solid (0.46g, yield 61%) to obtain title compound.
MS(ESI,pos.ion)m/z:667.5M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.12 (s, 1H), 7.67 (d, J=8.3Hz, 2H), 7.50 (s, 1H), 7.15 (d, J=8.2Hz, 2H), 6.33 (s, 1H), 4.89 (d, J=8.1Hz, 1H), 3.93 (s, 3H), 3.77-3.64 (m, 1H),3.40-3.31(m,4H),2.33(s,3H),2.14(s,3H),1.96-1.87(m,2H),1.76-1.66(m,4H), 1.53-1.45(m,4H),1.44(s,9H),1.37-1.31(m,2H)。
Step 4) 9- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) Amino) -3- azaspiros [5.5] hendecane -3- t-butyl formates
To 9- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3- B] pyridin-4-yl) amino) and -3- azaspiros [5.5] hendecane -3- t-butyl formates (0.46g, 0.69mmol) ethyl alcohol Sodium hydrate aqueous solution (7.0mL, 7.0mmol, 1M) is added in (7.0mL) solution.Reaction mixture is warming up to 60 DEG C and stirs Overnight.Reaction mixture is concentrated under reduced pressure.Gained residue add water (10mL) dilute, acquired solution successively use DCM (30mL × 3) and DCM/MeOH ((v/v)=10/1,30mL × 3) is extracted.Combined organic phase is dried over anhydrous sodium sulfate, filtering, and is depressurized dense Contracting, it is yellow solid (0.33g, 98%) to obtain crude product.Crude product is directly used in next step without further purification.
MS(ESI,pos.ion)m/z:513.3[M+H]+。
The chloro- 2- of step 5) 5- (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (3- azaspiros [5.5] hendecane -9- bases) - 1H- pyrrolo-es [2,3-b] pyridine -4- amine
To 9- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) ammonia Base) -3- azaspiros [5.5] hendecane -3- t-butyl formates (0.33g, 0.64mmol) dichloromethane (10mL) solution in plus Enter the ethyl acetate solution (10.0mL, 30.0mmol) of hydrogen chloride.Reaction system is stirred at room temperature 2 hours, then depressurizes dense Contracting.Gained residue is diluted with DCM (30mL) and the aqueous sodium carbonate (30mL) of saturation, and gained mixture is stirred at room temperature 30 clocks.It stands, separates organic layer, water layer uses DCM (50mL × 3) and DCM/MeOH ((v/v)=10/1,50mL × 3) to extract successively It takes.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/3M NH3MeOH solution (v/v)=30/1 to 20/1 to 10/1) purifying, obtain title compound be yellow solid (80mg, yield 30%).
MS(ESI,pos.ion)m/z:413.4[M+H]+。
11 3- of embodiment (9- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyrroles Pyridine -4- bases) amino) -3- azaspiros [5.5] hendecane -3- bases) -3- oxo propionitriles
To the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (3- azaspiros [5.5] hendecane -9- bases) -1H- pyrroles It coughs up in the suspending system formed in the DCM (10mL) that simultaneously [2,3-b] pyridine -4- amine (40mg, 0.097mmol) is suspended in and 2- is added Cyanoacetic acid (18mg, 0.21mmol), EDCI (30mg, 0.15mmol), HOAT (12mg, 0.15mmol) and triethylamine (31mg, 0.31mmol).Mixture is stirred to react 30 minutes at room temperature, and dichloromethane (30mL) dilution, gained mixture water is added (20mL × 2) are washed, and the organic phase separated is dried over anhydrous sodium sulfate, and are filtered, and be concentrated under reduced pressure.Gained residue is through silicagel column Chromatograph (the NH of DCM/3M3MeOH solution (v/v)=50/1 to 30/1 to 20/1) purifying, obtain title compound be yellow solid (36mg, yield 77%).
MS(ESI,pos.ion)m/z:480.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):9.93(br,s,1H),7.91(s,1H),7.58(s,1H),6.40(s, 1H), 4.97 (d, J=8.1Hz, 1H), 4.05-3.96 (m, 1H), 3.92 (s, 3H), 3.66-3.58 (m, 2H), 3.48 (d, J= 1.9Hz,2H),3.47-3.39(m,2H),2.46(s,3H),2.16-2.06(m,2H),1.87-1.77(m,2H),1.60- 1.48(m,4H),1.46-1.37(m,2H),1.29-1.23(m,2H)。
12 1- of embodiment (9- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyrroles Pyridine -4- bases) amino) -3- azaspiros [5.5] hendecane -3- bases) ethyl ketone
To the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (3- azaspiros [5.5] hendecane -9- bases) -1H- pyrroles Cough up in DCM (5.0mL) solution of simultaneously [2,3-b] pyridine -4- amine (32mg, 0.077mmol) be added acetic anhydride (11mg, 0.11mmol) and triethylamine (13mg, 0.13mmol).Reaction system is stirred at room temperature overnight, and is then concentrated under reduced pressure.Gained is residual Stay object through the silica gel column chromatography (NH of DCM/3M3MeOH solution (v/v)=50/1 to 30/1 to 20/1) purifying, obtain title compound Object is yellow solid (28mg, yield 79%).
MS(ESI,pos.ion)m/z:455.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.81 (s, 1H), 7.67 (d, J=4.0Hz, 1H), 6.36 (s, 1H), 4.00-3.89(m,1H),3.85(s,3H),3.57-3.49(m,2H),3.43-3.36(m,2H),2.41(s,3H),2.09- 2.00(m,5H),1.82-1.70(m,2H),1.61-1.47(m,4H),1.45-1.32(m,4H)。
The chloro- 2- of 13 5- of embodiment (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (octahydro pentamethylene simultaneously [c] pyrroles -5- Base) -1H- pyrrolo-es [2,3-b] pyridine -4- amine
Step 1) 5- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] pyridin-4-yl) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate
To 5- amino hexahydros pentamethylene, simultaneously [c] pyrroles -2 (1H)-t-butyl formate (245.6mg, 1.085mmol), 4- are bromo- The chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] pyridine (250mg, 0.5211mmol), cesium carbonate (514.2mg, 1.578mmol), BINAP (30.7mg, 0.0493mmol) and Pd (OAc)2 1,4- dioxane (20mL) is added in the mixture of (10.9mg, 0.0486mmol).Reaction mixture is warming up to 100 DEG C, It is stirred overnight in atmosphere of inert gases.Gained residue adds water (40mL) to dilute, and then uses DCM/MeOH (v/v=10/1,60mL × 3) it extracts.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) is purified, and it is yellow solid (260mg, yield 79%) to obtain title compound.
MS(ESI,pos.ion)m/z:625.5[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.11 (s, 1H), 7.68 (d, J=8.3Hz, 2H), 7.49 (s, 1H), 7.16 (d, J=8.1Hz, 2H), 6.40 (s, 1H), 5.01 (d, J=8.0Hz, 1H), 4.25 (s, 1H), 3.92 (s, 3H), 3.44 (d, J=6.9Hz, 2H), 3.31 (d, J=9.3Hz, 2H), 2.72-2.60 (m, 2H), 2.44-2.35 (m, 2H), 2.33 (s, 3H),2.15(s,3H),1.49-1.40(m,11H)。
Step 2) 5- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) Amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate
To 5- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3- B] pyridin-4-yl) amino) and hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate (260mg, 0.416mmol) ethyl alcohol Sodium hydroxide (10mL, 20mmol, 2M) is added in (10mL) solution.Reaction system is warming up to 60 DEG C and is stirred to react overnight, then Water (50mL) is added to dilute.The mixed extractant solvent of mixture (v/v=10/1,80mL × 3) DCM/MeOH.Combined organic phase Be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure crude product be yellow solid (205mg).Crude product is directly used without further purification In in next step.
MS(ESI,pos.ion)m/z:471.4[M+H]+。
The chloro- 2- of step 3) 5- (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) - 1H- pyrrolo-es [2,3-b] pyridine -4- amine
To 5- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) ammonia Base) hexahydro pentamethylene is simultaneously in ethyl acetate (5mL) solution of [c] pyrroles -2 (1H)-t-butyl formate (205mg, 0.435mmol) The ethyl acetate solution (10mL, 20mmol, 2M) of hydrogen chloride is added.Reaction 2 hours is stirred at room temperature in reaction mixture.Reaction Mixture is washed with water (50mL × 2).Combined water phase is adjusted to pH=12 with powdered sodium carbonate, then uses DCM/MeOH (v/v= 10/1,100mL × 4) mixed extractant solvent.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Gained Residue is through preparing the thin-layer chromatography (NH of DCM/7M3MeOH solution (v/v)=10/1) purifying, obtain title compound be yellow Solid (75mg, yield 46%).
MS(ESI,pos.ion)m/z:371.2[M+H]+。
14 3- of embodiment (5- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyrroles Pyridine -4- bases) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) -3- oxo propionitriles
The chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) -1H- pyrroles And [2,3-b] pyridine -4- amine (45mg, 0.1213mmol), 2- cyanoacetic acids (19.8mg, 0.233mmol), EDCI (47.9mg, 0.250mmol), the mixture of HOAT (35.34mg, 0.2596mmol) and triethylamine (71.5mg, 0.707mmol) is dissolved in The in the mixed solvent of DCM and DMF (10mL/0.5mL).Reaction 20 hours is stirred at room temperature in reaction system, then adds water (20mL) dilutes.Gained mixture is extracted with the mixed solvent (v/v=10/1,20mL × 4) of DCM/MeOH.Combined organic phase It is dried over anhydrous sodium sulfate, filters and is concentrated under reduced pressure.Gained residue is through preparing thin-layer chromatography (DCM/MeOH (v/v)=10/1) Purifying, it is faint yellow solid (39mg, yield 73%) to obtain title compound.
MS(ESI,pos.ion)m/z:438.2[M+H]+；
1H NMR(400MHz,CDCl3+CD3OD)δ(ppm):7.83(s,1H),7.66(s,1H),6.38(s,1H), 4.58-4.49 (m, 1H), 3.86 (s, 3H), 3.74-3.63 (m, 2H), 3.59 (dd, J=12.9,4.3Hz, 1H), 3.46- 3.38(m,2H),3.37-3.34(m,1H),2.93-2.86(m,1H),2.86-2.75(m,1H),2.62-2.55(m,2H), 2.42(s,3H),1.61-1.48(m,2H)。
15 1- of embodiment (5- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyrroles Pyridine -4- bases) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone
To the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) -1H- pyrroles Cough up the dichloromethane of simultaneously [2,3-b] pyridine -4- amine (30mg, 0.0809mmol) and triethylamine (38.7mg, 0.382mmol) The dichloromethane solution (4mL) of acetic anhydride (12.6mg, 0.123mmol) is added in (4mL) solution.Gained reaction system is in room temperature Lower stirring after twenty minutes, is concentrated under reduced pressure.Gained residue is obtained through preparing thin-layer chromatography (DCM/MeOH (v/v)=10/1) purifying Title compound is yellow solid (24.9mg, yield 74.6%).
MS(ESI,pos.ion)m/z:413.4[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):10.85(s,1H),7.88(s,1H),7.60(s,1H),6.44(s, 1H), 4.99 (d, J=7.9Hz, 1H), 4.63-4.51 (m, 1H), 3.92 (s, 3H), 3.70-3.57 (m, 3H), 3.42 (dd, J =10.8,3.8Hz, 1H), 2.92-2.74 (m, 2H), 2.58 (tt, J=14.4,7.3Hz, 2H), 2.46 (s, 3H), 2.08 (s, 3H),1.60-1.49(m,2H)。
16 6- of embodiment (4- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyrroles Pyridine -4- bases) amino) piperidin-1-yl)-nicotinonitrile
Step 1) 4- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] pyridin-4-yl) amino) piperidines -1- t-butyl formates
To the chloro- 2- of the bromo- 5- of 4- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3- B] pyridine (857mg, 1.786mmol), 4- amino piperidine -1- t-butyl formates (543mg, 2.711mmol) and cesium carbonate Pd (OAc) is added in 1,4- dioxane (40mL) solution of (1.77g, 5.43mmol)2(41mg, 0.1826mmol) and BINAP(112.5mg,0.1807mmol).Reaction mixture takes out most air 2 minutes, re-fills nitrogen.Reaction system is warming up to 100 DEG C are stirred 3 hours, are then concentrated under reduced pressure.Gained residue is pure through silica gel column chromatography (PE/EtOAc (v/v)=5/1 to 2/1) Change, it is faint yellow solid (307mg, yield 28.69%) to obtain title compound.
MS(ESI,pos.ion)m/z:599.5[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.13 (s, 1H), 7.68 (d, J=8.3Hz, 2H), 7.50 (s, 1H), 7.16 (d, J=8.2Hz, 2H), 6.32 (s, 1H), 4.85 (d, J=8.3Hz, 1H), 4.01 (d, J=8.2Hz, 2H), 3.93 (s, 3H), 3.88 (dd, J=11.3,7.4Hz, 2H), 2.94 (t, J=11.6Hz, 2H), 2.34 (s, 3H), 2.14 (s, 3H), 2.00(s,2H),1.45(s,9H)。
Step 2) 4- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) Amino) piperidines -1- t-butyl formates
To 4- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3- B] pyridin-4-yl) amino) and piperidines -1- t-butyl formates (300mg, 0.501mmol) ethyl alcohol (5mL) solution in hydrogen-oxygen is added Change sodium water solution (5mL, 5mmol, 1M).Reaction mixture is warming up to 60 DEG C and is stirred overnight.Gained residue adds water (10mL) molten Solution, acquired solution are extracted with the mixed solvent (v/v=10/1,20mL × 3) of DCM/MeOH.Combined organic phase is through saturated common salt Water (30mL) washs, and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (MeOH/DCM (v/ V) it=1/50 to 20/1) purifies, it is yellow solid (215mg, yield 96.48%) to obtain title compound.
MS(ESI,pos.ion)m/z:445.3[M+H]+。
The chloro- 2- of step 3) 5- (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] Pyridine -4- amine
To 4- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) ammonia Base) piperidines -1- t-butyl formates (215mg, 0.483mmol) dichloromethane (12mL) solution in be added hydrogen chloride acetic acid second Ester solution (5mL, 4M, 20mmol).Reaction mixture is stirred at room temperature 2 hours, is then concentrated under reduced pressure.Gained residue dissolves In water (20mL), saturated sodium bicarbonate aqueous solution is added thereto and is adjusted to pH=8~9, then uses DCM/MeOH (v/v=10/ 1,100mL × 3) extraction.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Gained residue is through silica gel Column chromatography (MeOH/DCM (v/v)=1/10 to 1/5) title compound is faint yellow solid (158mg, yield 94.84%).
MS(ESI,pos.ion)m/z:345.3[M+H]+。
Step 4) 6- (4- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridine -4- Base) amino) piperidin-1-yl)-nicotinonitrile
To the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyrrole Be added in ethyl alcohol (15mL) solution of pyridine -4- amine (53.8mg, 0.156mmol) 6- chloropyridine -3- formonitrile HCNs (43.5mg, 0.314mmol) and triethylamine (31.6mg, 0.312mmol).Reaction system is warming up to 85 DEG C and is stirred to react overnight, then depressurizes Concentration.Gained residue is purified through silica gel column chromatography (MeOH/DCM (v/v)=100/1 to 50/1), and it is light to obtain title compound Yellow solid (50mg, yield 71.7%).
MS(ESI,pos.ion)m/z:447.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):10.57 (s, 1H), 8.43 (d, J=2.1Hz, 1H), 7.92 (s, 1H), 7.63 (dd, J=9.0,2.3Hz, 1H), 7.60 (s, 1H), 6.67 (d, J=9.0Hz, 1H), 6.43 (s, 1H), 4.93 (d, J= 8.4Hz, 1H), 4.40 (d, J=13.9Hz, 2H), 4.31 (dd, J=11.2,7.1Hz, 1H), 3.93 (s, 3H), 3.33-3.22 (m, 2H), 2.47 (s, 3H), 2.31 (d, J=10.1Hz, 2H), 1.57 (dd, J=13.4,6.7Hz, 2H).
17 4- of embodiment (4- ((the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyrroles Pyridine -4- bases) amino) piperidin-1-yl) -3- benzonitriles
To the chloro- 2- of 5- (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyrrole Be added in dimethyl sulfoxide (DMSO) (15mL) solution of pyridine -4- amine (144mg, 0.418mmol) 4- fluorobenzonitriles (101.5mg, 0.838mmol) and potassium carbonate (115.4mg, 0.835mmol).Reaction mixture is warming up to 100 DEG C and is stirred to react 20 hours.Instead After answering, mixture adds water (10mL) to dilute, mixed solvent (v/v=10/1, the 20mL of gained mixture DCM and MeOH × 3) it extracts.Combined organic phase is washed through saturated salt solution (30mL), and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Gained Residue is yellow solid (25mg, yield through silica gel column chromatography (MeOH/DCM (v/v)=1/100 to 1/50) title compound 13.42%).
MS(ESI,pos.ion)m/z:446.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):10.89(s,1H),7.78(s,1H),7.69(s,1H),7.37(d,J =8.9Hz, 2H), 6.79 (d, J=8.9Hz, 2H), 6.29 (s, 1H), 4.74 (d, J=8.4Hz, 1H), 4.15-4.04 (m, 1H), 3.74 (d, J=7.9Hz, 5H), 3.01 (t, J=11.0Hz, 2H), 2.33 (s, 3H), 2.17 (d, J=10.4Hz, 2H), 1.60 (td, J=13.6,3.6Hz, 2H).
18 6- of embodiment (4- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridine -4- Base) amino) piperidin-1-yl)-nicotinonitrile
Step 1) 4- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3- B] pyridin-4-yl) amino) piperidines -1- t-butyl formates
To the chloro- 2- of the bromo- 5- of 4- (1- dimethyl -1H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] Pyridine (205mg, 0.4401mmol), 4- amino piperidine -1- t-butyl formates (132.5mg, 0.662mmol) and cesium carbonate Pd (OAc) is added in 1,4- dioxane (40mL) solution of (430.5mg, 1.321mmol)2(10mg, 0.04454mmol) and BINAP(27.5mg,0.0442mmol).Reaction mixture takes out most air 2 minutes and re-fills nitrogen.Reaction system is warming up to 100 DEG C are stirred 3 hours, are then concentrated under reduced pressure.Gained residue is pure through silica gel column chromatography (MeOH/DCM (v/v)=5/1 to 2/1) Change, it is yellow solid (162mg, yield 62.91%) to obtain title compound.
MS(ESI,pos.ion)m/z:585.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.11 (s, 1H), 7.74 (d, J=8.3Hz, 2H), 7.70 (s, 1H), 7.60 (s, 1H), 7.17 (d, J=8.2Hz, 2H), 6.38 (s, 1H), 4.83 (d, J=8.4Hz, 1H), 4.00 (s, 5H), 3.96-3.79 (m, 2H), 2.97 (t, J=11.5Hz, 2H), 2.34 (s, 3H), 2.00 (s, 2H), 1.45 (s, 9H).
Step 2) 4- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) ammonia Base) piperidines -1- t-butyl formates
To 4- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1- p-toluenesulfonyl -1H- pyrrolo-es [2,3-b] pyrroles Pyridine -4- bases) amino) piperidines -1- t-butyl formates (238mg, 0.407mmol) ethyl alcohol (4mL) solution in sodium hydroxide is added Aqueous solution (4mL, 4mmol, 1M).Reaction system is stirred overnight at 60 DEG C.Gained residue adds water (10mL) to dilute, then It is extracted with DCM/MeOH (v/v=10/1,20mL × 3).Combined organic phase is washed through saturated salt solution (30mL), anhydrous sodium sulfate It is dry, it filters and is concentrated under reduced pressure.Gained residue purifies to obtain mark through silica gel column chromatography (MeOH/DCM (v/v)=1/50 to 20/1) Topic compound is yellow solid (164mg, yield 93.57%).
MS(ESI,pos.ion)m/z:431.3[M+H]+。
The chloro- 2- of step 3) 5- (1- methyl-1 H- pyrazoles -4- bases)-N- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyrrole Pyridine -4- amine
To 4- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) amino) piperazine The ethyl acetate that hydrogen chloride is added in dichloromethane (12mL) solution of pyridine -1- t-butyl formates (164mg, 0.3806mmol) is molten Liquid (5mL, 4M, 20mmol).Reaction system stirs 2 hours at room temperature, is then concentrated under reduced pressure.Gained residue is dissolved in water In (20mL), gained mixture is adjusted to pH=8~9 with saturated sodium bicarbonate aqueous solution.Gained mixture is mixed with DCM/MeOH's Bonding solvent (v/v=10/1,100mL × 3) extracts.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Institute Residue through silica gel column chromatography (MeOH/DCM (v/v)=1/10 to 1/5) purify title compound be faint yellow solid (112mg, yield 88.96%).
MS(ESI,pos.ion)m/z:331.3[M+H]+。
Step 4) 6- (4- ((the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl) Amino) piperidin-1-yl)-nicotinonitrile
To the chloro- 2- of 5- (1- methyl-1 H- pyrazoles -4- bases)-N- (piperidin-4-yl) -1H- pyrrolo- [2,3-b] pyridines -4- 6- chloropyridine -3- formonitrile HCNs (103mg, 0.74341mmol) are added in ethyl alcohol (20mL) solution of amine (123mg, 0.3718mmol) With triethylamine (75.5mg, 0.746mmol).After gained reaction system is stirred overnight at 85 DEG C, it is concentrated under reduced pressure.Gained residue It is purified through silica gel column chromatography (MeOH/DCM (v/v)=100/1 to 50/1), it is yellow solid (105mg, production to obtain title compound Rate 65.23%).
MS(ESI,pos.ion)m/z:433.2[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):11.75 (s, 1H), 8.50 (d, J=2.2Hz, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.85 (dd, J=9.1,2.3Hz, 1H), 7.81 (s, 1H), 7.00 (d, J=9.2Hz, 1H), 6.75 (d, J=1.8Hz, 1H), 5.53 (d, J=9.0Hz, 1H), 4.46 (d, J=13.0Hz, 2H), 4.40-4.28 (m, 1H), 3.88 (s, 3H), 3.27 (d, J=11.6Hz, 2H), 2.05 (d, J=10.8Hz, 2H), 1.63 (dd, J=21.0,10.6Hz, 2H).
The chloro- 2- of 19 6- of embodiment (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (octahydro pentamethylene simultaneously [c] pyrroles -5- Base) -3H- imidazos [4,5-b] pyridine -7- amine
Step 1) 4,5- dichloro-3-nitropyridine -2- amine
1- chlorine is added into acetonitrile (150mL) suspension of the chloro- 3- nitro-pyridines -2- amine (5.00g, 28.85mmol) of 4- Pyrrolidine-2,5-dione (5.39g, 40.36mmol).Reaction mixture is stirred overnight at 80 DEG C, is then concentrated under reduced pressure.Gained Residue purifies to obtain crude product through silica gel column chromatography (pure DCM), crude product again through silica gel column chromatography (EA/PE (v/v)=1/5 to 1/3) it purifies, it is yellow solid (4.26g, yield 71%) to obtain title compound.
MS(ESI,pos.ion)m/z:207.9[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.27(s,1H),5.81(s,2H)。
Step 2) 5- ((the chloro- 3- nitropyridines -4- bases of 2- amino -5-) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H) - Carboxylate
Add into isopropanol (30.0mL) suspension of 4,5- dichloro-3-nitropyridine -2- amine (1.50g, 7.23mmol) Enter 5- amino hexahydros pentamethylene simultaneously [c] pyrroles -2 (1H)-carboxylate (3.27g, 14.4mmol) and DIPEA (4.22g, 32.7mmol).Reaction system is warming up to return stirring 24 hours, after reaction, is concentrated under reduced pressure.Gained residue is through silicagel column (DCM/MeOH (v/v)=100/1) purifying is chromatographed, it is yellow solid (1.62g, yield 56%) to obtain title compound.
MS(ESI,pos.ion)m/z:341.9[M-56+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.79(s,1H),7.83(s,1H),6.73(s,2H),4.72–4.62 (m,1H),3.54–3.46(m,2H),3.41–3.27(m,2H),2.71–2.63(m,2H),2.53–2.46(m,2H),1.49 (s,9H),1.47–1.43(m,2H)。
Step 3) 5- ((the chloro- 2- of 6- (1,3- dimethyl -1H- pyrazoles -4- bases) -3H- imidazos [4,5-b] pyrazoles -7- bases) Amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-carboxylate
To 5- ((the chloro- 3- nitropyridines -4- bases of 2- amino -5-) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-formic acid The EtOH (30.0mL) of tertiary butyl ester (0.62g, 1.60mmol) and 1,3- dimethyl pyrazole -4- formaldehyde (0.22g, 1.78mmol) The aqueous solution (6.30mL, 6.30mmol, 1.0mol/L) of the sodium dithionite newly prepared is added in suspension.Reaction system adds Heat is to 85 DEG C and is stirred overnight, and is then concentrated under reduced pressure.Through silica gel column chromatography, (DCM/MeOH (v/v)=50/1 is arrived gained residue 30/1 to 20/1) it purifies, it is white solid (0.50g, yield 68%) to obtain title compound.
MS(ESI,pos.ion)m/z:472.3[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.87(s,1H),7.72(s,1H),5.49–5.39(m,1H),5.03 (d, J=8.4Hz, 1H), 3.92 (s, 3H), 3.58-3.48 (m, 2H), 3.46-3.33 (m, 2H), 2.80-2.72 (m, 2H), 2.69–2.60(m,5H),1.50(s,9H),1.48–1.40(m,2H)。
The chloro- 2- of step 4) 6- (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases)) - 3H- imidazos [4,5-b] pyridine -7- amine
To 5- ((the chloro- 2- of 6- (1,3- dimethyl -1H- pyrazoles -4- bases) -3H- imidazos [4,5-b] pyrazoles -7- bases) ammonia Base) hexahydro pentamethylene is simultaneously in DCM (15.0mL) suspension of [c] pyrroles -2 (1H)-carboxylate (0.54g, 1.1mmol) The ethyl acetate solution (10.0mL, 30.0mmol, 3mol/L) of hydrogen chloride is added.Reaction mixture is stirred at room temperature 1 hour, Then, it is concentrated under reduced pressure.The Na of gained residue DCM (20mL) and saturation2CO3Aqueous solution (20mL) dilutes, and gained mixture exists 15 clocks are stirred at room temperature.It stands, separates organic layer, water layer uses DCM (20mL × 3) and DCM/MeOH (v/v)=10/1 successively (20mL × 3) extract.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Gained residue is through silicagel column (DCM/MeOH (v/v)=20/1 to 10/1 to 5/1) purifying is chromatographed, it is faint yellow solid (0.36g, yield to obtain title compound 85%).
MS(ESI,pos.ion)m/z:371.9[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):12.86(s,1H),8.19(s,1H),7.89(s,1H),5.69(d, J=8.7Hz, 1H), 5.49-5.35 (m, 1H), 3.84 (s, 3H), 3.28-3.20 (m, 2H), 3.08 (dd, J=11.6, 3.0Hz,2H),2.84–2.71(m,2H),2.51(s,3H),2.47–2.36(m,2H),1.71–1.59(m,2H)。
20 1- of embodiment (5- ((the chloro- 2- of 6- (1,3- dimethyl -1H- pyrazoles -4- bases) -3H- imidazos [4,5-b] pyrroles Pyridine -7- bases) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone
At 0 DEG C, to the chloro- 2- of 6- (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (octahydro pentamethylene simultaneously [c] pyrroles -5- Base)) -3H- imidazos [4,5-b] pyridine -7- amine (0.12g, 0.32mmol) and triethylamine (49.87mg, 0.49mmol) it is dry Acetic anhydride (40.14mg, 0.39mmol) is added in dry DCM (15.0mL) suspension.Reaction system moves to room temperature and stirs 30 points Then clock uses DCM (50mL) to dilute, gained mixture water (30mL × 2), NaHCO successively3Aqueous solution (30mL) and saturation NaCl Aqueous solution (30mL) washs.The organic phase separated is dried over anhydrous sodium sulfate, filtering, and is concentrated under reduced pressure.Gained residue is through silicon Plastic column chromatography DCM/MeOH (v/v)=30/1 to 15/1) purifying, it is white solid (75mg, yield 56%) to obtain title compound.
MS(ESI,pos.ion)m/z:413.9[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.95(s,1H),7.81(s,1H),5.55–5.40(m,1H),5.02 (d, J=8.7Hz, 1H), 3.96 (s, 3H), 3.73-3.61 (m, 3H), 3.44 (dd, J=10.8,3.7Hz, 1H), 2.92- 2.74(m,2H),2.74–2.66(m,2H),2.64(s,3H),2.11(s,3H),1.48–1.42(m,2H)。
21 3- of embodiment (5- ((the chloro- 2- of 6- (1,3- dimethyl -1H- pyrazoles -4- base -3H- imidazos [4,5-b] pyridines - 7- yls) amino) hexahydro ring penta [c] pyrroles -2 (1H)-yl) -3- oxo propionitriles
To the chloro- 2- of 6- (1,3- dimethyl -1H- pyrazoles -4- bases)-N- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases)) -3H- 2- cyano second is added in the suspension of the drying DCM (20.0mL) of imidazo [4,5-b] pyridine -7- amine (0.15g, 0.40mmol) Sour (0.052g, 0.61mmol), EDCl (0.16g, 0.81mmol) and HOAT (0.11g, 0.81mmol).Gained mixture is in room The lower stirring of temperature 30 minutes, then uses DCM (50mL) to dilute.Gained mixture is water-soluble with water (30mL × 2) respectively and saturation NaCl Liquid (30mL) washs.The organic phase separated is dried over anhydrous sodium sulfate, filtering, and is concentrated under reduced pressure.Gained residue is through silicagel column (DCM/MeOH (v/v)=30/1 to 15/1) purifying is chromatographed, it is white solid (85mg, yield 48%) to obtain title compound.
MS(ESI,pos.ion)m/z:439.3[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.92(s,1H),7.76(s,1H),5.52–5.42(m,1H),4.99 (d, J=8.5Hz, 1H), 3.94 (s, 3H), 3.78-3.61 (m, 4H), 3.45 (s, 2H), 2.96-2.78 (m, 2H), 2.76- 2.65(m,2H),2.62(s,3H),1.48–1.40(m,2H)。
The chloro- 2- of 22 6- of embodiment (1- methyl-1 H- pyrazoles -4- bases)-N- (octahydro pentamethylene [c] pyrroles -5- bases) -3H- Imidazo [4,5-b] pyridine -7- amine
Step 1) 5- ((the chloro- 2- of 6- (1- methyl-1 H- pyrazoles -4- bases) -3H- imidazos [4,5-b] pyridin-7-yl) ammonia Base) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-carboxylate
To 5- ((the chloro- 3- nitropyridines -4- bases of 2- amino -5-) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-formic acid The EtOH (50.0mL) of tertiary butyl ester (1.00g, 2.52mmol) and 1- methylpyrazole -4- formaldehyde (0.31g, 2.80mmol) suspends The aqueous solution (10.0mL, 10.0mmol, 1mol/L) of the sodium dithionate newly prepared is added in liquid.Reaction system is heated to 85 DEG C And be stirred overnight, then it is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 30/1 to 20/ 1) it purifies, it is white solid (0.71g, yield 62%) to obtain title compound.
MS(ESI,pos.ion)m/z:458.3[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.04(s,1H),8.00(s,1H),7.96(s,1H),5.53–5.41 (m, 1H), 5.08 (d, J=8.8Hz, 1H), 4.03 (s, 3H), 3.60-3.52 (m, 2H), 3.46-3.34 (m, 2H), 2.85- 2.73 (m, 2H), 2.69-2.59 (m, 2H), 1.51 (s, 9H), 1.48-1.43 (m, J=7.5,4.0Hz, 2H).
The chloro- 2- of step 2) 6- (1- methyl-1 H- pyrazoles -4- bases)-N- (octahydro pentamethylene [c] pyrroles -5- bases) -3H- imidazoles And [4,5-b] pyridine -7- amine
To 5- ((the chloro- 2- of 6- (1- methyl-1 H- pyrazoles -4- bases) -3H- imidazos [4,5-b] pyridin-7-yl) amino) six It is added in DCM (15.0mL) aaerosol solution of hydrogen pentamethylene [c] pyrroles -2 (1H)-carboxylate (0.62g, 1.40mmol) The EtOAc solution (15.0mL, 45.0mmol, 3.0mol/L) of hydrogen chloride.Gained mixture is stirred at room temperature 1 hour, then, It is concentrated under reduced pressure.The Na of gained residue DCM (20mL) and saturation2CO3Aqueous solution (20mL) dilutes, and gained mixture is in room temperature 15 clocks of lower stirring.Stand, separate organic layer, water layer use successively DCM (20mL × 3) and DCM/MeOH (v/v)=10/1 (20mL × 3) it extracts.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/2MNH3MeOH solution (v/v)=20/1 to 10/1 to 5/1) purifying, obtain title compound be white solid (0.32g, Yield 66%).
MS(ESI,pos.ion)m/z:358.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.00(s,1H),7.99(s,1H),7.84(s,1H),5.36–5.25 (m,1H),3.96(s,3H),2.88–2.82(m,4H),2.75–2.65(m,2H),2.55–2.44(m,2H),1.30–1.23 (m,2H)。
23 3- of embodiment (5- ((the chloro- 2- of 6- (1- methyl-1 H- pyrazoles -4- bases) -3H- imidazos [4,5-b] pyridine -7- Base) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) -3- oxo propionitriles
To the chloro- 2- of 6- (1- methyl-1 H- pyrazoles -4- bases)-N- (octahydro pentamethylene [c] pyrroles -5- bases) -3H- imidazos In DCM (10.0mL) suspension of the drying of [4,5-b] pyridine -7- amine (0.10g, 0.28mmol) be added EDCI (0.11g, 0.60mmol), HOAT (0.077g, 0.57mmol) and 2- cyanoacetic acids (0.049g, 0.58mmol).Gained mixture is in room temperature Under be stirred overnight, then use DCM (50mL) dilute.Gained mixture water (20mL) respectively and saturation NaCl aqueous solutions (20mL) Washing.The organic phase separated is dried over anhydrous sodium sulfate, filtering, and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/ MeOH (v/v)=50/1 to 20/1 to 15/1) purifying, it is faint yellow solid (64mg, yield 54%) to obtain title compound.
MS(ESI,pos.ion)m/z:425.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.07(s,1H),8.04(s,1H),8.01(s,1H),5.57–5.44 (m, 1H), 5.12 (d, J=8.5Hz, 1H), 4.05 (s, 3H), 3.82-3.70 (m, 2H), 3.68-3.62 (m, 1H), 3.52- 3.50 (m, 1H), 3.48 (d, J=1.9Hz, 2H), 3.03-2.81 (m, 2H), 2.77-2.66 (m, 2H), 1.54-1.41 (m, 2H)。
24 1- of embodiment (5- ((the chloro- 2- of 6- (1- methyl-1 H- pyrazoles -4- bases) -3H- imidazos [4,5-b] pyridine -7- Base) amino) hexahydro pentamethylene [c] pyrroles -2 (1H)-yl) ethyl ketone
To the chloro- 2- of 6- (1- methyl-1 H- pyrazoles -4- bases)-N- (octahydro pentamethylene [c] pyrroles -5- bases) -3H- imidazos Triethylamine is added in DCM (10.0mL) suspension of the drying of [4,5-b] pyridine -7- amine (0.090g, 0.25mmol) (0.040g, 0.39mmol) and acetic anhydride (0.032g, 0.32mmol).Reaction system is in room temperature and stirs 30 minutes, then uses DCM (50mL) dilutes, and water (20mL) and saturation NaCl aqueous solutions (30mL) wash gained mixture successively.The organic phase warp separated Anhydrous sodium sulfate is dried, filtering, and is concentrated under reduced pressure.Through silica gel column chromatography, (DCM/MeOH (v/v)=50/1 is arrived gained residue 20/1) it purifies, it is white solid (86mg, yield 85%) to obtain title compound.
MS(ESI,pos.ion)m/z:400.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.06(s,1H),8.03(s,1H),7.99(s,1H),5.56–5.44 (m, 1H), 5.05 (d, J=8.7Hz, 1H), 4.05 (s, 3H), 3.74-3.65 (m, 2H), 3.61 (dd, J=12.5,4.2Hz, 1H), 3.45 (dd, J=10.8,3.8Hz, 1H), 2.92-2.79 (m, 2H), 2.74-2.64 (m, 2H), 2.11 (s, 3H), 1.50–1.42(m,2H)。
25 2- of embodiment (1- methyl-1 H- pyrazoles -4- bases) -8- ((octahydro pentamethylene [c] pyrroles -5- bases) amino) imidazoles And [1,2-b] pyridazine -7- formamides
Step 1) 1- amino -1H- imidazoles -2- Ethyl formates
0 DEG C, add into dry THF (600mL) suspension of 1H- imidazoles -2- Ethyl formates (40.01g, 285.5mmol) Enter sodium hydride (13.82g, 345.5mmol, mass fraction 60%).Reaction mixture is stirred at room temperature 1 hour, then cools down To 0 DEG C, then O- (2,4- dinitrophenyl) azanol (80.00g, 401.8mmol) is added portionwise.Reaction system is stirred at room temperature Overnight, it is then diluted in water (600mL), gained mixture is extracted with EA (600mL × 10), and the organic phase separated is through anhydrous sulphur Sour sodium drying, filtering, and be concentrated under reduced pressure.Gained residue is pure through silica gel column chromatography (EA/PE (v/v)=1/2 to 1/1 to 2/1) Change, it is brown solid (37.6g, yield 85%) to obtain title compound.
MS(ESI,pos.ion)m/z:156.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.19 (s, 1H), 7.07 (s, 1H), 5.82 (s, 2H), 4.43 (q, J= 7.1Hz, 2H), 1.44 (t, J=7.1Hz, 3H).
Step 2) 1- ((tert- butoxy carbonyl) amino) -1H- imidazoles -2- Ethyl formates
N is added into DMF (100mL) suspension of 1- amino -1H- imidazoles -2- Ethyl formates (9.20g, 59.3mmol), N- lutidines -4- amine (1.45g, 11.89mmol), triethylamine (12.40mL, 88.90mmol) and di-tert-butyl dicarbonate (15.65g,71.69mmol).Reaction system is warming up to 85 DEG C and is stirred overnight, and is then concentrated under reduced pressure.Gained residue is through silicagel column Chromatography (EA/PE (v/v)=1/4 to 1/2 to 1/1) title compound is faint yellow solid (11.2g, yield 74%).
MS(ESI,pos.ion)m/z:256.3[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.92 (s, 1H), 7.24 (s, 1H), 7.14 (d, J=0.7Hz, 1H), 4.40 (q, J=7.1Hz, 2H), 1.50 (s, 9H), 1.41 (t, J=7.1Hz, 3H).
The bromo- 1- of step 3) 4- ((tertbutyloxycarbonyl) amino) -1H- imidazoles -2- Ethyl formates
To the DMF of 1- ((tert- butoxy carbonyl) amino) -1H- imidazoles -2- Ethyl formates (12.50g, 48.97mmol) 1- bromines pyrrolidine-2,5-dione (8.73g, 49.03mmol) is added in (100mL) suspension.Reaction system is stirred at room temperature Overnight, it is then concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (EA/PE (v/v)=1/8 to 1/6 to 1/4), must be marked Topic compound is faint yellow viscous shape liquid (12.45g, yield 76%).It is yellow solid to obtain 2.10g by-products simultaneously.
MS(ESI,pos.ion)m/z:333.8[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.08 (s, 1H), 7.22 (s, 1H), 4.38 (q, J=7.1Hz, 2H), 1.48 (s, 9H), 1.38 (t, J=7.1Hz, 3H).
By-product：
The bromo- 1- of 5- ((tertbutyloxycarbonyl) amino) -1H- imidazoles -2- Ethyl formates
MS(ESI,pos.ion)m/z:334.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.72 (s, 1H), 7.15 (s, 1H), 4.37 (q, J=7.1Hz, 2H), 1.48 (s, 9H), 1.38 (t, J=7.1Hz, 3H).
Step 4) 3- (the bromo- 1- of 4- ((tertbutyloxycarbonyl) amino) -1H- imidazoles -2- bases) -3- ethyl 3-oxopropanoates
By the drying of the bromo- 1- of 4- ((tertbutyloxycarbonyl) amino) -1H- imidazoles -2- Ethyl formates (0.35g, 1.06mmol) THF (1.0mL) suspension be cooled to 0 DEG C, the tetrahydrofuran solution of the potassium tert-butoxide cooled down in advance is then added thereto (3.20mL,3.20mmol,1mol/L).Reaction mixture stirs 5 minutes at 0 DEG C, at 0 DEG C, is added thereto cold in advance The ethyl acetate (0.26mL, 2.70mmol) of good drying.Gained mixture stirs 15 minutes at 0 DEG C, then moves to room Temperature is stirred overnight.After having reacted, reaction solution is cooled to 0 DEG C, HCl (1M, 1.0mL) is then added thereto, reaction solution becomes clear Clearly, while pH is 7.Gained mixture, which is concentrated under reduced pressure, removes most of solvent, gained residue with Ethyl acetate (10mL × 3) extraction It takes.Combined organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (EA/PE (v/v)=5/1 to 3/1 it) purifies, it is white solid (0.23g, yield 58%) to obtain title compound.
MS(ESI,pos.ion)m/z:375.8[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.25 (br, 1H), 7.33 (s, 1H), 4.20 (q, J=7.1Hz, 2H), 4.07 (s, 2H), 1.50 (s, 9H), 1.26 (t, J=7.1Hz, 3H).
The bromo- 8- oxos -5,8- glyoxalidine of step 5) 2- simultaneously [1,2-b] pyridazine -7- Ethyl formates
To 3- (the bromo- 1- of 4- ((tertbutyloxycarbonyl) amino) -1H- imidazoles -2- bases) -3- ethyl 3-oxopropanoates (1.60g, Be added in DCM (15.0mL) suspension 4.25mmol) N,N-dimethylformamide dimethylacetal (1.57g, 13.20mmol).Then reaction system is stirred overnight at room temperature to be concentrated under reduced pressure.Gained residue is not purified be directly used in it is next Step reaction (1.22g, yield 100%).
MS(ESI,pos.ion)m/z:285.8[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.53 (s, 1H), 7.63 (s, 1H), 4.30 (q, J=7.1Hz, 2H), 1.39 (t, J=7.1Hz, 3H).
The bromo- 8- oxos -5,8- glyoxalidine of step 6) 2- simultaneously [1,2-b] pyridazine -7- formic acid
To 2- bromo- 8- oxos -5,8- glyoxalidine simultaneously [1,2-b] pyridazine -7- Ethyl formates (1.22g, 4.26mmol) The aqueous solution (4.30mL, 30.10mmol, 7mol/L) of potassium hydroxide is added in EtOH (15.0mL) suspension.Mixture heats It reacts 1 hour to 100 DEG C, is then concentrated under reduced pressure.Then gained residue diluted with water is washed with EA (20mL).Water phase HCl (1M) adjusts pH=4, then filters, and filter cake is rinsed with cold water (5.0mL), then is dried under reduced pressure, and it is faint yellow to obtain title compound Solid (0.76g, yield 69%).
MS(ESI,neg.ion)m/z:255.9[M-H]-；
1H NMR(400MHz,DMSO-d6)δ(ppm):15.94(s,1H),8.27(s,1H),8.02(s,1H)。
Bromo- 8- chlorine imidazo [1,2-b] pyridazine -7- formamides of step 7) 2-
To addition trichlorine in the bromo- 8- hydroxyls of solid 2--imidazo [1,2-b] pyridazine -7- formic acid (0.72g, 2.80mmol) Oxygen phosphorus (15.0mL) and DIPEA (0.50mL, 3.00 mmol).Reaction system is reacted overnight, instead under 120 DEG C and nitrogen protection It after having answered, is concentrated under reduced pressure, gained residue is diluted and stirred 5 minutes with THF (15mL), then is concentrated under reduced pressure.This process repeats three It is secondary, gained residue is diluted with THF (10mL), is subsequently cooled to -40 DEG C, and NH is added thereto3THF solution (20mL, 3.0mol/L).Gained mixture stirs 15 minutes at -40 DEG C, then moves to and is stirred at room temperature 20 minutes, then is concentrated under reduced pressure.Institute It obtaining residue to be diluted with water (20mL), and stirs 30 minutes, filtering, filter cake is washed with water (10mL) and MTBE (10mL) successively, Be dried under reduced pressure again title compound be faint yellow solid (0.39g, yield 51%).MS(ESI,pos.ion)m/z:274.8[M +H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.73(s,1H),8.64(s,1H),8.18(br.s,1H),8.07 (br.s,1H)。
Step 8) 5- ((the bromo- 7- carbamoylimidazoles of 2- simultaneously [1,2-b] pyridazine -8- bases) amino) hexahydro pentamethylene is simultaneously [c] pyrroles -2 (1H)-carboxylate
To the n-BuOH of the bromo- 8- of 2- chloro- imidazo [1,2-b] pyridazine -7- formamides (0.39g, 1.40mmol) Be added in the suspension of (10.0mL) 5- amino hexahydros pentamethylene simultaneously [c] pyrroles -2 (1H)-carboxylate (0.66g, 2.91mmol) and N- methyl-N-isopropyls -propyl- 2- amine (0.50mL, 3.00mmol).Reaction system is heated to reflux 12 hours, Then it is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 30/1 to 20/1), must be marked Topic compound is brown solid (0.58g, yield 88%).
MS(ESI,pos.ion)m/z:464.8[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):10.54 (d, J=8.4Hz, 1H), 8.48 (s, 1H), 8.29 (s, 1H),7.97(s.br,1H),7.39(s.br,1H),5.40-5.26(m,1H),3.46–3.37(m,2H),3.26–3.17(m, 2H),2.72–2.61(m,2H),2.48–2.40(m,2H),1.40(s,9H),1.36–1.26(m,2H)。
Step 9) 5- ((7- carbamoyls -2- (1- methyl-1 H- pyrazoles -4- bases) imidazo [1,2-b] pyridazine -8- bases) Amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-carboxylate
To 5- ((the bromo- 7- carbamoylimidazoles of 2- simultaneously [1,2-b] pyridazine -8- bases) amino) hexahydro pentamethylene simultaneously [c] pyrrole It coughs up in the DME (15.0mL) of -2 (1H)-carboxylates (0.56g, 1.20mmol) and the suspension of water (3.0mL) and 1- is added Methyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- bases) -1H- pyrazoles (0.51g, 2.44mmol), 1,1'- Bis- (diphenyl is seen) ferrocene (II) palladium chloride dichloromethane complex (0.20g, 0.24mmol) and cesium carbonate (0.79g, 2.43mmol).Reaction mixture takes out air to the greatest extent, and it is multiple to be filled with nitrogen, then, is warming up to and flows back and be stirred overnight.Reaction is mixed Object is closed to be concentrated under reduced pressure.Gained residue is dissolved in water (20mL), then DCM (30mL × 5) is used to extract, combined organic phase warp Saturated salt solution (50mL) is washed, and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/ MeOH (v/v)=50/1 to 30/1) purifying, it is brown solid (0.29g, yield 52%) to obtain title compound.
MS(ESI,pos.ion)m/z:467.4[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):10.07 (d, J=8.2Hz, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.81(s,1H),7.76(s,1H),5.81–5.66(m,3H),3.99(s,3H),3.60–3.50(m,2H),3.44–3.29(m, 2H),2.82–2.71(m,2H),2.69–2.58(m,2H),1.53–1.46(m,11H)。
Step 10) 2- (1- methyl-1 H- pyrazoles -4- bases) -8- ((octahydro cyclopenta simultaneously [c] pyrroles -5- bases) amino) imidazoles And [1,2-b] pyridazine -7- formamides
To 5- ((7- carbamoyls -2- (1- methyl-1 H- pyrazoles -4- bases) imidazo [1,2-b] pyridazine -8- bases) ammonia Base) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-carboxylate (0.29g, 0.62mmol) DCM (15.0mL) suspension The middle ethyl acetate solution (15.0mL, 45.0mmol, 3mol/L) that hydrogen chloride is added.It is small that reaction mixture is stirred at room temperature 2 When, then, it is concentrated under reduced pressure.The Na of gained residue DCM (20mL) and saturation2CO3Aqueous solution (20mL) dilutes, gained mixing 15 clocks are stirred at room temperature in object.It stands, separates organic layer, water layer is extracted with DCM (20mL × 3).Water layer is concentrated under reduced pressure, and gained is solid Body is washed with MeOH (100mL), is then combined with all organic phases, then be concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/3M NH3MeOH solution (v/v)=30/1 to 20/1 to 10/1) purifying, obtain title compound be faint yellow solid (0.17g, yield 75%).
MS(ESI,pos.ion)m/z:367.3[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):10.41–10.27(m,1H),8.39(s,1H),8.20(s,1H), 8.07(s,1H),7.98–7.69(m,2H),7.27(br.s,1H),5.46–5.30(m,1H),3.89(s,3H),2.69–2.53 (m, 6H), 2.40 (dd, J=12.1,6.1Hz, 2H), 1.23-1.13 (m, 2H).
26 8- of embodiment ((2- (2- Cyanoacetyls) octahydro pentamethylene [c] pyrroles -5- bases) amino) -2- (1- methyl - 1H- pyrazoles -4- bases) imidazo [1,2-b] pyridazine -7- formamides
To 2- (1- methyl-1 H- pyrazolyl -4- bases) -8- ((octahydro pentamethylene simultaneously [c] pyrroles -5- bases) amino) imidazo In DCM (1.0mL) suspension of [1,2-b] pyridazine -7- formamides (61mg, 0.17mmol) be added EDCI (65mg, 0.34mmol), HOAT (47mg, 0.34mmol), 2- cyanoacetic acids (29mg, 0.34mmol) and Et3N(38mg,0.38mmol)。 Gained mixture is stirred at room temperature 2 hours, is then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/3M NH3's MeOH solution (v/v)=50/1 to 30/1) purifying, it is white solid (48mg, yield 66%) to obtain title compound.
MS(ESI,pos.ion)m/z:434.4[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.11–8.07(m,1H),7.76(s,1H),7.75–7.72(m,1H), 7.70 (s, 1H), 5.69-5.60 (m, 1H), 3.89 (d, J=1.6Hz, 3H), 3.73-3.65 (m, 1H), 3.65-3.56 (m, 2H),3.55–3.51(m,1H),3.51–3.45(m,1H),3.44–3.38(m,2H),2.95–2.85(m,1H),2.83–2.73 (m,1H),2.61–2.50(m,2H),1.59–1.46(m,2H)。
27 8- of embodiment ((2- acetyl group octahydros pentamethylene simultaneously [c] pyrroles -5- bases) amino) -2- (1- methyl-1 H- pyrroles Azoles -4- bases) imidazo [1,2-b] pyridazine -7- formamides
To 2- (1- methyl-1 H- pyrazolyl -4- bases) -8- ((octahydro pentamethylene simultaneously [c] pyrroles -5- bases) amino) imidazo In DCM (5.0mL) suspension of [1,2-b] pyridazine -7- formamides (65mg, 0.18mmol) be added acetic anhydride (23mg, 0.22mmol) and triethylamine (29mg, 0.29mmol).Reaction system moves to room temperature and stirs 30 minutes, is then concentrated under reduced pressure.Institute It obtains residue to purify through silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 30/1 to 20/1), it is white to obtain title compound Solid (65mg, yield 90%).
MS(ESI,pos.ion)m/z:408.9[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.08(s,1H),7.75(s,1H),7.73(s,1H),7.70(s, 1H),5.69–5.57(m,1H),3.88(s,3H),3.67–3.61(m,1H),3.59–3.52(m,1H),3.47–3.44(m, 1H),3.38–3.33(m,1H),3.29(s,2H),2.84–2.70(m,2H),2.62–2.52(m,2H),2.00(s,3H), 1.49–1.36(m,2H)。
28 8- of embodiment (3- azaspiros [5.5] hendecane -9- bases amino) -2- (1- methyl-1 H- pyrazoles -4- bases) imidazoles And [1,2-b] pyridazine -7- formamides
Step 1) 9- ((the bromo- 7- carbamoylimidazoles of 2- simultaneously [1,2-b] pyridazine -8- bases) amino) -3- azaspiros [5.5] Hendecane -3- carboxylates
To the n-BuOH of the bromo- 8- of 2- chloro- imidazo [1,2-b] pyridazine -7- formamides (0.40g, 1.46mmol) In (20.0mL) suspension be added 9- amino -3- azaspiros [5.5] hendecane -3- t-butyl formates (0.60g, 2.23mmol) and DIPEA(0.50mL,3.00mmol).Gained mixture, which is warming up to, to be flowed back and is stirred overnight, and is then concentrated under reduced pressure.Gained residue Through silica gel column chromatography (DCM/3M NH3MeOH solution (v/v)=50/1 to 30/1 to 20/1) purifying, obtaining title compound is Yellow solid (0.56g, yield 76%).
MS(ESI,pos.ion)m/z:451.2[M-56+H]+。
Step 2) 9- ((7- carbamoyls -2- (1- methyl-1 H- pyrazoles -4- bases) imidazo [1,2-b] pyridazine -8- bases) Amino) -3- azaspiros [5.5] hendecane -3- carboxylates
To 9- ((the bromo- 7- carbamoylimidazoles of 2- simultaneously [1,2-b] pyridazine -8- bases) amino) -3- azaspiros [5.5] 11 1- first is added in the DME (15.0mL) of alkane -3- carboxylates (0.53g, 1.00mmol0) and the suspension of water (3.0mL) Base -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- bases) -1H- pyrazoles (0.44g, 2.12mmol), 1,1'- are bis- (diphenyl is seen) ferrocene (II) palladium chloride dichloromethane complex (0.18g, 0.21mmol) and cesium carbonate (0.69g, 2.13mmol).Reaction mixture takes out air to the greatest extent, and it is multiple to be filled with nitrogen, then, is warming up to and flows back and be stirred overnight.Reaction is mixed Object is closed to be concentrated under reduced pressure.Gained residue is dissolved in the water in (20mL), then DCM (30mL × 5) is used to extract, combined organic phase It is washed through saturated salt solution (50mL), anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 30/1) is purified, and it is brown solid (0.42g, yield 79%) to obtain title compound.
MS(ESI,pos.ion)m/z:509.4[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):9.99 (d, J=8.3Hz, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.77(s,1H),7.72(s,1H),5.67(s,2H),5.28–5.19(m,1H),3.96(s,3H),3.47–3.32(m,4H), 2.12–1.98(m,2H),1.75–1.70(m,2H),1.63–1.49(m,4H),1.46(s,9H),1.44–1.37(m,4H)。
Step 3) 8- (3- azaspiros [5.5] hendecane -9- bases amino) -2- (1- methyl-1 H- pyrazoles -4- bases) imidazo [1,2-b] pyridazine -7- formamides
To 9- ((7- carbamoyls -2- (1- methyl-1 H- pyrazoles -4- bases) imidazo [1,2-b] pyridazine -8- bases) ammonia Base) -3- azaspiros [5.5] hendecane -3- carboxylates (0.42g, 0.83mmol) DCM (15.0mL) solution in be added The ethyl acetate solution (15.0mL, 45.0mmol, 3mol/L) of hydrogen chloride.Reaction mixture is stirred at room temperature 30 minutes, so Afterwards, it is concentrated under reduced pressure.The Na of gained residue DCM (20mL) and saturation2CO3Aqueous solution (20mL) dilutes, and gained mixture is in room Temperature is lower to stir 15 clocks, is then concentrated under reduced pressure, obtained solid is rinsed with MeOH (100mL).Filter cake is concentrated under reduced pressure, gained residue warp Silica gel column chromatography (DCM/3M NH3MeOH solution (v/v)=30/1 to 20/1 to 10/1) purifying, obtain title compound be it is light Yellow solid (0.18g, yield 53%).
MS(ESI,pos.ion)m/z:409.0[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):10.41 (d, J=8.4Hz, 1H), 8.40 (s, 1H), 8.20 (s, 1H),8.04(s,1H),8.00–7.74(m,2H),7.27(s,br,1H),5.21–5.09(m,1H),3.89(s,3H),3.45– 3.38(m,1H),2.74–2.62(m,3H),1.97–1.87(m,2H),1.73–1.63(m,2H),1.53–1.39(m,4H), 1.38–1.28(m,4H)。
29 8- of embodiment ((3- (2- Cyanoacetyls) -3- azaspiros [5.5] hendecane -9- bases) amino) -2- (1- first Base -1H- pyrazoles -4- bases) imidazo [1,2-b] pyridazine -7- formamides
To 8- (3- azaspiros [5.5] hendecane -9- bases amino) -2- (1- methyl-1 H- pyrazoles -4- bases) imidazo [1,2- B] pyridazine -7- formamides (0.11g, 0.26mmol) DCM (10.0mL) suspension in be added 2- cyanoacetic acids (47mg, 0.55mmol), HATU (0.21g, 0.54mmol) and triethylamine (0.15mL, 1.10mmol).Gained mixture stirs at room temperature It mixes 4 hours, is then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/3M NH3MeOH solution (v/v)=50/1 to 30/1 to 20/1) it purifies, it is white solid (55mg, yield 43%) to obtain title compound
MS(ESI,pos.ion)m/z:476.4[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):10.01 (d, J=8.1Hz, 1H), 8.08 (s, 1H), 7.78 (d, J= 3.4 Hz, 1H), 7.73 (s, 1H), 7.70 (d, J=1.5Hz, 1H), 5.25-5.14 (m, 1H), 3.91 (s, 3H), 3.59- 3.51(m,2H),3.51–3.47(m,1H),3.42–3.34(m,2H),3.34–3.31(m,1H),2.08–1.99(m,2H), 1.77–1.67(m,2H),1.66–1.35(m,8H)。
30 8- of embodiment ((3- acetyl group -3- azaspiros [5.5] hendecane -9- bases) amino) -2- (1- methyl-1 H- pyrroles Azoles -4- bases) imidazo [1,2-b] pyridazine -7- formamides
To 8- (3- azaspiros [5.5] hendecane -9- bases amino) -2- (1- methyl-1 H- pyrazoles -4- bases) imidazo [1,2- B] pyridazine -7- formamides (50mg, 0.12mmol) DCM (10.0mL) suspension in be added acetic anhydride (15mg, 0.15mmol) With triethylamine (20mg, 0.19mmol).Reaction system moves to room temperature and stirs 30 minutes, is then concentrated under reduced pressure.Gained residue Through silica gel column chromatography (DCM/3M NH3MeOH (v/v)=50/1 to 30/1 to 20/1) purifying, obtain title compound be white Solid (42mg, yield 75%).
MS(ESI,pos.ion)m/z:450.9[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):10.00 (d, J=8.1Hz, 1H), 8.01 (s, 1H), 7.85 (d, J= 9.1Hz, 1H), 7.78 (d, J=2.3Hz, 1H), 7.72 (d, J=5.4Hz, 1H), 5.56 (s, 2H), 5.34-5.20 (m, 1H), 3.97(s,3H),3.63–3.53(m,2H),3.47–3.37(m,2H),2.13–2.03(m,5H),1.82–1.72(m,2H), 1.60–1.51(m,4H),1.50–1.40(m,4H)。
Biologic test
The LC/MS/MS systems of analysis include the serial vacuum degassing furnaces of Agilent 1200, and binary syringe pump, orifice plate is certainly Dynamic sampler, column insulating box, charged spray ionize the Agilent G6430 three-level level four bars mass spectrographs in the source (ESI).Quantitative analysis It is carried out under MRM patterns, the parameter of MRM conversions is as in Table A：
Table A
More reaction detection scannings 490.2→383.1
Fragmentation voltage 230V
Capillary voltage 55V
Dry temperature degree 350℃
Atomizer 0.276MPa
Dry gas stream speed 10L/min
Analysis uses the Agilent μM columns of XDB-C18,2.1 × 30mm, 3.5, injects 5 μ L samples.Analysis condition：Mobile phase For 0.1% aqueous formic acid (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient such as table Shown in B：
Table B
Time The gradient of Mobile phase B
0.5min 5%
1.0min 95%
2.2min 95%
2.3min 5%
5.0min It terminates
In addition, also having 6330 series LC/MS/MS spectrometers of Agilent for analysis, noted equipped with G1312A binary Penetrate pump, G1367A automatic samplers and G1314C UV detectors；LC/MS/MS spectrometers use ESI radioactive sources.Use titer Suitable cationic model treatment is carried out to each analyte and MRM conversions carry out best analysis.It uses during analysis Capcell MP-C18 columns, specification are：100 × 4.6mm 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.
Stability in embodiment A people and rat liver microsomes
People or rat liver microsomes are placed in duplicate hole in polypropylen tubes to be incubated.It is typical be incubated mixed liquor include people or Rat liver microsomes (0.5mg protein/mL), target compound (5 μM) and total volume are NADPH (1.0mM) phosphoric acid of 200 μ L Potassium buffer solution (PBS, 100mM, pH value 7.4), untested compound is dissolved in DMSO, and is diluted using PBS, it is made A concentration of the 0.05% of final DMSO solution.And it is incubated in the water-bath communicated with air at 37 DEG C, preincubate 3 minutes Albumen is added in backward mixed liquor and starts to react.Point (0,5,10,15,30 and 60 minute) in different times is added androgynous Product ice-cold acetonitrile terminates reaction.Sample is preserved at -80 DEG C until carrying out LC/MS/MS analyses.
Concentration of the compound in people or rat liver microsomes mixtures incubated is measured 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, reaction is when different Between point (0,15 and 60 minute) terminate.
Verapamil (1 μ Μ) be used as positive control, hatch at 37 DEG C, reaction in different times point (0,5,10,15, 30 and 60 minutes) it terminates.All include positive and negative control sample in each assay method, to ensure that microsome hatches system Integrality.
In addition, stability data of the compound of the present invention in people or rat liver microsomes can also be obtained by following tests It arrives.People or rat liver microsomes are placed in duplicate hole in polypropylen tubes to be incubated.Typical mixtures incubated includes people or rat Hepatomicrosome (ultimate density：0.5mg albumen/mL), untested compound (ultimate density：1.5 μM) and total volume be 30 μ L phosphorus Sour potassium buffer solution (EDTA containing 1.0mM, 100mM, pH7.4).Untested compound is dissolved in DMSO, is used in combination potassium phosphate slow Solution dilution is rushed, it is 0.2% to make the ultimate density of DMSO.After ten minutes, 15 μ L NADPH (ultimate densities are added in preincubate： Enzymatic reaction 2mM) is carried out, entire experiment carries out in 37 DEG C of incubation tube.(0,15,30 and 60 point of point in different times Clock), 135 μ L acetonitriles (containing IS) are added and terminate reaction.It is centrifuged 10 minutes with 4000rpm, removes deproteinized, collect supernatant liquor, used LC-MS/MS is analyzed.In above-mentioned experiment, ketanserin (1 μM) is selected as positive control, hatches at 37 DEG C, reacts different (0,15,30 and 60 minute) time point terminated.All include positive and negative control sample in each assay method, it is micro- to ensure Plastochondria hatches the integrality of system.
Data analysis
For each reaction, concentration of the compound in people or rat liver microsomes are incubated is pressed (as a percentage) The plotted as percentage of opposite zero time point infers internal liver clearance rate CL 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.)。
When the compounds of this invention is incubated in people and rat liver microsomes, compound of the present invention is shown suitably Stability.
Embodiment B mouse, rat, dog and monkey oral or intravenous quantify the pharmacokinetics after the compounds of this invention Evaluation
Pharmacokinetic of the compounds of this invention in mouse, rat, dog or monkey body is assessed.This hair Bright compound is with aqueous solution or the aqueous solution of 2%HPMC+1% twen-80s, the saline solution of 5%DMSO+5%, 4%MC or glue Scrotiform formula is administered.Intravenous injection is administered, animal gives the dosage of 1 or 2mg/kg.For oral dose (p.o.), greatly Mouse and mouse are 5 or 10mg/kg, and dog and monkey are 10mg/kg.It is 0.25,0.5,1.0,2.0,3.0,4.0 at time point, Blood (0.3mL) is taken within 6.0,8.0,12 and 24 hours, and is centrifuged 10 minutes at 3,000 or 4,000rpm.Plasma solutions are collected, and It is preserved at -20 DEG C or -70 DEG C until carrying out above-mentioned LC/MS/MS analyses.
When compound intravenous injection provided by the invention is administered or is administered orally, compound of the present invention shows good Good pharmacokinetic property absorbs good and has ideal half-life period (T1/2) and higher oral administration biaavailability (F).
Embodiment C Kinase activity assays
Disclosed compound of present invention can be evaluated as the effectiveness of kinases inhibitor by following experiment.
The general description of kinase assay
Kinase assay mixes γ-by detection33The 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), it is coated with white 384 orifice plate (Greiner) of high associativity, per 60 μ L of hole.At 4 DEG C, it is incubated 24 hours.It Afterwards with 100 μ L TBS board-washings 3 times.Kinase reaction (is prepared, for example, 5mM as needed in the kinase buffer liquid that total volume is 34 μ L Hepes pH7.6,15mM NaCl, 0.01% bovine serum albumin(BSA) (Sigma#I-5506), 10mM MgCl2,1mM DTT, It is carried out in 0.02%TritonX-100).Compound is dissolved in DMSO, is added in each hole, compound is most in DMSO solution Final concentration of 1%.The measurement of each compound is at least tested twice.For example, the ultimate density of enzyme is 10nM or 20nM.Add Enter not having markd ATP (10 μM) and γ-33The ATP of P labels is (per hole 2 × 106Cpm, 3000Ci/mmol) start to react.Reaction Concussion carries out 1 hour at room temperature.384 orifice plates with 7 × PBS clean, the scintillation solution per 50 μ L of hole is then added.With Wallac Trilux counter testing results.To those of ordinary skill in the art, this is only in numerous detection methods One kind, 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 when 50% enzymatic activity.The curve for including 10 concentration points is made using the extension rate of 1/2log, is estimated IC50Value by following compound concentration (for example, make a typical curve：3μM、1μM、0.3μM、0.1μM、0.03μM、 0.01μM、0.003μM、0.001μM、0.0003μM、0μM)。
JAK1(h)
JAK1 (h) is in 20mM Tris/HCl pH=7.5,0.2mM EDTA, 500 μM of GEEPLYWSFPAKKK, 10mM vinegar Sour magnesium and [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing. Start to react after MgATP mixtures are added.After being incubated 40 minutes at room temperature, it is anti-to terminate that 3% phosphoric acid solution is added thereto It answers.The reaction solution of 10 μ L is distributed in mottled on P30 filters, 75mM phosphoric acid is used in combination to clean in 5 minutes 3 times, and It is put into methanol solution and preserves at once before dry and scinticounting.
JAK2(h)
JAK2 (h) is in 8mM MOPS pH=7.0,0.2mM EDTA, 100 μM of KTFCGTPEYLAPEVRREPRILSEEEQ EMFRDFDYIADWC, 10mM magnesium acetate and [γ-33P-ATP] (specific activity about 500cpm/pmol, concentration determine according to demand) deposit It is incubated under the conditions.Start to react after MgATP mixtures are added.After being incubated 40 minutes at room temperature, it is added thereto 3% phosphoric acid solution reacts to terminate.The reaction solution of 10 μ L is distributed in mottled on P30 filters, is used in combination 75mM phosphoric acid 5 Cleaning 3 times in minute, and be put into methanol solution and preserve at once before dry and scinticounting.
JAK3(h)
JAK3 (h) is in 8mM MOPS pH=7.0,0.2mM EDTA, 500 μM of GGEEEEYFELVKKKK, 10mM magnesium acetates [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing.It is added Start to react after MgATP mixtures.After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto to terminate reaction.It will The reaction solution of 10 μ L is distributed on P30 filters in mottled, and 75mM phosphoric acid is used in combination to clean in 5 minutes 3 times, and dry and It is put into methanol solution and preserves at once before scinticounting.
TYK2(h)
TYK2 (h) is in 8mM MOPS pH=7.0,0.2mM EDTA, 250 μM of GGMEDIYFEFMGGKKK, 10mM acetic acid Magnesium and [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing.Add Start to react after entering MgATP mixtures.After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto to terminate reaction. The reaction solution of 10 μ L is distributed in mottled on P30 filters, is used in combination 75mM phosphoric acid to clean in 5 minutes 3 times, and in drying It is preserved with being put into methanol solution at once before scinticounting.
FLT3(h)
FLT3 (h) is in 8mM MOPS pH=7.0,0.2mM EDTA, 50 μM of EAIYAAPFAKKK, 10mM magnesium acetates and [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing.It is added Start to react after MgATP mixtures.After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto to terminate reaction.It will The reaction solution of 10 μ L is distributed on P30 filters in mottled, and 75mM phosphoric acid is used in combination to clean in 5 minutes 3 times, and dry and It is put into methanol solution and preserves at once before scinticounting.
Aurora-A(h)
Aurora-A (h) is in 8mM MOPS pH=7.0,0.2mM EDTA, 200 μM of LRRASLG (Kemptide), 10mM Magnesium acetate and [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing It educates.Start to react after MgATP mixtures are added.After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto to terminate Reaction.The reaction solution of 10 μ L is distributed in mottled on P30 filters, 75mM phosphoric acid is used in combination to clean in 5 minutes 3 times, and It is put into methanol solution and preserves at once before dry and scinticounting.
Aurora-B(h)
Aurora-B (h) is in 8mM MOPS pH=7.0,0.2mM EDTA, 30 μM of AKRRRLSSLRA, 10mM magnesium acetates [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing.It is added Start to react after MgATP mixtures.After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto to terminate reaction.It will The reaction solution of 10 μ L is distributed on P30 filters in mottled, and 75mM phosphoric acid is used in combination to clean in 5 minutes 3 times, and dry and It is put into methanol solution and preserves at once before scinticounting.
Kinase assay in the present invention be completed by Millipore companies of Britain (Millipore UK Ltd, Dundee Technology Park,Dundee DD2 1SW,UK)。
In addition, the kinase activity of compound can pass through KINOMEscanTMDetection, this detection are to be based on using active sites Point guidance type Competition binding assay method quantifies detection compound.The experiment is by being combined progress, i.e. DNA marks with three kinds of compounds Remember enzyme, fixed ligand and detection compound, the competition energy of qPCR detection compounds and fixed ligands is carried out by DNA marker Power.
Most of experiment is all that the T7 bacteriophage bacterium of kinases label are cultivated from escherichia coli host derived from BL21 bacterial strains Strain, after being in the Escherichia coli of exponential phase with T7 phage-infects, 32 DEG C of oscillation incubations centrifuge lysate to bacteriolyze Filtering removal cell fragment, remaining kinases go in HEK-293 cells and carry out qPCR detections with DNA marker.Streptavidin After coated particle handles 30min with biotinylated smaller ligand room temperature, affine resin can be generated for kinase assay.Match Body particle is after extra biotin closing, through confining liquid (SEABLOCKTM(Pierce), 1% bovine serum albumin(BSA), 0.05% Polysorbas20,1mM DTT) the unbonded ligand of cleaning, reduces non-specific binding.By 1 × combination buffer (20% SEABLOCKTM, 0.17 × phosphate buffer solution, 0.05% polysorbas20,6mM DTT) in combine kinases, ligand is affine particle and Test compound is combined reaction, and all reactions are carried out in 96 orifice plates, and reaction final volume is 0.135mL, and room temperature is shaken Incubation 1 hour is swung, washing buffer (1 × phosphate buffer solution, 0.05% polysorbas20) is added and cleans affine particle, addition is washed After (1 × phosphate buffer solution, 0.05% polysorbas20,0.5 μM of non-biotinylated affinity ligand) is resuspended in de- buffer solution, room temperature Oscillation incubation 30min detects the concentration of kinases in eluent by qPCR.Kinase activity measurement described herein is in the U.S. The KINOMEscan of DiscoveRx companies (Albrae St.Fremont, CA 94538, USA)TMDepartment is measured.Kinases Activity test result is referring to Tables 1 and 2.
The JAK1 kinase assay results of 1 compound provided by the invention of table
As shown in Table 1, compound of the present invention shows that extraordinary JAK1 inhibitory activity is notable in kinase assay.
JAK2, TYK2, JAK3, Aurora-A, Aurora-B and FLT3 kinase assay of 2 compound provided by the invention of table As a result
NT expressions are not tested
As shown in Table 2, compound of the present invention shown in kinase assay preferable JAK2, TYK2, JAK3, Aurora-A, Aurora-B and FLT3 kinase inhibiting activity.
Finally it should be noted that also other modes are used for implementing the present invention.Correspondingly, the embodiment of the present invention is It will illustratively illustrate, but be not limited to content described in the invention, it is also possible to made by within the scope of the present invention Modification or the equivalents added in the claims.All publications or patent cited in the present invention will all be used as this hair Bright bibliography.

Claims (20)

1. a kind of compound is stereoisomer, the tautomerism of compound shown in formula (I) compound represented or formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein,
Z is C7-C12Spiral shell bicyclic alkyl, C7-C12Condensed-bicyclic alkyl, the 7-12 former molecular miscellaneous bicyclic group of spiral shell or 7-12 original It is molecular to condense miscellaneous bicyclic group, wherein each C7-C12Spiral shell bicyclic alkyl, C7-C12Condensed-bicyclic alkyl, 7-12 atom The miscellaneous bicyclic group of spiral shell of composition and 7-12 former molecular condensed miscellaneous bicyclic group are individually optionally by 1,2,3,4 or 5 R2Group Replaced；Or Z is C3-C7Monocyclic cycloalkyl or 3-7 former molecular monocyclic heterocycles base, wherein each C3-C7Monocycle ring Alkyl and 3-7 former molecular monocyclic heterocycles base are individually optionally by 1,2,3,4 or 5 R3Group is replaced；
Z1For H, C1-C12Alkyl, C3-C12Naphthenic base or 3-12 former molecular heterocycle, wherein each C1-C12Alkyl, C3-C12Naphthenic base and 3-12 former molecular heterocycle are individually optionally by 1,2,3,4 or 5 R3Group is replaced；
Work as U1For N when, U2For CH, U3For N；
Work as U1For C when, U2For NH, U3For N or CH；
Respectively --- -- independently is a singly-bound or a double bond；
A is pyrazolyl, optionally by 1,2 or 3 R4Group is replaced；
R1For H, F, Cl, Br, I, N3、CN、NO2、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl or-(CR6R7)nC (=O) NRaRb, wherein each C1-C12Alkyl, C2-C12Alkenyl and C2-C12Alkynyl is individually optionally by 1,2,3,4 or 5 R8Group Replaced；
Each R2It independently is F, Cl, Br, I, NO2、N3, CN, oxo (=O), C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3- C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl, 5-12 former molecular heteroaryl ,-C (=O) CH2CN、-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb,-C (=NRd)NRaRb、-N(Rd) C (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRbOr two R2, and together with the atom that they are connected, form C3-C12Naphthenic base, C6-C12Aryl, 3-12 Former molecular heterocycle or 5-12 former molecular heteroaryl groups, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl and 5-12 former molecular heteroaryl Base is individually optionally by 1,2,3,4 or 5 R8Group is replaced；
R3For F, Cl, CN, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Virtue Base, 5-12 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N (Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRb, wherein each C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12 Aryl and 5-12 former molecular heteroaryl are individually optionally by 1,2,3,4 or 5 R8Group is replaced；
R4For F, Cl, CN, C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 former molecular heterocycle Base, C6-C12Aryl, 5-12 former molecular heteroaryl ,-(CR6R7)n-ORc、-(CR6R7)n-NRaRb,-C (=O) R5、-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、-(CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRb, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 atom group At heterocycle, C6-C12Aryl and 5-12 former molecular heteroaryl are individually optionally by 1,2,3,4 or 5 R8Group institute Substitution；
Each R5It independently is C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12Alkoxy, C1-C12Alkylamino, C3-C12Ring Alkyl, 3-12 former molecular heterocycle, C6-C12Aryl, 5-12 former molecular heteroaryl ,-(C1-C4Alkylidene)- (C3-C12Naphthenic base) ,-(C1-C4Alkylidene)-(3-12 former molecular heterocycle) ,-(C1-C4Alkylidene)-(C6-C12Virtue Base) or-(C1-C4Alkylidene)-(5-12 former molecular heteroaryl), wherein above-mentioned each group individually optionally by 1,2,3, 4 or 5 R8Group is replaced；
Each R6And R7It is separately H, F, Cl, Br, I, NO2、N3、CN、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3- C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Virtue or 5-12 former molecular heteroaryl, alternatively, R6、R7With C is formed with together with the carbon atom that they are connected3-C12Naphthenic base, 3-12 former molecular heterocycle, C6-C12Aryl or 5-12 A molecular heteroaryl of original, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 The molecular heterocycle of a original, C6-C12Aryl and 5-12 former molecular heteroaryl are individually optionally by 1,2,3,4 or 5 R8Group is replaced；
Each R8It independently is F, Cl, Br, I, CN, NO2、N3、OH、NH2、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C1-C12 Halogenated alkyl, C3-C12Naphthenic base, C6-C12Aryl, 3-12 former molecular heterocycle, the molecular heteroaryl of 5-12 original, C1-C12Aminoalkyl, C1-C12Alkylamino, C1-C12Alkoxy, C1-C12Hydroxy alkyl ,-NH (C0-C4Alkylidene)-(C3-C12Ring Alkyl) ,-NH (C0-C4Alkylidene)-(C6-C12Aryl) ,-NH (C0-C4Alkylidene)-(3-12 former molecular heterocycle) ,- NH(C0-C4Alkylidene)-(5-12 former molecular heteroaryl) ,-N [(C0-C4Alkylidene)-(C3-C12Naphthenic base)]2、-N [(C0-C4Alkylidene)-(C6-C12Aryl)]2、-N[(C0-C4Alkylidene)-(3-12 former molecular heterocycle)]2、-N [(C0-C4Alkylidene)-(5-12 former molecular heteroaryl)]2、-O(C0-C4Alkylidene)-(C3-C12Naphthenic base) ,-O (C0- C4Alkylidene)-(C6-C12Aryl) ,-O (C0-C4Alkylidene)-(3-12 former molecular heterocycle) or-O (C0-C4Alkylene Base)-(5-12 former molecular heteroaryl)；
Each Ra、Rb、RcAnd RdIt is separately H, C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 The molecular heterocycle of a original, C6-C12Aryl, 5-12 former molecular heteroaryl ,-(C1-C4Alkylidene)-(C3-C12Cycloalkanes Base) ,-(C1-C4Alkylidene)-(3-12 former molecular heterocycle) ,-(C1-C4Alkylidene)-(C6-C12Aryl) or-(C1-C4 Alkylidene)-(5-12 former molecular heteroaryl) or Ra、Rb3-12 original is formed together with the nitrogen-atoms being connected with them Molecular heterocycle, wherein each C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Naphthenic base, 3-12 original Molecular heterocycle, C6-C12Aryl, 5-12 former molecular heteroaryl ,-(C1-C4Alkylidene)-(C3-C12Naphthenic base) ,- (C1-C4Alkylidene)-(3-12 former molecular heterocycle) ,-(C1-C4Alkylidene)-(C6-C12Aryl) and-(C1-C4Alkylene Base)-(5-12 former molecular heteroaryl) optionally by 1,2,3,4 or 5 independently selected from F, Cl, Br, CN, N3、NO2、 OH、NH2、C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Hydroxy alkyl, C1-C6Aminoalkyl or C1-C6Alkyl The substituent group of amino is replaced；
Each m independently is 1 or 2；With
Each n independently is 0,1,2,3 or 4.
2. compound according to claim 1, wherein Z is：
Or they Stereoisomer, wherein each X and X1It is separately-CH2,-NH- ,-S- or-O-；X2For-NH- ,-S- or-O-；Formula (Z-1) each minor structure or its stereoisomer shown in~(Z-54) are individually optionally by 1,2,3,4 or 5 R2Group is taken Generation；(Z-55) each minor structure or its stereoisomer shown in~(Z-59) are individually optionally by 1,2,3,4 or 5 R3Group institute Substitution.
3. compound according to claim 1, wherein Z is:
Or their stereoisomer, wherein formula (Z-61)~ (Z-79) each minor structure or its stereoisomer shown in are individually optionally by 1,2,3,4 or 5 R2Group is replaced；Formula (Z- 80) each minor structure or its stereoisomer shown in~(Z-95) are individually optionally by 1,2,3,4 or 5 R3Group is replaced.
4. compound according to claim 1, wherein Z1For H, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.
5. compound according to claim 1, wherein A is：
Wherein, each minor structure individually optional ground quilt shown in formula (A-1)~(A-3) 1,2 or 3 R4Group is replaced.
6. compound according to claim 1, wherein R1For H, F, Cl, Br, I, N3、CN、NO2、C1-C6Alkyl, C2-C6Alkene Base, C2-C6Alkynyl or-(CR6R7)nC (=O) NRaRb, wherein each C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is independent Optionally by 1,2 or 3 R8Group is replaced.
7. compound according to claim 1, wherein each R2It independently is F, Cl, Br, CN, oxo (=O), C1-C4Alkane Base, C2-C4Alkenyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, furyl, imidazole radicals, isoxazolyl, Evil Oxazolyl, pyrrole radicals, pyridyl group, pyriconyl, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, thiazolyl, isothiazolyl, tetrazole base, Triazol radical, thienyl, pyrazolyl, oxadiazolyls, thiadiazolyl group, pyrazinyl, triazine radical ,-C (=O) CH2CN、-(CR6R7)n- ORc、-(CR6R7)n-NRaRb,-C (=O) R5,-OC (=O) R5、-N(Rd) C (=O) R5、-(CR6R7)nC (=O) ORc、- (CR6R7)nC (=O) NRaRb、-N(Rd) S (=O)mR5Or-S (=O)2NRaRb, wherein each C1-C4Alkyl, C2-C4Alkenyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, furyl, imidazole radicals, isoxazolyl, oxazolyl, pyrrole radicals, pyrrole Piperidinyl, pyriconyl, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, thiazolyl, isothiazolyl, tetrazole base, triazol radical, thiophene Base, pyrazolyl, oxadiazolyls, thiadiazolyl group, pyrazinyl and triazine radical are individually optionally by 1,2 or 3 R8Group is replaced.
8. compound according to claim 1, wherein R3It is molecular miscellaneous for F, Cl, CN, cyclopropyl, phenyl, 4-7 original Ring group or 5-6 former molecular heteroaryl, wherein each cyclopropyl, phenyl, 4-7 former molecular heterocycle and 5-6 A molecular heteroaryl of original is individually optionally by 1,2 or 3 R8Group is replaced；
R4For F, Cl, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, 4-7 former molecular heterocycle or 5-6 A molecular heteroaryl of original, wherein each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, 4-7 atom group At heterocycle and 5-6 former molecular heteroaryl it is individually optional by 1,2 or 3 R8Group is replaced.
9. compound according to claim 1, wherein each R5It independently is C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Alkoxy, C1-C4Alkylamino, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 original are molecular Heteroaryl ,-(C1-C2Alkylidene)-(C3-C6Naphthenic base) ,-(C1-C2Alkylidene)-(4-7 former molecular heterocycle) ,- (C1-C2Alkylidene)-phenyl or-(C1-C2Alkylidene)-(5-6 former molecular heteroaryl), wherein above-mentioned each group is independent Optionally by 1,2 or 3 R8Group is replaced.
10. compound according to claim 1, wherein each R6And R7It is separately H, F, Cl, Br, CN, C1-C6Alkane Base, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl or 5-6 are former molecular Heteroaryl, wherein each C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle The former molecular heteroaryl of base, phenyl and 5-6 is individually optionally by 1,2 or 3 R8Group is replaced.
11. compound according to claim 1, wherein each R8It independently is F, Cl, Br, CN, NO2、OH、NH2、C1-C6Alkane Base, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C3-C6Naphthenic base, phenyl, 4-7 former molecular heterocycle, 5-6 The molecular heteroaryl of a original, C1-C6Aminoalkyl, C1-C6Alkylamino, C1-C6Alkoxy, C1-C6Hydroxy alkyl ,-NH (C0-C2 Alkylidene)-(C3-C6Naphthenic base) ,-NH (C0-C2Alkylidene)-phenyl ,-NH (C0-C2Alkylidene)-(4-7 is former molecular miscellaneous Ring group) ,-NH (C0-C2Alkylidene)-(5-6 former molecular heteroaryl) ,-N [(C0-C2Alkylidene)-(C3-C6Naphthenic base) ]2、-N[(C0-C2Alkylidene)-phenyl]2、-N[(C0-C2Alkylidene)-(4-7 former molecular heterocycle)]2、-N[(C0-C2 Alkylidene)-(5-6 former molecular heteroaryl)]2、-O(C0-C2Alkylidene)-(C3-C6Naphthenic base) ,-O (C0-C2Alkylene Base)-(4-7 former molecular heterocycle) or-O (C0-C2Alkylidene)-(5-6 former molecular heteroaryl).
12. compound according to claim 1, wherein each Ra、Rb、RcAnd RdIt is separately H, C1-C6Alkyl, C2- C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, the molecular heteroaryl of 5-6 original ,- (C1-C2Alkylidene)-(C3-C6Naphthenic base) ,-(C1-C2Alkylidene)-(4-7 former molecular heterocycle) ,-(C1-C2Alkylene Base)-phenyl or-(C1-C2Alkylidene)-(5-6 former molecular heteroaryl), wherein each C1-C6Alkyl, C2-C6Alkene Base, C2-C6Alkynyl, C3-C6Naphthenic base, 4-7 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-(C1- C2Alkylidene)-(C3-C6Naphthenic base) ,-(C1-C2Alkylidene)-(4-7 former molecular heterocycle) ,-(C1-C2Alkylidene)- Phenyl and-(C1-C2Alkylidene)-(5-6 former molecular heteroaryl) optionally by 1,2 or 3 independently selected from F, Cl, Br, CN、N3、OH、NH2、C1-C3Alkyl, C1-C3Halogenated alkyl, C1-C3Alkoxy, C1-C3Hydroxy alkyl, C1-C3Aminoalkyl or C1- C3The substituent group of alkylamino is replaced.
13. compound according to claim 1 is the compound of one of：
Or its stereoisomer, tautomerism Body, nitrogen oxides, solvate or pharmaceutically acceptable salt.
14. a kind of pharmaceutical composition, it includes the compounds described in claim 1-13 any one, further include pharmacy Upper acceptable auxiliary material.
15. pharmaceutical composition according to claim 14, further includes therapeutic agent, the therapeutic agent is selected from chemotherapy Agent, antiproliferative, phosphodiesterase 4 inhibitors, beta-2-adrenoreceptor agonists, corticosteroid, nonsteroidal GR excitements Agent, anticholinergic drug, antihistamine, anti-inflammatory reagent, immunosuppressor, immunomodulator, for treating atherosclerosis Drug, drug and combination thereof for treating pulmonary fibrosis.
16. compound described in claim 1-13 any one or claim 14-15 any one described pharmaceutical compositions exist The purposes in drug is prepared, the drug is for preventing, handling, treating or mitigating protein kinase mediated disease.
17. purposes according to claim 16, wherein the disease that the protein kinase mediated disease, which is JAK-, to be mediated, The disease that the disease or Aurora- that FLT3- is mediated mediate.
18. purposes according to claim 16, wherein the protein kinase mediated disease is proliferative diseases, exempts from self Epidemic disease, anaphylactia, inflammatory disease, graft rejection or cancer.
19. purposes according to claim 16, wherein the protein kinase mediated disease is colorectal cancer, Huo Qijin leaching Bar tumor, non-Hodgkin lymphoma, gastric cancer, cancer of the esophagus, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, wing Guang cancer, kidney, brain tumor, head and neck cancer, the cancer of CNS (central nervous system), glioblastoma, non-small cell lung cancer, cervical carcinoma, Orchioncus, lymph cancer, Huppert's disease, malignant lymphoma, Small Cell Lung Cancer, neuroblastoma, neuroendocrine are thin Palpebral edema tumor, medullary carcinoma of thyroid gland, melanoma, retinoblastoma, uterine cancer, oophoroma, primary macroglobulinaemia, Monocytic leukemia, Sezary syndromes, infectious mononucleosis, colitis, pancreatitis, atherosclerosis, It is pulmonary fibrosis, polycythemia vera, primary thrombocytosis, myelofibrosis, acute myelocytic leukemia, slow Property myelocytic leukemia, acute lymphoblastic leukemia, Chronic Obstructive Pulmonary Disease, asthma, systemic loupus erythematosus, skin Type lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren syndrome, psoriasis, type-1 diabetes mellitus, respiratory anaphylactic disease, nose Sinusitis, eczema, measles, food hypersenstivity, insect venom allergies, inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile form Arthritis, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or cell transplant rejection.
20. compound described in claim 1-13 any one or claim 14-15 any one described pharmaceutical compositions exist Prepare the purposes in drug, the drug is used for the activity of regulatory protein kinases, wherein the protein kinase be JAK1 kinases, JAK2 kinases, JAK3 kinases, Aurora-A kinases, Aurora-B kinases, Aurora-C kinases or combination thereof.
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