CN104926824B - Substituted heteroaryl compound and combinations thereof and purposes - Google Patents

Substituted heteroaryl compound and combinations thereof and purposes Download PDF

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CN104926824B
CN104926824B CN201510114658.XA CN201510114658A CN104926824B CN 104926824 B CN104926824 B CN 104926824B CN 201510114658 A CN201510114658 A CN 201510114658A CN 104926824 B CN104926824 B CN 104926824B
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disease
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CN104926824A (en
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习宁
李敏雄
李晓波
戴伟龙
王婷瑾
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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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

Heteroaryl compound the invention provides class substitution and combinations thereof and their purposes.Described compound is the compound shown in formula (I) or the stereoisomer of compound, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug shown in formula (I).Present invention also offers the pharmaceutical composition comprising the compound, described compound and pharmaceutical composition can be with the activity of regulatory protein kinases, for preventing, processing, treat and mitigating protein kinase mediated disease or disorder.

Description

Substituted heteroaryl compound and combinations thereof and purposes
Invention field
The invention belongs to drug field, and in particular to a class as kinase activity inhibitor noval chemical compound, prepare them Method, the pharmaceutical composition comprising the compound and the compound and its pharmaceutical composition treating various different diseases Application in disease.More specifically, compound of the present invention can as 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 or function inhibitor.
Background of invention
Protein kinase family includes the related enzyme of a big class formation, and they control intracellular various signal transduction processes, 250-300 similar amino acid catalytic domain is usually contained, the phosphorylation of target proteins matter substrate is catalyzed.It was reported that many diseases It is relevant with the abnormal cell response that protein kinase mediated event triggers.These diseases include benign and pernicious proliferative disease Disease, allograft rejection, graft versus host disease, LADA caused by disease, the inappropriate activation of immune system Disease, inflammatory disease, bone disease, metabolic disease, sacred 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 the various biological processes of regulation such as cell propagation, migration, differentiation and life One of central event deposited.The acceptor 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.At present, above-mentioned each kinase families general homology is had confirmed that 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 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 highly relevant serine/threonine kinase of a class, and it is mitotic crucial tune Section agent, 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 relevant kinases of three classes, referred to as Aurora-A, Aurora-B and Aurora-C (also referred to as Aurora-1, Aurora-2 and Aurora-3).Although these kinases have significant program homology, its localization and work( Still can greatly there are different (Richard D.Carvajal, et al., Clin Cancer Res., 2006,12 (23) 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 through the M phases from the phase in late period S, including centerbody into Ripe, (Berdnik D, et al., Curr Biol., 2002,12:640-647), mitosis enters (Hirota T, et al.,Cell 2003,114:585-598；Dutertre S,et al.,J Cell Sci.2004,117:2523-2531), in Heart body separates (Marumoto T, et al., J Biol Chem., 2003,278:51786-51795), the two poles of the earth mitotic spindle assembly Thing (Eyers PA, et al., Curr Biol.2003,13:691-7.), on equatorial plate Chromosomal arrangement (Marumoto T, et 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. All increase through M phases Aurora-A protein level and kinase activity from G2, its peak activity is in the prometaphase.Once activation, Aurora-A mediates its various function by including that centrosome protein (centrosomin) interacts with various substrates, conversion Acidity curling-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), to kinetochore and centromere, (Murata-Hori M, et are adhered in correct micro-pipe-centromere for protein localization al.,Curr Biol.2002,12:894-899), and the crucial chromosome passenger's albumen of regulation Mitotic checkpoint.Aurora- B first during early stage localization in chromosome, then during prometaphase and mid-term localization between sister chromatids Interior kinetochore area (Zeitlin SG, et al., J Cell Biol., 2001；155:1147-1157).Aurora-B is participated in The biological orientation of chromosome is established, wherein sisters centromere is connected to the opposite pole of the two poles of the earth spindle via double orientation attachment.The mistake The mistake of journey, shows as partially oriented connection status (centromere is connected to from bipolar micro-pipe) or altogether orientation connection shape State (two sisters centromeres are connected to the micro-pipe from same stages), if the not correction up before the later stage starts, will cause dye The unstability and aneuploidy of colour solid.The Main Function of the Aurora-B of mitosis point be the incorrect micro-pipe of repairing- Centromere attachment (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 There is (Weaver BA, et al., Cancer Cell, 2005,8 in qualitative and tumour:7-12).
Aurora-A overexpression is the tumorigenic required feature of Aurora-A- inductions.In tool Aurora-A overexpression Cell in, mitotic feature be exist multiple centerbodies and multipolar spindle (Meraldi Pet al., EMBO J, 2002,21：483-92.).Although obtaining abnormal microtubule-centromere attachment, cell is still abolished Mitotic checkpoint and is entered from mid-term Exhibition causes many chromosome separation defects to the later stage.These cells will not occur cytokinesis, and develop other cell Cycle, polyploidy and progressive chromosome instability (Anand S, et al., Cancer Cell, 2003,3:51-62).
It is verified Aurora overexpression and various malignant proliferative disorders, such as 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 stomach cancer etc., it is closely related, excite and be developed for cancer The interest of the Aurora inhibitor for the treatment of.In normal cell, Aurora-A suppresses to cause to delay but and non-blacked mitosis Centerbody into, monopole mitotic spindle separates defect 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-type-person In class pancreatic carcinoma (Panc- Ι, Μ Ι Α PaCa-2dnSU.86.86), wherein having growth inhibition in cell culture And the tumorigenicity in murine xenogralt it is intimate all eliminate (Hata T, et al., Cancer Res., 2005, 65:2899-2905)。
Aurora-B suppresses to cause abnormal centromere-micro-pipe attachment, cannot realize biological orientation, the cytokinesis of chromosome 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 does not cause huge many times Property simultaneously ultimately results in 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)。
Suppressing Aurora-A or Aurora-B activity in tumour cell causes Chromosomal arrangement to damage, 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 more preferably (Ditchfield C, et al., J Cell Biol., 2003,161:267-280), so that, target Aurora can realize the internal selectivity to cancer.Although it is foreseen that may be to the quick of hemopoietic system and gastrointestinal system to it Noble cells has certain toxicity, but activity and clinical tolerability in xenograft models still shows that rational treatment refers to Number.On the premise of preclinical antitumor activity and tumor-selective potentiality, several Aurora As are had been developed at present and is suppressed Agent.
FLT3 (Flt3, FMS- related EGFR-TK 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.Cell.Biochem.,1983,21: 151-159；Yarden Y,et al.,EMBO J,1987,6:3341-3351).FLT3 is transmembrane protein, by four structures Domain constitutes, comprising five extracellular ligand-binding domain of immunoglobulin class structure composition, cross-film (TM) domain, nearly film (JM) domain With cytoplasm C- terminal tyrosines kinases (TK) domain.(Agnes F,et al.Gene,l994,145:283-288；Scheijen B,et al.,Oncogene,2002,21:3314-3333)。
The part of FLT3 was cloned in 1993, was shown according to the study, and it is that Hematopoietic marrow microenvironment cell includes marrow Expressed in fibroblast and other cells type I transmembrane proteins (Lyman SD, et al., Cell, 1993,75, 1157-1167).Film combination and soluble form can activated receptor tyrosine kinase activity and stimulate ancestral in marrow and blood Cell growth.The zygotic induction receptor dimer of ligand-receptor, and activated protein kinase domain；Then its autophosphorylation and it is catalyzed each The substrate protein phosphorylation of signal transduction pathway is planted, such as transcribes 5 signal transducer and activator (STAT5), RAS/ mitogens The protein kinase (RAS/MAPK) of original activation, phosphoinositide 3-kinase (PI3K), Src of the same race and glue protogene (SHC), contain Inositol -5- phosphatases (SHIP) of SH2 and with 2 cytoplasmic tyrosine phosphoric acid of Src- homologys 2 (SH2) domain (SHP2) Enzyme, it is bred in cell, play a significant role in differentiation and existence (Dosil M., et al., Mol Cell Biol., 1993, 13:6572-6585.Zhang S,Biochem Biophys Res Commun.,l999,254:440-445).Except hematopoiesis is thin Outside born of the same parents, FLT3 genes also expression (Maroc N, the et al., Oncogene, 1993,8 in placenta, sexual gland and brain:909- 918) and in immune response play a significant role (deLapeyriere O.et al., Leukemia, 1995,9:1212- 1218)。
FLT3 also with malignant proliferative lesion before hemopoietic system dysfunction, 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 not limited to leukaemia, (NHL), 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), CNL (CNL), closely related.Acute myeloid leukaemias (AML) of the FLT3 in 70-100% In, and in the ALL (ALL) of high percentage with each horizontal overexpression (Griffin JD, et al., Haematol J.,2004,5:188-190).In BC, it is also in the smaller of chronic myelogenous leukemia (CML) Overexpression in hypotype.Research has shown that B pedigree leukaemias ALL and AML are continually co-expressed FL, causes FLT3 composing types to be lived The circulation of autocrine or paracrine signal transduction (the Zheng R, et.al.Blood., 2004,103 of change:267-274).Additionally, FLT3L is in langerhans cell histiocytosis and Patients with SLE cell serum with high-level table Reach, further display FLT3 is extremely closely related with the dendritic cells Signal Regulation of autoimmune disease.
Increasing evidence shows that polytype leukaemia and myeloproliferative syndrome have the prominent of EGFR-TK Become.FLT3 mutation are one of most frequent body changes in AML, are occurred in about 1/3 patient.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, it includes Asp835Tyr (D835Y), Asp835Val (D835V), Asp835His (D835H), Asp835Glu (D835E), Asp835Ala (D835A), Asp835Asn (D835N), Asp835 lack The Ile836 that becomes estranged missings (Yamamoto Y, et al., Blood, 2001,97:2434-2439；Abu-Duhier FM, et al.,Br.J.Haematol.,2001,113:983-988).Internal series-connection duplication (ITD) mutation in JM domains contributes in AML The FLT3 Activating mutations of about 17-34%.FLT3-ITD is also able to detect (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 always inframes, and it is confined to JM domains.However, in different patients, there is change its length and position Change.These repetitive routines can be used to destroy JM domains from inhibitory activity, cause FLT3 composing types to activate.FLT3-ITD and FLT3-Asp835 mutation it is relevant 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)。
At present, the FLT3 inhibitor for grinding has the recurrence or obstinate AML patient that FLT3 is mutated as some or all Monotherapy reached clinical test.Generally, these as shown by data FLT3 is for being developed for AML with other about disease The attractive therapeutic targets of the kinase inhibitor of disease.
Janus kinases (JAK) is an intracellular non-receptor tyrosine kinase family, is led to by turning JAK-STAT Road, the signal of transducer cell factor mediation.Propagation regulation and be related to the cell of immune response that JAK families rely in cell factor Played an important role in function.Cell factor is combined with their acceptor, causes receptor dimerization, can so promote JAKs phases Mutual phosphorylation, can also promote cytokine receptor internal specific tyrosine motif phosphorylation.Recognize these phosphorylation motifs STATs is focused on acceptor, is then activated during the tyrosine phosphorylation that JAK is relied on.Due to activation, STATs with Acceptor dissociates, dimerization, and is displaced to nucleus, is combined with specific DNA sites, and change transcription.
It is currently, there are mammal JAK family members known to four kinds：(Janus swashs for 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 preferentially expressed in NKT (NK) cell, without at other T cell in express (" Biology and significance of the JAK/STAT signaling pathways. " Growth Factors,April 2012；30(2):88).
JAK1 is necessary to the signal transduction of some I types and II cytokines.Its γ with I cytokines acceptors Public chain (γ c) interacts, and induces IL-2 receptor families, IL-4 receptor families, gp130 receptor families to send signal.It is to I The signal of type (IFN-α/β) and II types (IFN-γ) interferon, and by the IL-10 family members of II cytokines acceptors 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 Ground, the sign to the tissue from JAK1 knock-out mices demonstrates the kinases in IFN, and IL-IO, IL-2/IL-4 and IL-6 lead to Key effect in road.
JAK1 expression in cancer cell can promote individual cells atrophy, them is fled from tumour, be transferred to body Other positions of body.By the cell factor of JAK1 transduction signals, the raising of its level involves substantial amounts of immune and inflammation disease Disease.JAK1 or JAK family kinase inhibitors can be used to 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 source of IL-6 paths Monoclonal antibody (Torr pearl monoclonal antibody Tocilizumab) is ratified for treating moderate to severe rheumatoid joint by EU Committee 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 acceptors man The signal transduction of race member is relevant.JAK2 signals are activated in the downstream of hprl receptor.Research shows in myeloproliferative In the disease such as disease such as polycythemia vera, primary thrombocytosis and idiopathic myelofibrosis, generally deposit (JAK2V617F) is mutated in the JAK2 of acquired activation.The JAK2 albumen of mutation can be in situation about stimulating without cell factor Lower activation downstream signal, causes spontaneous growth and/or the hypersensitivity to cell factor, and it is considered as 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 is had 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 main to express in immunocyte, and the tyrosine phosphorus for passing through interleukin-2-receptor Acidifying activation, transduction signal.Due to being limited to express JAK3 in candidate stem cell, relative to other JAKs, it is in cell factor more Effect in signal transduction is stricter.The mutation of JAK3 can cause severe combined immunodeficiency (SCID) (O'Shea et al.,2002,Cell,109(suppl.):S121-S131).Based on its adjust lymphocyte in effect, targeting JAK3 and The path of JAK3 mediations has been used for treatment 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 and IL-12 signal transduction are related.Biochemical research and knock out mice Disclose important function of the TYK2 in immunology.TYK2 deficient mice energy growth and breedings, but panimmunity defect is shown, most Hypersensitivity and defective oncological surveillance mainly to infecting.Opposite, suppressing TYK2 can improve resistance allergy, autologous exempt from The ability of epidemic disease and inflammatory disease.Especially, targeting TYK2 seems to turn into the disease for the treatment of IL-12-, IL-23- or I types IFN- mediation The innovative strategy of disease.The disease includes but is not limited to rheumatoid arthritis, multiple sclerosis, lupus, psoriasis, silver bits Disease arthritis, IBD, 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 total 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 Outward, targeting IL-12 and IL-23 paths antibody carried out for treat Crohn disease clinical test (Mannon et al., 2004,N.Engl.J.Med.351:2069-79)。
When adjusting not normal, the response of JAK- mediations can positively or negatively influence cell, cause overactivity to be disliked respectively Property tumour, or immune and hematopoietic defect, which imply the practicality of jak kinase inhibitor.JAK/STAT signal paths involve To many propagation 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).Additionally, 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 paths, particularly JAK families, are considered as in asthma reaction, chronic resistance Plug property tuberculosis, works in bronchitis, and the pathogenesis of other related lower respiratory tract inflammatory diseases.JAK/STAT leads to Road equally (includes, but not limited to iritis, uvea in ocular inflammatory disease (diseases)/disease (conditions) Inflammation, sclerotitis, conjunctivitis) and chronic anaphylaxis reaction in work.Because the JAK of the various multi-forms of cell factor application swashs Enzyme (O'Sullivan et al., Mol.Immunol, 2007,44:2497；Murray J.,Immunol,2007,178: 2623), the jak kinase of different choice is logical to treat the related disease of the specific cells factor or JAK/STAT in antagonism family Variability or the related disease of polymorphism are probably useful in road.
Rheumatoid arthritis (RA) is a kind of autoimmune disease being characterized with chronic joint inflammation.Take JAK suppressions The patient with rheumatoid arthritis of preparation shows the suppression of the JAK1 and JAK3 module by signal triggered 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.367,495–507(2012)].It is assumed that directly making specific JAK sub- The micromolecular inhibitor of type inactivation can not only mitigate the clinical symptoms of RA, it is also possible to suppress those and promote being permitted for RA disease progressions Undue regulation (" the Inhibitors of JAK for the treatment of rheumatoid of many 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 Knurl, prostate tumor, ovarioncus and liver cancer, while in existing in substantial amounts of blood tumor, including lymthoma and leukaemia.In this side Face, the inactivation propagation capable of inhibiting cell and/or inducing cell apoptosis of the JAK/STAT signals in neoplastic hematologic disorder.Although tumour cell In STAT3 can be by many kinase activations, JAK2 is still counted as most important upstream activat person, it can activate come from it is each Plant STAT3 (Mohamad Bassam Sonbol, the Belal Firwana, Ahmad in the human tumor cell line of 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 JAK2inhibitor AZD1480potently blocks Stat3signaling and oncogenesis in solid tumors.”Cancer Cell 2009；16(6):487–97.).Therefore, jak kinase is suppressed Treatment to these diseases plays beneficial effect.
Know clearly, kinases inhibitor is poly- as new immunosupress, anti-inflammatory double action medicine and anticancer medicine Numerous concerns are collected.Therefore, the novel agent of suppression protein kinase such as Aurora A, FLT3 kinases and jak kinase is needed for a long time Or reagent is improved, it can be used as the immunodepressant of organ transplant, antitumor agent, it can also be used to prevent and treat autoimmunity disease Disease is (for example, multiple sclerosis, psoriasis, rheumatoid arthritis, asthma, type i diabetes, IBD, Crow grace Disease, polycythemia vera, primary thrombocytosis, myelofibrosis, AITD, A Erzi seas 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, ALL, white blood Disease, Huppert's disease) and the immune response (for example, fash, contact dermatitis or diarrhoea) that causes of other treatment, etc..This Compound, composition and the method for inventing description directly correspond to these needs and other purposes.
Abstract of invention
Suppress the invention provides a class, adjust and/or one or more protein kinase of regulation and control, such as jak kinase, FLT3 swashs The compound of enzyme and Aurora A activity, for treating proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease Disease, graft rejection and their complication.Method present invention provides these compounds are prepared, uses these chemical combination The method of the above-mentioned disease of thing treatment mammal, the especially mankind, and the pharmaceutical composition comprising these compounds.This hair Bright compound and combinations thereof possesses preferable potential applicability in clinical practice.Compared with existing similar compound, of the inventionization Compound has more preferable pharmacological activity, medicine for property, physicochemical property and/or toxicological characteristics.Specifically, the compounds of this invention pair Kinase targets show preferable inhibitory activity, shown in pharmacokinetic trial in animal body good absorption and compared with Bioavilability high, and the compounds of this invention solubility is preferably, with more excellent druggability.
Specifically：
On the one hand, compound the present invention relates to one kind as shown in formula (I) or the alloisomerism of compound shown in formula (I) Body, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein, Z, Z1, A, W and R1With implication as described in the present invention.
In some embodiments, Z isWherein, X and X ' are each independently O, Z is optionally by 1,2,3, 4 or 5 R3Group is replaced；
Z1It is H, C1-C12Alkyl, C3-C12Cycloalkyl or 3-12 former molecular heterocyclic radical, wherein, Z1Optionally by 1, 2nd, 3,4 or 5 R4Group is replaced；
A is pyrazolyl, and it is optionally by 1,2,3,4 or 5 R5Group is replaced；
W is N；
R1It is H, F, Cl, Br, I, NO2、N3、CN、C1-C12Alkyl, C1-C12Haloalkyl, C1-C12Alkoxy, C2-C12Alkene Base, C2-C12Alkynyl, C3-C12Cycloalkyl, 3-12 former molecular heterocyclic radical, C6-C12Aryl, 5-12 original are molecular miscellaneous Aryl ,-(CR7R8)n-ORc、-(CR7R8)n-NRaRb,-C (=O) R6,-OC (=O) R6、-O(CR7R8)n-R6、-N(Rc) C (=O) R6、-(CR7R8)nC (=O) ORc、-(CR7R8)nC (=O) NRaRb,-C (=NRc)NRaRb、-N(Rc) C (=O) NRaRb、-N(Rc)S (=O)mR6Or-S (=O)2NRaRb, wherein, R1Optionally by 1,2,3,4 or 5 R9Group is replaced；
Each R3It independently is H, F, Cl, Br, I, NO2、CN、N3、OH、NH2,-C (=O) CH2CN、C1-C12Alkyl, C1-C12Halogen Substituted alkyl, C1-C12Alkoxy, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6-C12Aryl, 3-12 original are molecular Heterocyclic radical, 5-12 former molecular heteroaryl ,-(CR7R8)n-ORc、-(CR7R8)n-NRaRb,-C (=O) R6,-S (=O)2R6,-OC (=O) R6、-O(CR7R8)n-R6、-O(CR7R8)n-ORc、-N(Rc) C (=O) R6、-(CR7R8)nC (=O) ORc、- (CR7R8)nC (=O) NRaRb,-C (=NRc)NRaRb、-N(Rc) C (=O) NRaRb、-N(Rc) S (=O)mR6Or-S (=O)2NRaRb, or two adjacent R3, and together with the atom being connected with them, form C3-C12Cycloalkyl or 3-12 atom composition Heterocycloalkyl, wherein, it is above-mentioned it is each substitution base individually optionally by 1,2,3,4 or 5 R9Group is replaced；
Each R4And R5It is separately H, F, Cl, Br, I, NO2、CN、N3、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynes Base, C3-C12Cycloalkyl ,-(C1-C4Alkylidene)-(C3-C12Cycloalkyl), C6-C12The individual former molecular heterocyclic radical of aryl, 3-12 ,- (C1-C4Alkylidene)-(3-12 former molecular heterocyclic radical), 5-12 former molecular heteroaryl ,-(CR7R8)n-ORc、- (CR7R8)n-NRaRb,-C (=O) R6,-OC (=O) R6、-O(CR7R8)n-R6、-N(Rc) C (=O) R6、-(CR7R8)nC (=O) ORc、-(CR7R8)nC (=O) NRaRb,-C (=NRc)NRaRb、-N(Rc) C (=O) NRaRb、-N(Rc) S (=O)mR6Or-S (= O)2NRaRb, wherein, above-mentioned each R4And R5Individually optionally by 1,2,3,4 or 5 R9Group is replaced；
Each R6It independently is H, C1-C12Alkyl, C1-C12Haloalkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, wherein, each R6It is individually optional Ground is by 1,2,3,4 or 5 R9Group is replaced；
Each R7And R8It is separately H, F, Cl, Br, I, NO2、N3、CN、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynes Base, C3-C12Cycloalkyl, C6-C12Aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, or R7And R8, and together with the carbon atom being connected with them, form C3-C12Cycloalkyl, C6-C12Aryl, 3-12 former molecular heterocycle Base or 5-12 former molecular heteroaryl groups, wherein, above-mentioned each substitution base is individually optionally by 1,2,3,4 or 5 R9Base Group is replaced；
Each R9It independently is F, Cl, Br, I, CN, NO2、N3、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Ring Alkyl, C6-C12Aryl, 3-12 former molecular heterocyclic radical, 5-12 former molecular heteroaryl, NH2、-NH(C1-C12Alkane Base) ,-NH (CH2)n-(C3-C12Cycloalkyl) ,-NH (CH2)n-(C6-C12Aryl) ,-NH (CH2)n- (3-12 is former molecular miscellaneous Ring group) ,-NH (CH2)n- (5-12 former molecular heteroaryl) ,-N (C1-C12Alkyl)2、-N[(CH2)n-(C3-C12Cycloalkanes Base)]2、-N[(CH2)n-(C6-C12Aryl)]2、-N[(CH2)n- (3-12 former molecular heterocyclic radical)]2、-N[(CH2)n-(5- 12 molecular heteroaryls of original)]2、OH、-O(C1-C12Alkyl) ,-O (CH2)n-(C3-C12Cycloalkyl) ,-O (CH2)n-(C6-C12 Aryl) ,-O (CH2)n- (3-12 former molecular heterocyclic radical) or-O (CH2)n- (5-12 former molecular heteroaryl)；
Each Ra、RbAnd RcIt is separately H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl ,-(C1- C4Alkylidene)-(C3-C6Cycloalkyl), 3-6 former molecular heterocyclic radical ,-(C1-C4Alkylidene)-(3-6 is former molecular miscellaneous Ring group), C6-C10Aryl ,-(C1-C4Alkylidene)-(C6-C10Aryl), 5-10 former molecular heteroaryls or-(C1-C4Alkylene Base)-(5-10 former molecular heteroaryl), or RaAnd Rb, and together with the nitrogen-atoms being connected with them, form 3-8 atom The heterocyclyl groups of composition, wherein, it is above-mentioned it is each substitution base individually optionally by 1,2,3 or 4 be independently selected from F, Cl, Br, CN, N3、OH、NH2、C1-C6Alkyl, C1-C6Haloalkyl, C1-C6Alkoxy or C1-C6The substitution base 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, Z1It is H, C1-C6Alkyl, C3-C6Cycloalkyl or 3-6 former molecular heterocyclic radical, Wherein, Z1Optionally by 1,2 or 3 R4Group is replaced.
In some embodiments, R1It is H, F, Cl, CN, N3、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogen Substituted alkyl, C1-C6Alkoxy, C3-C6Cycloalkyl, 3-6 former molecular heterocyclic radical ,-(CR7R8)n-ORc、-(CR7R8)n- NRaRb,-C (=O) R6、-(CR7R8)nC (=O) NRaRbOr-S (=O)2NRaRb, wherein, R1Optionally by 1,2 or 3 R9Group Replaced.
In other embodiments, each R3It independently is H, F, Cl, CN, N3、NO2、OH、NH2,-C (=O) CH2CN、C1- C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Haloalkyl, C3-C6Cycloalkyl, phenyl, 3-6 atom group Into heterocyclic radical, 5-6 former molecular heteroaryl ,-(CR7R8)n-ORc、-(CR7R8)n-NRaRb,-C (=O) R6,-S (=O)2R6、-O(CR7R8)n-R6、-O(CR7R8)n-ORc、-N(Rc) C (=O) R6、-(CR7R8)nC (=O) NRaRb、-N(Rc) C (=O) NRaRb、-N(Rc) S (=O)mR6Or-S (=O)2NRaRb, or two adjacent R3, and together with the atom being connected with them, shape Into C3-C6Cycloalkyl or 3-6 former molecular heterocycloalkyl, wherein, above-mentioned each substitution base is individually optionally by 1,2 or 3 Individual R9Group is replaced.
In some embodiments, each R4And R5It is separately H, F, Cl, Br, I, NO2、N3、CN、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl ,-(C1-C2Alkylidene)-(C3-C6Cycloalkyl), phenyl, 3-6 atom composition Heterocyclic radical ,-(C1-C2Alkylidene)-(3-6 former molecular heterocyclic radical), 5-6 former molecular heteroaryl ,- (CR7R8)n-ORc、-(CR7R8)n-NRaRb,-C (=O) R6,-OC (=O) R6、-O(CR7R8)n-R6、-N(Rc) C (=O) R6、- (CR7R8)nC (=O) ORc、-(CR7R8)nC (=O) NRaRb、-N(Rc) S (=O)mR6Or-S (=O)2NRaRb, wherein, each R4And R5 Individually optionally by 1,2 or 3 R9Group is replaced.
In other embodiments, each R6It independently is H, C1-C6Alkyl, C1-C6Haloalkyl, C2-C6Alkenyl, C2-C6 Alkynyl, C3-C6Cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, wherein, each R6Solely Stand optionally by 1,2 or 3 R9Group is replaced.
In some embodiments, each R7And R8It is separately H, F, Cl, Br, I, CN, N3、NO2、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl Base, or R7And R8, and together with the carbon atom being connected with them form C3-C6Cycloalkyl, phenyl, 3-6 former molecular heterocycle Base or 5-6 former molecular heteroaryl groups, wherein, above-mentioned each substitution base is individually optionally by 1,2 or 3 R9Group is taken Generation.
In other embodiments, each R9It independently is F, Cl, CN, N3、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical, 5-6 former molecular heteroaryl, NH2、-NH(C1-C6Alkane Base) ,-NH (CH2)n-(C3-C6Cycloalkyl) ,-NH (CH2)n- phenyl ,-NH (CH2)n- (3-6 atom constitutes heterocyclic radical) ,-NH (CH2)n- (5-6 former molecular heteroaryl) ,-N (C1-C4Alkyl)2、-N[(CH2)n-(C3-C6Cycloalkyl)]2、-N [(CH2)n- phenyl]2、-N[(CH2)n- (3-6 former molecular heterocyclic radical)]2、-N[(CH2)n- (5-6 is former molecular miscellaneous Aryl)]2、OH、-O(C1-C6Alkyl) ,-O (CH2)n-(C3-C6Cycloalkyl) ,-O (CH2)n- phenyl ,-O (CH2)n- (3-6 atom The heterocyclic radical of composition) or-O (CH2)n- (5-6 former molecular heteroaryl).
In some embodiments, each Ra、RbAnd RcIt is separately H, C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C3-C6Cycloalkyl ,-(C1-C2Alkylidene)-(C3-C6Cycloalkyl), 3-6 former molecular heterocyclic radical ,-(C1-C2Alkylidene)- (3-6 former molecular heterocyclic radical), phenyl ,-(C1-C2Alkylidene)-phenyl, 5-6 former molecular heteroaryl or-(C1- C2Alkylidene)-(5-6 former molecular heteroaryl), or RaAnd Rb, and together with the nitrogen-atoms being connected with them, form 3-6 Individual former molecular heterocyclyl groups, wherein, it is above-mentioned it is each substitution base individually optionally by 1,2 or 3 be independently selected from F, Cl, CN, N3、OH、NH2、C1-C4Alkyl, C1-C4Haloalkyl, C1-C4Alkoxy or C1-C4The substitution base of alkyl amino is replaced.
In other embodiments, A is
In some embodiments, Z1It is H, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.
In other embodiments, R1It is H, F, Cl, CN, N3、C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4 Haloalkyl, C1-C4Alkoxy, C3-C6Cycloalkyl, 3-6 former molecular heterocyclic radical ,-(CR7R8)n-ORc、-(CR7R8)n- NRaRb,-C (=O) R6、-(CR7R8)nC (=O) NRaRbOr-S (=O)2NRaRb, wherein, R1Optionally by 1,2 or 3 R9Group Replaced.
In some embodiments, each R3It independently is H, F, Cl, CN, N3、NO2、OH、NH2,-C (=O) CH2CN、C1-C4 Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Alkoxy, C1-C4Haloalkyl, C3-C6Cycloalkyl, phenyl, 3-6 atom group Into heterocyclic radical, 5-6 former molecular heteroaryl ,-(CR7R8)n-ORc、-(CR7R8)n-NRaRb,-C (=O) R6,-S (=O)2R6、-O(CR7R8)n-R6、-O(CR7R8)n-ORc、-N(Rc) C (=O) R6、-(CR7R8)nC (=O) NRaRb、-N(Rc) S (=O)mR6 Or-S (=O)2NRaRb, wherein, each R3Individually optionally by 1,2 or 3 R9Group is replaced.
In other embodiments, each R6It independently is H, C1-C4Alkyl, C1-C4Haloalkyl, C2-C4Alkenyl, C2-C4 Alkynyl, C3-C6Cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, wherein, each R6Solely Stand optionally by 1,2 or 3 R9Group is replaced.
On the other hand, the present invention relates to a kind of pharmaceutical composition, it includes compound disclosed by the invention.
In some embodiments, pharmaceutical composition of the present invention further includes pharmaceutically acceptable figuration Agent, carrier, adjuvant, solvent or combinations thereof.
In other embodiments, pharmaceutical composition of the present invention, wherein therapeutic agent is further included, it is described Therapeutic agent is selected from chemotherapeutics, antiproliferative, phosphodiesterase 4 (PDE4) inhibitor, beta-2-adrenoreceptor agonists, cortex Steroids, nonsteroidal GR activators, anticholinergic drug, antihistamine, anti-inflammatory reagent, immunodepressant, immunostimulant, For treating the medicine of atherosclerosis, the medicine for treating pulmonary fibrosis and combinations thereof.
On the other hand, the purposes the present invention relates to compound disclosed by the invention or pharmaceutical composition in medicine is prepared, The medicine is used to preventing, process, treat or mitigating protein kinase mediated disease.
In some embodiments, protein kinase mediated disease of the present invention is JAK-, FLT3- or Aurora- The disease of mediation.
In some embodiments, protein kinase mediated disease of the present invention is proliferative diseases, autoimmunity 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, acute myelocytic leukemia, ALL, myelofibrosis, acute marrow Cell leukemia, chronic granulocytic leukemia, ALL, COPD, asthma, system Property lupus erythematosus, skin lupus erythematosus, LN, dermatomyositis, Sjogren syndrome, psoriasis, type i diabetes, breathing Road anaphylactia, nasosinusitis, eczema, measles, food hypersenstivity, insect venom allergies, inflammatory bowel disease, Crohn disease, rheumatoid Property arthritis, juvenile arthritis, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or cell transplant rejection.
On the other hand, the purposes the present invention relates to compound disclosed by the invention or pharmaceutical composition in medicine is prepared, The medicine is used for the activity of regulatory protein kinases.
In some embodiments, protein kinase of the present invention be jak kinase, FLT3 kinases, Aurora A or Combinations thereof.
In yet a further aspect, the preparation of the compound for being included the present invention relates to formula (I), the method for separating and purifying.
Biological results show that the compound that the present invention is provided can be used as preferable kinases inhibitor.
Any embodiment of either side of the invention, can be combined with other embodiments, as long as they Be not in contradiction.Additionally, in any embodiment of either side of the present invention, any technical characteristic goes for it Technical characteristic in its embodiment, 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 below make more specific complete description.
Detailed description of the invention book
Definition and general terms
Certain embodiments of the present invention will now be described in more detail, the example is by the structural formula enclosed and chemical formula explanation.This Invention intention covers all of replacement, modification and equivalent technical solutions, and they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.In the document, patent that are combined and the one of similar material Or many it is different from the application or in the case of contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be defined by the application.
It will further be appreciated that some features of the invention, are clearly visible, carried out in multiple independent embodiments Description, but it is also possible to provide in combination in single embodiment.Conversely, various features of the invention, for brevity, It is described in single embodiment, but it is also possible to individually or with any suitable sub-portfolio provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise indicated, following definition should be obtained using used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS editions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can join Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by reference.
There are obvious conflict, article " " used herein, " one (kind) " unless otherwise indicated or in context " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the implementation method of the embodiment and use or use.
Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.It is tested right As for example also referring to primate (such as the mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described to receive Examination pair as if people.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term "comprising" is open language, i.e., including the content specified by the present invention, but be not precluded from otherwise Content.
" stereoisomer " refers to but atom or the group spatially different change of arrangement mode with identical chemical constitution Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be have with its mirror image can not overlap property molecule；And " achirality " refer to can be overlap with its mirror image Molecule.
" enantiomter " refers to the two of compound isomers that can not be overlapped but be mutually mirror.
" diastereoisomer " refers to have two or more chiral centres and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer is mixed Compound can be operated such as electrophoresis and chromatogram by high resolution analysis, and such as HPLC is separated.
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley＆Sons, Inc., New York, 1994.
Many organic compounds exist with optical active forms, i.e., they have rotates the plane of linearly polarized light Ability.When optically active compound is described, represent molecule on one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for the rotation of linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix is dextrorotation for the compound of (+) or d.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or stereospecificity when, May occur in which such case.
Any asymmetric atom (for example, carbon etc.) that the present invention discloses compound can be enriched with racemic or enantiomer Form exist, for example (R)-, (S)-or (R, S)-configuration be present.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least at least 80% enantiomeric excess, at least 90% enantiomeric excess, 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with possible isomers or they Mixture, the form of such as racemic modification and the non-corresponding isomer mixture quantity of asymmetric carbon atom (this depend on) deposits .Optically active (R)-or (S)-isomers can be used chiral synthon or chiral reagent to prepare, or be torn open using routine techniques Point.If compound contains a double bond, substitution base may be E or Z configurations；If containing dibasic cycloalkanes in compound Base, the substitution base of cycloalkyl may have cis 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.
The racemic modification of any gained end-product or intermediate can be passed through into those skilled in the art with known method Familiar method splits into optical antipode, e.g., is separated by its diastereoisomeric salt for obtaining.Racemic product Thing can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is referred to, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
Term " dynamic isomer " or " tautomeric form " refer to that can build (low by low energy with different-energy Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of dynamic isomer.For example, proton tautomer (protontautomer) (also referred to as proton translocation mutually makes a variation Structure body (prototropic tautomer)) include the mutual inversion of phases that is carried out by proton migration, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electrons come The mutual inversion of phases for carrying out.The instantiation of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyls are mutual The change of tautomeric.Tautomeric another example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one dynamic isomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
As described in the invention, compound of the invention optionally can be replaced by one or more substitution bases, such as General formula compound above, or as the special example in embodiment the inside, subclass, and the class compound that the present invention is included.
In general, term it is " substituted " represent the hydrogen atom that can be substituted to one or more in structure it is specific Substitution base is replaced.Unless other aspects show, a group for replacing can have a substitution base, and in group, each may replace Position replaced.When more than one position can be selected from one or more substitutions of specific group in given structural formula Base is replaced, then substitution base can be replaced with identical or different in each position.
Term " unsubstituted ", represents specified group without substituted base.
Term " optionally by ... replaces ", can be exchanged with term " unsubstituted or quilt ... .. replaces " makes With that is, described structure is unsubstituted or is replaced by one or more substitution bases of the present invention, of the present invention to take Dai Ji includes, but are not limited to D, F, Cl, Br, I, CN, N3、-CN、-NO2、-OH、-SH、-NH2,-C (=O) CH2CN、- (CR7R8)n-ORc、-(CR7R8)n-NRaRb,-C (=O) R6,-S (=O)2R6,-OC (=O) R6、-O(CR7R8)n-R6、-O (CR7R8)n-ORc、-N(Rc) C (=O) R6、-(CR7R8)nC (=O) ORc、-(CR7R8)nC (=O) NRaRb,-C (=NRc) NRaRb、-N(Rc) C (=O) NRaRb、-N(Rc) S (=O)mR6,-C (=O) NRaRb, alkyl, haloalkyl, alkenyl, alkynyl, alkane Epoxide, alkylthio group, alkyl amino, cycloalkyl, heterocyclic radical, aryl and heteroaryl etc., wherein, R6、R7、R8、Ra、Rb、Rc, m and n tool There is definition as described in the present invention.
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode for being used in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used Referring in different groups, not influenceed mutually between expressed specific option between same-sign, it is also possible to represent in phase In same group, do not influenceed mutually between expressed specific option between same-sign.
In each several part of this specification, the substitution base that the present invention discloses compound is disclosed according to radical species or scope.It is special Do not point out, each independent sub-combinations thereof of each member of the present invention including these radical species and scope.For example, term “C1-C6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each several part of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.If for example, the structure needs linking group and for this The Markush group definition of variable lists " alkyl " or " aryl ", then represented respectively it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group ", represent contain 1 to 20 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group, wherein, the alkyl group can optionally by the substitution base institute of one or more present invention descriptions Substitution.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In some embodiments, alkyl group contains 1-12 carbon atom；In other embodiments, alkyl group contains 1-6 carbon atom；In other embodiment, alkane Base group contains 1-4 carbon atom；Also in some embodiments, alkyl group contains 1-3 carbon atom.The alkyl group Substitution base that can be optionally by one or more present invention descriptions replaces.
The example of alkyl group is included, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr、-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,- CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl isophthalic acids-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- amyl groups (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyl groups (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl groups (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
The saturation obtained by two hydrogen atoms is removed in term " alkylidene " expression from the straight or branched alkyl of saturation Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In some embodiments, it is sub- Alkyl group contains 1-6 carbon atom；In other embodiments, alkylidene group contains 1-4 carbon atom；Other In embodiment, alkylidene group contains 1-3 carbon atom；Also in some embodiments, alkylidene group contains 1-2 carbon Atom.Such example includes methylene (- CH2-), ethylidene (- CH2CH2-), isopropylidene (- CH (CH3)CH2-) etc..
Term " alkenyl " is represented and contains the 2-12 straight or branched monovalent hydrocarbon of carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp2Double bond, wherein, the alkenyl group can be retouched optionally by one or more present invention The substitution base stated is replaced, its positioning for including " cis " and " tans ", or " E " and " Z " positioning.In some embodiments In, alkenyl group includes 2-8 carbon atom；In other embodiments, alkenyl group includes 2-6 carbon atom；Another In a little embodiments, alkenyl group includes 2-4 carbon atom.The example of alkenyl group is included, but is not limited to, vinyl (- CH =CH2), pi-allyl (- CH2CH=CH2) etc..The alkenyl group can optionally by one or more present invention descriptions Substitution base is replaced.
Term " alkynyl " is represented and contains the 2-12 straight or branched monovalent hydrocarbon of carbon atom, wherein at least one insatiable hunger And site, that is, there is a key of carbon-to-carbon sp tri-, wherein, the alkynyl group can be retouched optionally by one or more present invention The substitution base stated is replaced.In some embodiments, alkynyl group includes 2-8 carbon atom；In other embodiments, Alkynyl group includes 2-6 carbon atom；In other embodiment, alkynyl group includes 2-4 carbon atom.Alkynyl group Example is included, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), 1- propinyls (- C ≡ C-CH3) etc..
Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In some implementations In scheme, alkoxy base contains 1-6 carbon atom；In other embodiments, alkoxy base contains 1-4 carbon original Son；In other embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can optionally by one The substitution base that individual or multiple present invention are described is replaced.
The example of alkoxy base is included, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), 1- amoxys (n- amoxys ,-OCH2CH2CH2CH2CH3), 2- amoxys (- OCH (CH3) CH2CH2CH3), 3- amoxys (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourths Epoxide (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, and alkenyl or alkoxy base are by one Individual or multiple halogen atoms are replaced, and such example is included, but is not limited to, trifluoromethyl, trifluoromethoxy etc..
Term " carbocylic radical " or " carbocyclic ring " represented containing 3-12 carbon atom, the nonaromatic saturation of univalent or multivalence Or unsaturated monocyclic, the bicyclic or three-ring system in part.Carbon bicyclic group includes spiral shell carbon bicyclic group, condenses carbon bicyclic group and bridge carbon pair Ring group, suitable carbocylic radical group is included, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of carbocylic radical group enters One step includes, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkene Base, cyclohexyl, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, Cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..
Term " cycloalkyl " represents that, containing 3-12 carbon atom, the saturation of univalent or multivalence is monocyclic, bicyclic or three ring bodies System.In some embodiments, cycloalkyl includes 3-12 carbon atom；In other embodiments, cycloalkyl includes 3-8 Carbon atom；In other embodiments, cycloalkyl includes 3-6 carbon atom；Also in some embodiments, cycloalkyl is C7-C12Cycloalkyl, comprising C7-C12Spiral shell bicyclic alkyl, C7-C12Condensed-bicyclic alkyl and C7-C12Bridge bicyclic alkyl；In other reality Apply in scheme, cycloalkyl is C8-C11Cycloalkyl, comprising C8-C11Spiral shell bicyclic alkyl, C8-C11Condensed-bicyclic alkyl and C8-C11Bridged ring Bicyclic alkyl.The group of naphthene base can be independently unsubstituted or by one or more substitution base institutes described in the invention Substitution.
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising 3-12 annular atom, unit price or Multivalence, saturation or part is undersaturated, nonaromatic monocyclic, bicyclic or tricyclic system, the choosing of wherein at least one annular atom From nitrogen, sulphur and oxygen atom.Unless otherwise indicated, heterocyclic radical can be carbon-based or nitrogen base, and-CH2- group can optionally by-C (=O)-substitute.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.Heterocyclic radical includes the heterocyclic radical of saturation (i.e.：Heterocyclylalkyl) and the undersaturated heterocyclic radical in part.The reality of heterocyclic radical Example includes, but are not limited to：Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolins Base, 3- pyrrolinyls, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydrochysene Thienyl, dihydro-thiophene base, 1,3- dioxies cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxins, dithiane base, thioxanes Base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase (e.g., Isosorbide-5-Nitrae-oxygen azepineBase, 1,2- oxygen azepinesBase), diazaBase (e.g., Isosorbide-5-Nitrae-diazaBase, 1,2- diazasBase), dioxaBase is (e.g., 1,4- dioxasBase, 1,2- dioxasBase), 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- azabicyclo [2.2.1] hept- 5- Base, 2- azaspiros [4.4] nonyl, 1,6- dioxo spiros [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 simultaneously [c] pyrrole radicals, hexahydro furyl simultaneously [3,2-b] furyl and ten dihydro-isoquinolines Base, etc..- CH in heterocyclic radical2- group by-C (=O)-substitute example include, but not limited to 2- oxo-pyrrolidines base, oxo- 1,3- thiazolidinyls, 2- piperidone bases and 3,5- dioxy piperazine piperidinyls.The oxidized example of sulphur atom includes in heterocyclic radical, but not It is limited to, sulfolane base, 1,1- dioxothiomorpholinyls, 1,1- dioxotetrahydros thienyl and 1,1- dioxotetrahydro -2H- thiophenes Mutter base, etc..Described heterocyclyl groups optionally can be replaced by one or more substitution bases described in the invention.
In some embodiments, heterocyclic radical is 3-8 former molecular heterocyclic radicals, refer to it is comprising 3-8 annular atom, Unit price or multivalence, saturation or part it is undersaturated, nonaromatic monocyclic, wherein at least one annular atom be selected from nitrogen, sulphur and Oxygen atom.Unless otherwise indicated, 3-8 former molecular heterocyclic radical can be carbon-based or nitrogen base, and-CH2- group can be optional Ground is by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can optionally by It is oxidized to N- oxygen compounds.The example of 3-8 former molecular heterocyclic radical includes, but are not limited to：Azelidinyl, oxa- ring fourth Base, thietanyl, pyrrolidinyl, 2- pyrrolinyls, 3- pyrrolinyls, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazoles Alkyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxies cyclopenta, two sulphur cyclopenta, four Hydrogen pyranose, dihydro pyranyl, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, Piperazinyl, alkyl dioxin, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptane Base, oxygen azepineBase, diazaBase, sulphur azepineBase, etc..- CH in heterocyclic radical2- group is by the example of-C (=O)-replacement Include, but not limited to 2- oxo-pyrrolidines base, oxo -1,3-thiazoles alkyl, 2- piperidone bases and 3,5- dioxy piperazine piperidinyl, Deng.The oxidized example of sulphur atom includes, but not limited to sulfolane base and 1,1- dioxothiomorpholinyl in heterocyclic radical.Institute The 3-8 former molecular heterocyclyl groups stated optionally can be taken by one or more substitution bases described in the invention Generation.
In other embodiments, heterocyclic radical is 3-6 former molecular heterocyclic radical, refers to comprising 3-6 annular atom , unit price or multivalence, saturation or part it is undersaturated, nonaromatic monocyclic, wherein at least one annular atom be selected from nitrogen, sulphur And oxygen atom.Unless otherwise indicated, 3-6 former molecular heterocyclic radical can be carbon-based or nitrogen base, and-CH2- group can appoint Selection of land is by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can be optionally It is oxidized to N- oxygen compounds.The example of 3-6 former molecular heterocyclic radical includes, but are not limited to：Azelidinyl, oxa- ring Butyl, thietanyl, pyrrolidinyl, 2- pyrrolinyls, 3- pyrrolinyls, pyrazolinyl, pyrazolidinyl, imidazolinyl, miaow Oxazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxies cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl, morpholinyl, thiomorpholine Base, piperazinyl, alkyl dioxins, dithiane base are He thioxane base.3-6 described former molecular heterocyclyl groups can be optional Ground is replaced by one or more substitution bases described in the invention.
In other embodiments, heterocyclic radical is 7-12 former molecular heterocyclic radical, refers to former comprising 7-12 ring Son, unit price or multivalence, the miscellaneous bicyclic group of the undersaturated spiral shell of saturation or part, condense miscellaneous bicyclic group or the miscellaneous bicyclic group of bridge, wherein At least one annular atom is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, 7-12 former molecular heterocyclic radical can be carbon-based Or nitrogen base, and-CH2- group can optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxidations Thing.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.The example of 7-12 former molecular heterocyclic radicals includes, but It is not limited to：Indoline base, 1,2,3,4- tetrahydro isoquinolyl, 1,3- Ben Bing bis- Evil cyclopentadienyls, 2- oxa- -5- azabicyclos [2.2.1] hept- 5- bases, 2- azaspiros [4.4] nonyl (such as 2- azaspiros [4.4] nonane -4- bases, 2- azaspiros [4.4] nonyl Alkane -2- bases), 1,6- dioxo spiros [4.4] nonyl (such as 1,6- dioxo spiros [4.4] nonane -9- bases, 1,6- dioxo spiros [4.4] nonane -4- bases), 2- azaspiros [4.5] decyl (e.g., 2- azaspiros [4.5] decane -8- bases, 2- azaspiros [4.5] last of the ten Heavenly stems Alkane -2- bases), 7- azaspiros [4.5] decyl (such as 7- azaspiros [4.5] decane -2- bases, 7- azaspiros [4.5] decane -8- Base), 3- azaspiros [5.5] undecyl (e.g., 3- azaspiros [5.5] hendecane -3- bases, 3- azaspiros [5.5] hendecane -9- Base), 2- azaspiros [5.5] undecyl, 8- azaspiros [4.5] decyl, Decahydroisoquinolinpreparation base, octahydro -1H- isoindolyls (e.g., octahydro -1H- iso-indoles -5- bases, octahydro -1H- iso-indoles -7- bases), octahydro pentamethylene simultaneously [c] pyrrole radicals (e.g., octahydro ring Pentane simultaneously [c] pyrroles -5- bases, octahydro pentamethylene simultaneously [c] pyrroles -2- bases), hexahydro furyl simultaneously [3,2-b] furyl (e.g., hexahydro Furans simultaneously [3,2-b] furans -2- bases, hexahydro furyl simultaneously [3,2-b] furans -3- bases) and ten dihydro-isoquinoline bases.Described 7-12 Individual former molecular heterocyclyl groups optionally can be replaced by one or more substitution bases described in the invention.
In other embodiment, heterocyclic radical is the 7-12 former molecular miscellaneous bicyclic group of spiral shell, refers to comprising 7-12 Annular atom, unit price or multivalence, saturation or part is undersaturated, the nonaromatic miscellaneous bicyclic group of spiral shell, wherein at least one ring Atom is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, the 7-12 former molecular miscellaneous bicyclic group of spiral shell can be carbon-based or nitrogen Base, and-CH2- group can optionally by-C (=O)-replacement.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 7-12 described former molecular miscellaneous bicyclic group of spiral shell includes 7- 12 miscellaneous bicyclic groups of spiral shell of the molecular saturation of original are (i.e.：7-12 former molecular miscellaneous bicyclic alkyls of spiral shell) and part it is undersaturated The miscellaneous bicyclic group of spiral shell.The example of the 7-12 former molecular miscellaneous bicyclic group of spiral shell includes, but are not limited to：2- azaspiros [4.4] nonyl (such as 2- azaspiros [4.4] nonane -4- bases, 2- azaspiros [4.4] nonane -2- bases), 1,6- dioxo spiros [4.4] nonyl are (such as 1,6- dioxo spiros [4.4] nonane -9- bases, 1,6- dioxo spiros [4.4] nonane -4- bases), 2- azaspiros [4.5] decyl (e.g., 2- azaspiros [4.5] decane -8- bases, 2- azaspiros [4.5] decane -2- bases), 7- azaspiros [4.5] decyl (such as 7- nitrogen Miscellaneous spiral shell [4.5] decane -2- bases, 7- azaspiros [4.5] decane -8- bases), 3- azaspiros [5.5] undecyl (e.g., 3- azaspiros [5.5] hendecane -3- bases, 3- azaspiros [5.5] hendecane -9- bases), 2- azaspiros [5.5] undecyl, 8- azaspiros [4.5] decyl, etc..The 7-12 described former molecular miscellaneous bicyclic group group of spiral shell can optionally by one or more this hairs Bright described substitution base is replaced.
Also in other embodiments, heterocyclic radical is the 8-11 former molecular miscellaneous bicyclic group of spiral shell, refers to comprising 8-11 Individual annular atom, unit price or multivalence, saturation or part is undersaturated, the nonaromatic miscellaneous bicyclic group of spiral shell, wherein at least one Annular atom is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, the 8-11 former molecular miscellaneous bicyclic group of spiral shell can be carbon-based or nitrogen Base, and-CH2- group can optionally by-C (=O)-replacement.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 8-11 described former molecular miscellaneous bicyclic group of spiral shell includes 8- 11 miscellaneous bicyclic groups of spiral shell of the molecular saturation of original (the 8-11 former molecular miscellaneous bicyclic alkyl of spiral shell) and the undersaturated spiral shell in part Miscellaneous bicyclic group.The example of the 8-11 former molecular miscellaneous bicyclic group of spiral shell includes, but are not limited to：2- azaspiros [4.4] nonyl is (such as 2- azaspiros [4.4] nonane -4- bases, 2- azaspiros [4.4] nonane -2- bases), 1,6- dioxo spiros [4.4] nonyl (such as 1,6- Dioxo spiro [4.4] nonane -9- bases, 1,6- dioxo spiros [4.4] nonane -4- bases), 2- azaspiros [4.5] decyl (e.g., 2- Azaspiro [4.5] decane -8- bases, 2- azaspiros [4.5] decane -2- bases), 7- azaspiros [4.5] decyl (such as 7- azaspiros [4.5] decane -2- bases, 7- azaspiros [4.5] decane -8- bases), 3- azaspiros [5.5] undecyl (e.g., 3- azaspiros [5.5] Hendecane -3- bases, 3- azaspiros [5.5] hendecane -9- bases), 2- azaspiros [5.5] undecyl, 8- azaspiros [4.5] decane Base, etc..The 8-11 described former molecular miscellaneous bicyclic group group of spiral shell can be optionally described in the invention by one or more Substitution base replaced.
Also in other embodiment, heterocyclic radical be 7-12 original it is molecular condense miscellaneous bicyclic group, refer to comprising 7- 12 annular atoms, unit price or multivalence, saturation or part are undersaturated, nonaromatic condense miscellaneous bicyclic group, wherein at least One annular atom is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, 7-12 former molecular to condense miscellaneous bicyclic group can be carbon Base or nitrogen base, and-CH2- group can optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxygen Compound.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.Described 7-12 it is former it is molecular condense it is miscellaneous bicyclic Base condenses miscellaneous bicyclic group (i.e. comprising the individual former molecular saturations of 7-12：7-12 former molecular to condense miscellaneous bicyclic alkyl) and Part is undersaturated to condense miscellaneous bicyclic group.The 7-12 former molecular example for condensing miscellaneous bicyclic group includes, but are not limited to：Octahydro Cyclopenta simultaneously [c] pyrrole radicals, octahydro -1H- isoindolyls, indoline base, 1,2,3,4- tetrahydro isoquinolyls, 1,3- Ben Bing bis- Evil Cyclopentadienyl, hexahydro furyl simultaneously [3,2-b] furyl, hexahydro furyl simultaneously [2,3-b] furyl and ten dihydro-isoquinoline bases.Described 7- 12 originals are molecular to condense miscellaneous bicyclic group group optionally can be taken by one or more substitution bases described in the invention Generation.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " and " condensed ring radical " are used interchangeably herein, all referring to list Valency or multivalence, saturation or part is unsaturated but nonaromatic member ring systems, two rings in the member ring systems share a key. Such system can include independent or conjugation unsaturated system, but its core texture does not include aromatic rings or heteroaromatic (but aromatic group can be as substitution base thereon).
Term " volution base ", " volution ", " spiral shell bicyclic group " or " spiral shell is bicyclic " are used interchangeably herein, refer to unit price or many Valency, the undersaturated member ring systems of saturation or part, one of ring originates from specific ring carbon atom on another ring.For example, As described by following formula a, a member ring systems for saturation (ring B and B ') is referred to as " condensed-bicyclic ", and ring A and ring B are at two A carbon atom is shared in the member ring systems of saturation, is referred to as " volution " or " spiral shell is bicyclic ".In condensed-bicyclic base and spiral shell bicyclic group Each ring can be carbocylic radical or heterocyclic radical, and each ring is optionally by one or more substitution bases described in the invention Replaced.
Term " Heterocyclylalkyl " refer to the unit price containing 3-12 annular atom or multivalence saturation is monocyclic, bicyclic or three rings System, wherein at least one annular atom is selected from nitrogen, sulphur or oxygen atom.Unless otherwise indicated, Heterocyclylalkyl can be carbon-based or nitrogen Base, and-CH2- group can optionally by-C (=O)-replacement.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 example of miscellaneous bicyclic alkyl includes, but are not limited to：Azetidin Base, oxetanylmethoxy, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydro-thienyl, tetrahydrofuran base, piperazine Piperidinyl, piperazinyl, morpholinyl, alkyl dioxin, dithiane base, isoxazolidinyl, isothiazole alkyl, 1,2- oxazinyls, 1,2- thiophenes Piperazine base, hexahydro-pyridazine base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase (e.g., 1, 4- oxygen azepinesBase, 1,2- oxygen azepinesBase), diazaBase (e.g., Isosorbide-5-Nitrae-diazaBase, 1,2- diazasBase), two Oxa-Base (e.g., Isosorbide-5-Nitrae-dioxaBase, 1,2- dioxasBase), sulphur azepineBase (e.g., Isosorbide-5-Nitrae-sulphur azepineBase, 1,2- Sulphur azepineBase), 2- azaspiros [4.4] nonyl, 1,6- dioxo spiros [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] ten One alkyl, octahydro cyclopenta simultaneously [c] pyrrole radicals, octahydro -1H- isoindolyls, hexahydro furyl simultaneously [3,2-b] furyl, hexahydro furan Mutter simultaneously [2,3-b] furyl and ten dihydro-isoquinoline bases.Described heterocycloalkyl can be optionally by one or more originally The described substitution base of invention is replaced.
In some embodiments, Heterocyclylalkyl is 7-12 former molecular Heterocyclylalkyl, refers to contain 7-12 ring Atom, unit price or multivalence, condense miscellaneous bicyclic alkyl or the miscellaneous bicyclic alkyl of bridge, wherein at least at the miscellaneous bicyclic alkyl of spiral shell of saturation One annular atom is selected from nitrogen, sulphur or oxygen atom.Unless otherwise indicated, Heterocyclylalkyl can be carbon-based or nitrogen base, and-CH2- group Can optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can be with Optionally it is oxidized to N- oxygen compounds.Described 7-12 former molecular heterocycloalkyl can optionally by one or Multiple substitution bases described in the invention are replaced.
In some embodiments, Heterocyclylalkyl is 3-6 former molecular Heterocyclylalkyl, refers to former containing 3-6 ring Son, univalent or multivalence, the heterocyclic radical of saturation, wherein at least one annular atom is selected from nitrogen, sulphur or oxygen atom.Unless said in addition Bright, Heterocyclylalkyl can be carbon-based or nitrogen base, and-CH2- group can optionally by-C (=O)-replacement.The sulphur atom of ring can To be optionally oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.3-6 atom composition The example of Heterocyclylalkyl include, but are not limited to：Azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, pyrazoles Alkyl, imidazolidinyl, piperidyl, piperazinyl, morpholinyl, alkyl dioxin, dithiane base, isoxazolidinyl, isothiazole alkyl and Hexahydro-pyridazine base.3-6 described former molecular heterocycloalkyl can be retouched optionally by one or more present invention The substitution base stated is replaced.
In other embodiments, Heterocyclylalkyl is the 7-12 former molecular miscellaneous bicyclic alkyl of spiral shell, refers to contain 7- 12 annular atoms, the univalent or miscellaneous bicyclic alkyl of spiral shell, wherein at least one annular atom are selected from nitrogen, sulphur or oxygen Atom.Unless otherwise indicated, Heterocyclylalkyl can be carbon-based or nitrogen base, and-CH2- group can optionally by-C (=O)-replace Generation.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxidations and close Thing.The example of the 7-12 former molecular miscellaneous bicyclic alkyl of spiral shell includes, but are not limited to：2- azaspiros [4.4] nonyl, 1,6- bis- Oxaspiro [4.4] nonyl, 2- azaspiros [4.5] decyl, 8- azaspiros [4.5] decyl, 7- azaspiros [4.5] decane Base, 3- azaspiros [5.5] undecyl and 2- azaspiros [5.5] undecyl, etc..7-12 described former molecular spiral shell is miscellaneous Bicycloalkyl radicals optionally can be replaced by one or more substitution bases described in the invention.
In other embodiments, Heterocyclylalkyl be 7-12 original it is molecular condense miscellaneous bicyclic alkyl, refer to containing 7-12 annular atom, unit price or it is multivalence, saturation condense miscellaneous bicyclic alkyl, wherein at least one annular atom is selected from nitrogen, sulphur Or oxygen atom.Unless otherwise indicated, Heterocyclylalkyl can be carbon-based or nitrogen base, and-CH2- group can optionally by-C (= O)-substitute.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen Compound.The 7-12 former molecular example for condensing miscellaneous bicyclic alkyl includes, but are not limited to：Octahydro -1H- isoindolyls are (e.g., Octahydro -1H- iso-indoles -5- bases, octahydro -1H- iso-indoles -7- bases), octahydro pentamethylene simultaneously [c] pyrrole radicals (e.g., octahydro pentamethylene And [c] pyrroles -5- bases, octahydro pentamethylene simultaneously [c] pyrroles -2- bases), hexahydro furyl simultaneously [3,2-b] furyl (e.g., hexahydro furyl And [3,2-b] furans -2- bases, hexahydro furyl simultaneously [3,2-b] furans -3- bases), hexahydro furyl simultaneously [2,3-b] furyl and 12 Hydrogen isoquinoline base.Described 7-12 it is former it is molecular condense miscellaneous bicycloalkyl radicals can optionally by one or more this hairs Bright described substitution base is replaced.
In other embodiments, Heterocyclylalkyl be 8-10 original it is molecular condense miscellaneous bicyclic alkyl, refer to containing 8-10 annular atom, unit price or multivalence, saturation condenses miscellaneous bicyclic alkyl, and wherein at least one annular atom is selected from nitrogen, sulphur Or oxygen atom.Unless otherwise indicated, 8-10 it is former it is molecular to condense miscellaneous bicyclic alkyl can be carbon-based or nitrogen base, and-CH2- Group can optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring N- oxygen compounds can be optionally oxidized to.The 8-10 former molecular example for condensing miscellaneous bicyclic alkyl includes, but does not limit In：Octahydro -1H- isoindolyls (e.g., octahydro -1H- iso-indoles -5- bases, octahydro -1H- iso-indoles -7- bases), octahydro pentamethylene are simultaneously [c] pyrrole radicals (e.g., octahydro pentamethylene simultaneously [c] pyrroles -5- bases, octahydro pentamethylene simultaneously [c] pyrroles -2- bases), hexahydro furyl simultaneously [3, 2-b] furyl (e.g., hexahydro furyl simultaneously [3,2-b] furans -2- bases, hexahydro furyl simultaneously [3,2-b] furans -3- bases), hexahydro furyl And [2,3-b] furyl and ten dihydro-isoquinoline bases.Described 8-10 it is former it is molecular condense miscellaneous bicycloalkyl radicals can be with Optionally replaced by one or more substitution bases described in the invention.
Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular Heterocyclylalkyls of original, and 1,2,3,4- tetralyl It is 10 molecular carbocylic radical groups of original.
Contain one or more degrees of unsaturation in " undersaturated " the expression group of term for being used in the present invention.
Term " hetero atom " refers to O, S, N, P and Si, including any oxidation state of N, S and P form；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (as the NR in the pyrrolidinyl that N- replaces).
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " azido " or " N3" represent a nitrine structure.This group can be connected with other groups, for example, Triazonmethane (MeN can be connected to form with a methyl3), or it is connected to form phenylazide (PhN with a phenyl3)。
Term " aryl " represents and contains 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, double The carbocyclic ring system of ring and three rings, wherein, at least one member ring systems are aromatic, and each of which member ring systems are former comprising 3-7 Molecular ring, and there are one or more tie points to be connected with the remainder of molecule.Term " aryl " can be with term " fragrance Ring " is exchanged and used.The example of aromatic yl group can include phenyl, naphthyl and anthryl.The aromatic yl group can be with individually optional Replaced by one or more substitution bases described in the invention.
Term " heteroaryl " represents and contains 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom it is monocyclic, Bicyclic and three-ring system, wherein at least one member ring systems are aromatic, and at least one aromatic ring system includes one or many Individual hetero atom, each of which member ring systems include 5-7 former molecular rings, and have one or more tie points and molecule remaining Part is connected.Term " heteroaryl " can be exchanged and used with term " hetero-aromatic ring " or " heteroaromatics ".In some embodiment party In case, heteroaryl is comprising 1,2,3 or 4 heteroatomic 5-12 for being independently selected from O, S and N former molecular heteroaryls. In other embodiments, heteroaryl is comprising 1,2,3 or 4 heteroatomic 5-10 atom compositions for being independently selected from O, S and N Heteroaryl.Also in some embodiments, heteroaryl is comprising 1,2,3 or 4 heteroatomic 5-6 for being independently selected from O, S and N Individual former molecular heteroaryl.The heteroaryl groups are optionally taken by one or more substitution bases described in the invention Generation.The example of heteroaryl groups is included, but is not limited to, 2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazoles Base, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, N- pyrroles Cough up base, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, pyriconyl, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyrimidine ketone group, hybar X base, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, four Oxazolyl (such as 5- tetrazole radicals), triazolyl (such as 2- triazolyls and 5- triazolyls), 2- thienyls, 3- thienyls, pyrazolyl (such as 2- pyrroles Oxazolyl), isothiazolyl, 1,2,3- oxadiazolyls, 1,2,5- oxadiazolyls, 1,2,4- oxadiazolyls, 1,2,3- triazolyls, 1,2, 3- thio biphospholes base, 1,3,4- thio biphospholes base, 1,2,5- thio biphospholes base, pyrazinyl, cyanuro 1,3,5；Also include following It is bicyclic, but it is bicyclic to be not limited to these：Benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indoles Base), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls), isoquinolyl (such as 1- isoquinolyls, 3- isoquinolines Quinoline base or 4- isoquinolyls), imidazo [1,2-a] pyridine radicals, pyrazolo [1,5-a] pyridine radicals, pyrazolo [4,3-c] pyridine Base, pyrazolo [3,4-b] pyridine radicals, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine radicals, etc..
Term " oxazolyl " refers to comprising at least two hetero atoms and wherein at least one is nitrogen-atoms, by 5 or 9 Former molecular heteroaromatic ring systems.The example of oxazolyl include, but is not limited to pyrazolyl, imidazole radicals, oxazolyl, isoxazolyls, Oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, di azoly, triazolyl, indazolyl, pyrazolo [4,3-c] pyridine radicals, pyrrole Azoles simultaneously [3,4-b] pyridine radicals, imidazo [4,5-b] pyridine radicals and 1H- benzos [d] imidazole radicals.
No matter term " carboxyl ", be single use or be used in conjunction with other terms, such as " carboxyalkyl ", expression-CO2H；Term No matter " carbonyl ", be single use or be used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", represents-(C=O)-.
Term " alkyl amino " or " alkylamino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group.Some of them embodiment is that alkyl amino is one or two C1-C6Alkyl is connected to the alkylamino group of the lower level formed on nitrogen-atoms.Other embodiment is that alkyl amino is One or two C1-C4Alkyl is connected to the alkylamino group of the lower level formed on nitrogen-atoms.Suitable alkylamino group Can be alkyl monosubstituted amino or dialkyl amido, such example is included, but is not limited to, N- methylaminos, N- ethylaminos, N, N- Dimethylamino, N, N- lignocaine etc..
Term " fragrant amino " represents that amino group is replaced by one or two aromatic yl group, and such example includes, but It is not limited to N- phenylaminos.Some of them embodiment is that the aromatic ring in fragrant amino can further be substituted.
Term " aminoalkyl " includes the C replaced by one or more amino1-C10Straight or branched alkyl group.Its In some embodiments be that aminoalkyl is the C replaced by one or more amino groups1-C6" aminoalkyl of lower level ", Such example is included, but is not limited to,
Aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
As described in the invention, replace base to draw one and be bonded the member ring systems formed on the ring at the center of being connected to (such as formula b institutes Show) represent substitution base any commutable position in the member ring systems and can replace.For example, formula b represents C rings and D rings are taken up an official post The position what may be substituted, as shown in formula c~formula g.
As described in the invention, connecting key be connected to formed on the center of ring member ring systems (as shown in formula h, its In, X and X ' is separately CH2, NH or O) represent connecting key can in member ring systems any attachable position and molecule Remainder is connected.Formula h represents any position that may be connected on E rings and F rings can be connected with molecule remainder.
As described in the invention, two connecting keys are connected to the member ring systems (as formula i shows) formed on the center of ring and represent Two connecting keys can be connected any attachable position in member ring systems with molecule remainder.Formula i represents any on G rings Two positions that may be connected can be connected with molecule remainder.
When term " blocking group " or " PG " refer to a substitution base and other reacted with functional groups, resistance is commonly used to Break or protect special feature.For example, " blocking group of amino " refers to a substitution base to be connected to block with amino group Or protection compound in amino feature, suitable amido protecting group include acetyl group, trifluoroacetyl group, t-butyl formate (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylenes oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substitution base of base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refer to the substitution base of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group refers to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
Term " prodrug " used in the present invention, represents a compound and is converted into compound shown in formula (I) in vivo. It is such conversion hydrolyzed in blood by pro-drug or in blood or tissue through enzymatic conversion for precursor structure is influenceed.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that have of pro-drug, aliphatic in existing invention (C1-C24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.One for example in the present invention Compound includes hydroxyl, you can the compound of prodrug form is obtained to be acylated.Other prodrug forms include Phosphate, such as these phosphate compounds are obtained through the di on parent.Beg on pro-drug is complete By may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopted as stating and experimentally characterized.Such product can, by aoxidizing, be reduced, water by drug compound Solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc. method are obtained.Correspondingly, the present invention includes compound Metabolite, including compound of the invention and mammal are fully contacted the metabolite produced by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of compound of the invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:Described in 1-19..The salt that pharmaceutically acceptable nontoxic acid is formed is included, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphurs Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that appropriate alkali is obtained includes alkali metal, alkaline-earth metal, ammonium and N+(C1-C4Alkyl)4Salt.The present invention is also intended to contemplate and appoints The quaternary ammonium salt that the compound of the group what includes N is formed.Water-soluble or oil-soluble or dispersion product can be by quaternized Effect is obtained.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt is further included The amine cation that appropriate, nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulphur Acidulants, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to the association that one or more solvent molecules are formed with compound of the invention Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methyl alcohol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is associated matter that water is formed.
Term " treatment " any disease as used in the present invention or illness, refer to improvement disease in some of these embodiments Disease or illness (slow down or prevent or mitigate disease or the development of its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (for example stablize perceptible symptom) or physiologically (for example stablizes body Parameter) or above-mentioned two aspects regulation disease or illness.In other embodiments, " treatment " refer to prevention or postpone disease or disease Breaking-out, generation or the deterioration of disease.
" 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 infringement or function of organization any disease for losing, disorderly or symptom." inflammatory disease " also refers to by leucocyte Inflow and/or the pathologic state of Neutrophil chemotaxis mediation.
" inflammation " used in the present invention refers to that the topical protective caused by tissue damaged or destruction is responded, and it is used to break Tissue that is bad, diluting or separate (isolation) harmful material and be damaged.Inflammation is flowed into leucocyte and/or neutrophil cell becomes The property changed has significant contact.Inflammation can result from infection and the non-infectious mode of pathogenic organism and virus, such as heart Wound or Reperfu- sion after muscle infarction or apoplexy, to the immune response and autoimmune response of exotic antigen.Therefore, it can with this The inflammatory disease of disclosure of the invention compounds for treating includes：Reacted with the reaction of specific system of defense and non-specific defense system Related disease.
" specific system of defense " refers to that presence of the component of immune system to specific antigen reacts.Result from specificity The example of the inflammation of system of defense reaction includes the classical response to exotic antigen, autoimmune disease and delayed type hypersensitivity, DTH 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 any disease of related tissue damage.
" allergy " used in the present invention refers to that any symptom, histologic lesion or the function of organization for producing allergy lose.Such as " arthritis disease " used in the present invention refers to damage be characterized any to be attributable to various etiologic etiological arthritis Disease." dermatitis " refers to be attributable to the disease of skin that various etiologic etiological scytitises are characterized as used in the present invention Extended familys in any one." graft rejection " refers to be lost with the function of transplanting or surrounding tissue as used in the present invention The confrontation transplanting tissue that mistake, pain, swelling, leukocytosis and decrease of platelet are characterized, such as organ or cell (such as marrow) Any immune response.Treatment method of the invention includes the method for treating the disease related to inflammatory cell activation.
Term " cancer " and " cancer " refer to or description patient in the usual physiology that is characterized with cell growth out of control Illness." tumour " includes one or more cancer cell.The example of cancer includes but is not limited to cancer (carcinoma), lymthoma, embryo Cytoma, sarcoma and leukaemia, or malignant lymph proliferative disease (lymphoid malignancies).Such cancer is more Specific example includes squamous cell carcinoma (such as epithelium squamous cell carcinoma), lung cancer (including ED-SCLC, non-small cell lung cancer (NSCLC), adenocarcinoma of lung and lung carcinoma squamosum), peritoneal cancer, hepatocellular carcinoma (hepatocellular cancer), stomach cancer (gastric Or stomach cancer) (including human primary gastrointestinal cancers), cancer of pancreas, glioblastoma, cervical carcinoma, oophoroma, liver cancer (liver Cancer), carcinoma of urinary bladder, hepatoma (hepatoma), breast cancer, colon and rectum carcinoma, colorectal cancer, carcinoma of endometrium or The cancer of the uterus, salivary-gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, carcinoma of vulva, thyroid gland Cancer, liver cancer (hepatic carcinoma), cancer of anus, carcinoma of penis and head and neck cancer.
The description of compound of the invention
The invention discloses the novel compound of a class, can swash as protein kinase activity, particularly jak kinase, FLT3 The inhibitor of enzyme and Aurora A activity.Can be used to treat and unsuitable albumen as the compound of kinases inhibitor Kinase activity, particularly unsuitable jak kinase, FLT3 kinases and the Aurora A related disease of activity, such as treatment with Prevention is related to the disease of the jak kinase, FLT3 kinases and Aurora A mediation of signal path.Such disease includes proliferative Disease, autoimmune disease, anaphylactia, inflammatory disease, graft rejection and their complication.Especially, the present invention Compound can be used to treat following disease, such as cancer, polycythemia vera, primary thrombocytosis, marrow Fibrosis, acute myelocytic leukemia, ALL, chronic granulocytic leukemia (CML), COPD Property lung disease (COPD), asthma, systemic loupus erythematosus, skin lupus erythematosus, LN, dermatomyositis, dry it is comprehensive Levy, psoriasis, type i diabetes, respiratory anaphylactic disease, nasosinusitis, eczema, measles, food hypersenstivity, insect venom allergies, Inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis, psoriasis arthropathica, organ-graft refection, group Knit graft rejection, cell transplant rejection, etc..
In some embodiments, the present invention discloses compound and shows stronger suppression to one or more protein kinase Activity.
On the one hand, compound the present invention relates to one kind as shown in formula (I) or the alloisomerism of compound shown in formula (I) Body, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein, Z, Z1, A, W and R1With implication as described in the present invention.
In some embodiments, Z isWherein, X and X ' are each independently O, Z is optionally by 1,2,3, 4 or 5 R3Group is replaced；
Z1It is H, C1-C12Alkyl, C3-C12Cycloalkyl or 3-12 former molecular heterocyclic radical, wherein, work as Z1When being not H, Z1Optionally by 1,2,3,4 or 5 R4Group is replaced；
A is pyrazolyl, and it is optionally by 1,2,3,4 or 5 R5Group is replaced；
W is N；
R1It is H, F, Cl, Br, I, NO2、N3、CN、C1-C12Alkyl, C1-C12Haloalkyl, C1-C12Alkoxy, C2-C12Alkene Base, C2-C12Alkynyl, C3-C12Cycloalkyl, 3-12 former molecular heterocyclic radical, C6-C12Aryl, 5-12 original are molecular miscellaneous Aryl ,-(CR7R8)n-ORc、-(CR7R8)n-NRaRb,-C (=O) R6,-OC (=O) R6、-O(CR7R8)n-R6、-N(Rc) C (=O) R6、-(CR7R8)nC (=O) ORc、-(CR7R8)nC (=O) NRaRb,-C (=NRc)NRaRb、-N(Rc) C (=O) NRaRb、-N(Rc)S (=O)mR6Or-S (=O)2NRaRb, wherein, work as R1It is not H, F, Cl, Br, I, NO2、N3During with CN, R1Optionally by 1,2,3,4 Or 5 R9Group is replaced；
Each R3It independently is H, F, Cl, Br, I, NO2、CN、N3、OH、NH2,-C (=O) CH2CN、C1-C12Alkyl, C1-C12Halogen Substituted alkyl, C1-C12Alkoxy, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6-C12Aryl, 3-12 original are molecular Heterocyclic radical, 5-12 former molecular heteroaryl ,-(CR7R8)n-ORc、-(CR7R8)n-NRaRb,-C (=O) R6,-S (=O)2R6,-OC (=O) R6、-O(CR7R8)n-R6、-O(CR7R8)n-ORc、-N(Rc) C (=O) R6、-(CR7R8)nC (=O) ORc、- (CR7R8)nC (=O) NRaRb,-C (=NRc)NRaRb、-N(Rc) C (=O) NRaRb、-N(Rc) S (=O)mR6Or-S (=O)2NRaRb, or two adjacent R3, and together with the atom being connected with them, form C3-C12Cycloalkyl or 3-12 atom composition Heterocycloalkyl, wherein, above-mentioned each substitution base, is not H, F, Cl, Br, I, NO2, CN and N3When, individually optionally by 1,2, 3rd, 4 or 5 R9Group is replaced；
Each R4And R5It is separately H, F, Cl, Br, I, NO2、CN、N3、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynes Base, C3-C12Cycloalkyl ,-(C1-C4Alkylidene)-(C3-C12Cycloalkyl), C6-C12The individual former molecular heterocyclic radical of aryl, 3-12 ,- (C1-C4Alkylidene)-(3-12 former molecular heterocyclic radical), 5-12 former molecular heteroaryl ,-(CR7R8)n-ORc、- (CR7R8)n-NRaRb,-C (=O) R6,-OC (=O) R6、-O(CR7R8)n-R6、-N(Rc) C (=O) R6、-(CR7R8)nC (=O) ORc、-(CR7R8)nC (=O) NRaRb,-C (=NRc)NRaRb、-N(Rc) C (=O) NRaRb、-N(Rc) S (=O)mR6Or-S (= O)2NRaRb, wherein, as above-mentioned each R4And R5It is not H, F, Cl, Br, I, NO2, CN and N3When, each R4And R5Respectively optionally by 1, 2nd, 3,4 or 5 R9Group is replaced；
Each R6It independently is H, C1-C12Alkyl, C1-C12Haloalkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, wherein, work as R6When being not H, Each R6Individually optionally by 1,2,3,4 or 5 R9Group is replaced；
Each R7And R8It is separately H, F, Cl, Br, I, NO2、N3、CN、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynes Base, C3-C12Cycloalkyl, C6-C12Aryl, 3-12 former molecular heterocyclic radical or 5-12 former molecular heteroaryl, or R7And R8, and together with the carbon atom being connected with them, form C3-C12Cycloalkyl, C6-C12Aryl, 3-12 former molecular heterocycle Base or 5-12 former molecular heteroaryl groups, wherein, above-mentioned each substitution base, is not H, F, Cl, Br, I, NO2, CN and N3When, Individually optionally by 1,2,3,4 or 5 R9Group is replaced；
Each R9It independently is F, Cl, Br, I, CN, NO2、N3、C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Ring Alkyl, C6-C12Aryl, 3-12 former molecular heterocyclic radical, 5-12 former molecular heteroaryl, NH2、-NH(C1-C12Alkane Base) ,-NH (CH2)n-(C3-C12Cycloalkyl) ,-NH (CH2)n-(C6-C12Aryl) ,-NH (CH2)n- (3-12 is former molecular miscellaneous Ring group) ,-NH (CH2)n- (5-12 former molecular heteroaryl) ,-N (C1-C12Alkyl)2、-N[(CH2)n-(C3-C12Cycloalkanes Base)]2、-N[(CH2)n-(C6-C12Aryl)]2、-N[(CH2)n- (3-12 former molecular heterocyclic radical)]2、-N[(CH2)n-(5- 12 molecular heteroaryls of original)]2、OH、-O(C1-C12Alkyl) ,-O (CH2)n-(C3-C12Cycloalkyl) ,-O (CH2)n-(C6-C12 Aryl) ,-O (CH2)n- (3-12 former molecular heterocyclic radical) or-O (CH2)n- (5-12 former molecular heteroaryl)；
Each Ra、RbAnd RcIt is separately H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl ,-(C1- C4Alkylidene)-(C3-C6Cycloalkyl), 3-6 former molecular heterocyclic radical ,-(C1-C4Alkylidene)-(3-6 is former molecular miscellaneous Ring group), C6-C10Aryl ,-(C1-C4Alkylidene)-(C6-C10Aryl), 5-10 former molecular heteroaryls or-(C1-C4Alkylene Base)-(5-10 former molecular heteroaryl), or RaAnd Rb, and together with the nitrogen-atoms being connected with them, form 3-8 atom The heterocyclyl groups of composition, wherein, above-mentioned each substitution base, when not for H, individually optionally by 1,2,3 or 4 be independently selected from F, Cl、Br、CN、N3、OH、NH2、C1-C6Alkyl, C1-C6Haloalkyl, C1-C6Alkoxy or C1-C6The substitution base institute of alkyl amino Substitution；
Each m independently is 1 or 2；With
Each n independently is 0,1,2,3 or 4.
In some embodiments, Z1It is H, C1-C6Alkyl, C3-C6Cycloalkyl or 3-6 former molecular heterocyclic radical, its In, work as Z1When being not H, Z1Optionally by 1,2 or 3 R4Group is replaced.
In other embodiments, Z1It is H, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.
In some embodiments, A is
In some embodiments, R1It is H, F, Cl, CN, N3、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogen Substituted alkyl, C1-C6Alkoxy, C3-C6Cycloalkyl, 3-6 former molecular heterocyclic radical ,-(CR7R8)n-ORc、-(CR7R8)n- NRaRb,-C (=O) R6、-(CR7R8)nC (=O) NRaRbOr-S (=O)2NRaRb, wherein, work as R1It is not H, F, Cl, N3During with CN, R1Optionally by 1,2 or 3 R9Group is replaced.
In other embodiments, R1It is H, F, Cl, CN, N3、C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4 Haloalkyl, C1-C4Alkoxy, C3-C6Cycloalkyl, 3-6 former molecular heterocyclic radical ,-(CR7R8)n-ORc、-(CR7R8)n- NRaRb,-C (=O) R6、-(CR7R8)nC (=O) NRaRbOr-S (=O)2NRaRb, wherein, work as R1It is not H, F, Cl, N3During with CN, R1Optionally by 1,2 or 3 R9Group is replaced.
In some embodiments, each R3It independently is H, F, Cl, CN, N3、NO2、OH、NH2,-C (=O) CH2CN、C1-C6 Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Haloalkyl, C3-C6Cycloalkyl, phenyl, 3-6 atom group Into heterocyclic radical, 5-6 former molecular heteroaryl ,-(CR7R8)n-ORc、-(CR7R8)n-NRaRb,-C (=O) R6,-S (=O)2R6、-O(CR7R8)n-R6、-O(CR7R8)n-ORc、-N(Rc) C (=O) R6、-(CR7R8)nC (=O) NRaRb、-N(Rc) C (=O) NRaRb、-N(Rc) S (=O)mR6Or-S (=O)2NRaRb, or two adjacent R3, and together with the atom being connected with them, shape Into C3-C6Cycloalkyl or 3-6 former molecular heterocycloalkyl, wherein, above-mentioned each substitution base, is not H, F, Cl, NO2、CN And N3When, individually optionally by 1,2 or 3 R9Group is replaced.
In other embodiments, each R3It independently is H, F, Cl, CN, N3、NO2、OH、NH2,-C (=O) CH2CN、C1- C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Alkoxy, C1-C4Haloalkyl, C3-C6Cycloalkyl, phenyl, 3-6 atom group Into heterocyclic radical, 5-6 former molecular heteroaryl ,-(CR7R8)n-ORc、-(CR7R8)n-NRaRb,-C (=O) R6,-S (=O)2R6、-O(CR7R8)n-R6、-O(CR7R8)n-ORc、-N(Rc) C (=O) R6、-(CR7R8)nC (=O) NRaRb、-N(Rc) S (=O)mR6 Or-S (=O)2NRaRb, wherein, work as R3It is not H, F, Cl, NO2, CN and N3When, each R3Individually optionally by 1,2 or 3 R9Group Replaced.
In some embodiments, each R4And R5It is separately H, F, Cl, Br, I, NO2、N3、CN、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl ,-(C1-C2Alkylidene)-(C3-C6Cycloalkyl), phenyl, 3-6 atom composition Heterocyclic radical ,-(C1-C2Alkylidene)-(3-6 former molecular heterocyclic radical), 5-6 former molecular heteroaryl ,- (CR7R8)n-ORc、-(CR7R8)n-NRaRb,-C (=O) R6,-OC (=O) R6、-O(CR7R8)n-R6、-N(Rc) C (=O) R6、- (CR7R8)nC (=O) ORc、-(CR7R8)nC (=O) NRaRb、-N(Rc) S (=O)mR6Or-S (=O)2NRaRb, wherein, when above-mentioned Each R4And R5It is not H, F, Cl, Br, I, NO2, CN and N3When, each R4And R5Respectively optionally by 1,2 or 3 R9Group is replaced.
In some embodiments, each R6It independently is H, C1-C6Alkyl, C1-C6Haloalkyl, C2-C6Alkenyl, C2-C6Alkynes Base, C3-C6Cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, wherein, work as R6It is not During H, each R6Individually optionally by 1,2 or 3 R9Group is replaced.
In other embodiments, each R6It independently is H, C1-C4Alkyl, C1-C4Haloalkyl, C2-C4Alkenyl, C2-C4 Alkynyl, C3-C6Cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl, wherein, work as R6No During for H, each R6Individually optionally by 1,2 or 3 R9Group is replaced.
In some embodiments, each R7And R8It is separately H, F, Cl, Br, I, CN, N3、NO2、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical or 5-6 former molecular heteroaryl Base, or R7And R8, and together with the carbon atom being connected with them form C3-C6Cycloalkyl, phenyl, 3-6 former molecular heterocycle Base or 5-6 former molecular heteroaryl groups, wherein, above-mentioned each substitution base, is not H, F, Cl, Br, I, NO2, CN and N3When, Individually optionally by 1,2 or 3 R9Group is replaced.
In other embodiments, each R9It independently is F, Cl, CN, N3、C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkyl, phenyl, 3-6 former molecular heterocyclic radical, 5-6 former molecular heteroaryl, NH2、-NH(C1-C6Alkane Base) ,-NH (CH2)n-(C3-C6Cycloalkyl) ,-NH (CH2)n- phenyl ,-NH (CH2)n- (3-6 atom constitutes heterocyclic radical) ,-NH (CH2)n- (5-6 former molecular heteroaryl) ,-N (C1-C4Alkyl)2、-N[(CH2)n-(C3-C6Cycloalkyl)]2、-N [(CH2)n- phenyl]2、-N[(CH2)n- (3-6 former molecular heterocyclic radical)]2、-N[(CH2)n- (5-6 is former molecular miscellaneous Aryl)]2、OH、-O(C1-C6Alkyl) ,-O (CH2)n-(C3-C6Cycloalkyl) ,-O (CH2)n- phenyl ,-O (CH2)n- (3-6 atom The heterocyclic radical of composition) or-O (CH2)n- (5-6 former molecular heteroaryl).
In other embodiments, each Ra、RbAnd RcIt is separately H, C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynes Base, C3-C6Cycloalkyl ,-(C1-C2Alkylidene)-(C3-C6Cycloalkyl), 3-6 former molecular heterocyclic radical ,-(C1-C2Alkylene Base)-(3-6 former molecular heterocyclic radical), phenyl ,-(C1-C2Alkylidene)-phenyl, 5-6 former molecular heteroaryls or- (C1-C2Alkylidene)-(5-6 former molecular heteroaryl), or RaAnd Rb, and together with the nitrogen-atoms being connected with them, formed 3-6 former molecular heterocyclyl groups, wherein, above-mentioned each substitution base, when not for H, individually optionally by 1,2 or 3 independences Selected from F, Cl, CN, N3、OH、NH2、C1-C4Alkyl, C1-C4Haloalkyl, C1-C4Alkoxy or C1-C4The substitution base of alkyl amino 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 of compound shown in formula (I), dynamic isomer, solvate, metabolism is produced Thing, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
The present invention is disclosed compound and containing asymmetric or chiral centre, therefore can be deposited with different stereoisomer forms .It is contemplated that 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, turn into Part of the invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific is not indicated, then the structure All stereoisomers all consider within the present invention, and disclose compound and be included in the invention as the present invention.When Spatial chemistry is expressed when wedge shape line (solid wedge) or dotted line are indicated in fact of particular configuration, then the alloisomerism of the structure Body clearly and is defined with regard to this.
Compound shown in formula (I) can exist with different tautomeric forms, and all these dynamic isomers, As is described in the claims, it is included within the scope of the present invention.
Compound shown in formula (I) can exist in a salt form.In some embodiments, the salt refers to pharmaceutically may be used The salt of receiving.Term " pharmaceutically acceptable " refers to that material or composition must be with other compositions and/or use comprising preparation The mammal of its treatment is compatible chemically and/or in toxicology.In other embodiments, the salt is not necessarily pharmacy Upper acceptable salt, can be for preparing and/or purifying compound shown in formula (I) and/or for separating this formula (I) shownization The intermediate of the enantiomer of compound.
Pharmaceutically useful acid-addition salts can be formed with inorganic acid and organic acid, for example acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.
The inorganic acid that salt can be obtained by its derivative is including such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc..
The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, butanedioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..
Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.
The inorganic base of salt can be obtained by its derivative includes, the metal of I races to the XII races of such as ammonium salt and periodic table. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.
The organic base that salt can be obtained by its derivative includes primary amine, secondary amine and tertiary amine, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Some organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.
Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalescence or acidic moiety. In general, such salt can by make the free acid form of these compounds and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or by making the free alkali form of these compounds and chemistry The suitable acid reaction of metered amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile in the case of appropriate. Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts：Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) in can find the list of the suitable salt of other.
In addition, compound disclosed by the invention, the salt including them, it is also possible to their hydrate forms or comprising it The form of solvent (such as ethanol, DMSO, etc.) is obtained, for their crystallization.The present invention discloses compound can be with pharmacy Upper acceptable solvent (including water) inherently or by design forms solvate；Therefore, it is contemplated that including solvation And unsolvated form.
Any structural formula that the present invention is given is also intended to expression these compounds not by the form of isotope enrichment and same The form of position element enrichment.The compound of isotope enrichment has the structure that the formula that the present invention is provided is described, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced into Isotope including 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 the defined compound of the present invention of isotope enrichment, for example, its In there is radio isotope, such as3H、14C and18Those compounds of F, or wherein there is non radioactive isotope, such as2H and13C.The compound of such isotope enrichment can be used for metabolism research and (use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including medicine or substrate tissue measure of spread SPECT (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 shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art 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.
Additionally, higher isotope particularly deuterium is (i.e.,2H or D) substitution some treatment advantages can be provided, these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increases or volume requirements are reduced or therapeutic index obtains improving band Come.It should be appreciated that the deuterium in the present invention is counted as the substitution base of compound shown in formula (I).Isotope enrichment factor can be used To define the concentration of such higher isotope particularly deuterium.Term " isotope enrichment factor " used in the present invention refers to meaning Determine the ratio between the isotope abundance of isotope and natural abundance.If the substitution base of the compounds of this invention is designated as deuterium, The compound has at least 3500 (at each specified D-atoms 52.5% deuterium mix), at least for each D-atom specified 4000 (60% deuterium is mixed), at least 4500 (67.5% deuterium is mixed), at least 5000 (75% deuterium is mixed), at least 5500 (82.5% deuterium is mixed), at least 6000 (90% deuterium is mixed), at least 6333.3 (95% deuterium is mixed), at least 6466.7 The isotope enrichment of (97% deuterium is mixed), at least 6600 (99% deuterium is mixed) or at least 6633.3 (99.5% deuterium is mixed) The factor.The pharmaceutically useful solvate of the present invention can be such as D of isotope substitution including wherein recrystallisation solvent2O, acetone-d6、 DMSO-d6Those solvates.
On the other hand, the present invention relates to prepare the intermediate of compound shown in formula (I).
The method of preparation, separation and purifying on the other hand, the present invention relates to 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 a little embodiments, pharmaceutical composition of the present invention, further including pharmaceutically acceptable carrier, excipient, adjuvant, Solvent or combinations thereof.In other embodiments, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Mist formulation.
On the other hand, the present invention relates to treat by one or more protein kinase, such as jak kinase, FLT3 kinases and The disease of Aurora A regulation or the method for disorder, the treatment method include that the present invention for giving mammal effective dose is public Become civilized compound or pharmaceutical composition.In some embodiments, the disease or disorderly selected from proliferative diseases, autoimmunity disease Disease, anaphylactia, inflammatory disease or graft rejection.
On the other hand, the present invention relates to using the compounds of this invention disclosed by the invention or medicine composite for curing disease or Disorder, the disease or disorderly selected from proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease or transplanting row Reprimand.
On the other hand, treatment disease or disorder are being prepared the present invention relates to compound disclosed by the invention or pharmaceutical composition Medicine purposes, the disease be selected from proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease or transplanting row Reprimand.
On the other hand, the present invention relates to prepare medicine using the compounds of this invention disclosed by the invention or pharmaceutical composition Purposes, the medicine is used for the activity of regulatory protein kinases.
The pharmaceutical composition of the compounds of this invention, preparation and administration
The present invention provides a kind of pharmaceutical composition, and it includes the present invention and discloses listed compound in compound, or embodiment； With pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combinations thereof.Change in pharmaceutical composition disclosed by the invention The amount of compound refers to energy effective detection to the amount for suppressing biological specimen or patient's vivo protein kinases.
It will also be appreciated that some compounds of the invention can exist in a free form to be used to treat, or it is if appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some nonrestrictive implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when be administered to patient in need can it is direct or Any other adduct or derivative of compound of the present invention or its metabolite or residue is provided indirectly.
Drug pharmaceutical compositions disclosed by the invention can be prepared and be packaged as (bulk) form in bulk, wherein extractable safety Compound shown in the formula (I) of effective dose, then gives patient with powder or syrup form.Or, medicine disclosed by the invention Composition can be prepared and be packaged as unit dosage forms, and wherein each physically discrete unit contains formula (I) institute of safe and effective amount The compound for showing.When being prepared with unit dosage forms, pharmaceutical composition disclosed by the invention can generally contain, for example, 0.5mg to 1g, Or the compound disclosed by the invention of 1mg to 700mg or 5mg to 100mg.
" pharmaceutically acceptable excipient " means related to form of administration or pharmaceutical composition uniformity used by the present invention Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with other of pharmaceutical composition into Split-phase is held, and the interaction of effect for disclosing compound of the invention can be substantially reduced during avoiding that patient is administered and can be caused not It is the interaction of pharmaceutically acceptable pharmaceutical composition.Additionally, every kind of excipient must be pharmaceutically acceptable, example Such as, with sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific formulation.Additionally, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Some pharmaceutically acceptable excipient.Some the pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.May be selected to contribute to when patient be administered to carry or transport it is of the invention compound is disclosed from an organ of body or partly to Another organ of body or the pharmaceutically acceptable excipient of some partial.Some medicines of enhancing patient compliance may be selected Acceptable excipient on.
Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, rectify Taste agent, odor mask, colouring agent, anticaking agent, NMF, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.Technical staff can be appreciated that some pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends on existing in preparation in how much excipient and preparation in the presence of which other Excipient.
Technical staff grasps the knowledge and skills of this area, so that they can be selected for the suitable of appropriate amount of the invention Pharmaceutically acceptable excipient.Additionally, there are resource obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.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 Disclosed in Dekker, New York for configuring the various carriers of pharmaceutically acceptable composition, and prepared for it Known technology, the respective content of these documents is incorporated by reference into the present invention.Except any such as because producing any undesirable life Thing is acted on, or so that any other composition in harmful way and pharmaceutically acceptable composition occurs to interact with the present invention Outside the incompatible any commonly employed carrier of open compound, pay close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention is prepared using technology well known by persons skilled in the art and method.This area The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the technique the present invention relates to prepare pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, assistant agent, solvent or combinations thereof, the technique include that mixing is each Plant composition.The pharmaceutical composition of compound is disclosed comprising the present invention, can mix to make under such as environment temperature and atmospheric pressure It is standby.
Compound disclosed by the invention is usually formulated as the formulation for being suitable for that patient is administered by required approach.Example Such as, formulation is suitable for the formulation of following method of administration including those：(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent, containing tablet, pulvis, syrup, elixir, supensoid agent, solution, emulsion, granule and cachet；(2) parenteral, example Such as sterile solution agent, supensoid agent and freeze-dried powder agent；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) suck, such as aerosol, solution and dry powder doses；(6) it is local administration, such as cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gel.
In some embodiments, compound disclosed by the invention can be configured to peroral dosage form.In other embodiment party In case, compound disclosed by the invention can be configured to inhalant dosage form.In other embodiments, chemical combination disclosed by the invention Thing can be configured to nose administration formulation.In other embodiment, compound disclosed by the invention can be configured to transdermal Form of administration.Also in some embodiments, compound disclosed by the invention can be configured to Topical dosage forms.
The pharmaceutical composition that the present invention is provided can with compressed tablets, develop piece, chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets are provided.Enteric coatel tablets are to use to be resistant to the material bag that hydrochloric acid in gastric juice acts on but dissolved in intestines or be disintegrated The compressed tablets of clothing, so as to prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to aliphatic acid, fat Fat, phenyl salicylate, wax, shellac, ammonification shellac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat is surrounded Piece, it can be beneficial to cover taste beastly or smell and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water solubility The compressed tablets of thin layer or the film covering of material.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethylcellulose calcium Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses and sweet tablet identical general characteristic.It is multiple Compressing tablet is the compressed tablets by being prepared more than press cycles, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by the one kind in powder, crystallization or granular active component individually or with present invention description Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colouring agent.Fumet and sweetener are particularly useful when chewable tablets and lozenge is formed.
The pharmaceutical composition that the present invention is provided can be provided with soft capsule or hard shell capsules, and it can be fine by gelatin, methyl Element, starch or calcium alginate is tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is constituted by two sections, one section Fill in another section, therefore enclose active component completely.SEC (SEC) is soft, spherical shell, such as gelatin shell, It passes through to add glycerine, sorbierite or similar polyalcohol to plastify.Soft gelatin shell can be comprising the pre- preventing microorganism life of preservative It is long.Suitable preservative for as described in the present invention those, including methyl hydroxybenzoate and propylben, and sorbic acid.This Inventing liquid, semisolid and the solid dosage forms for providing can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and supensoid agent in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can 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 Coating as is known to persons skilled in the art is used, so as to improve or maintain the dissolution of active component.
The pharmaceutical composition that the present invention is provided 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 another liquid in pellet form, It can be oil-in-water type or water-in-oil type.Emulsion can include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and Preservative.Supensoid agent can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used Two (low alkyl group) acetals of the acetal of receiving, such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With with one or many The water-soluble solvent of individual hydroxyl, such as propane diols and ethanol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and also preservative can be included.For liquid dosage form, for example, the solution in polyethylene glycol 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 the active component provided comprising the present invention and two grades Change those formulations of list-or poly- alkylene glycol, the list-or poly- alkylene glycol include：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 mean molecule quantity 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, monoethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, Jiao Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.
Where appropriate, the dosage unit preparations microencapsulation that will can be administered orally.Can also be prepared into extending or tieing up The composition of release is held, for example, is coated or is embedded in polymer, wax or the like by by microparticle material.
The combination of oral medication that the present invention is provided can also be carried in the form of liposome, micella, microballoon or nanometer system For.Micella formulation can be prepared with the method for U.S.Pat.No.6,350,458 descriptions.
The pharmaceutical composition that the present invention is provided 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 can include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier and excipient used in effervescent or pulvis can be wrapped Include organic acid and carbon dioxide source.
Colouring agent and flavor enhancement can be used in all above-mentioned formulations.
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.Additionally, compound disclosed in this invention can with reality The class Biodegradable polymeric used in the control release of existing medicine is combined, for example, PLA, poly-epsilon-caprolactone, poly- The crosslinking of hydroxybutyric acid, poe, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel or amphiphilic block are common Polymers.
The pharmaceutical composition that the present invention is provided can be configured to immediately or Modified release dosage forms, including postpone-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
The pharmaceutical composition that the present invention is provided can be common with other active components that will not damage expected therapeutic action Prepare, or the material co-formulation with the expected effect of supplement.
The pharmaceutical composition that the present invention is provided can be by injection, infusion or implantation parenteral, for local or complete Body is administered.The parenteral used such as the present invention is included in intravenous, intra-arterial, intraperitoneal, intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical composition that the present invention is provided can be configured to be suitable to any formulation of parenteral, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and being suitable to is made consolidating for solution or suspension in a liquid before the injection Body form.Such formulation can according to known to the technical staff in pharmaceutical science field conventional method preparing (referring to Remington:The Science and Practice of Pharmacy, ibid).
Be intended for the pharmaceutical composition of parenteral can include one or more pharmaceutically acceptable carrier and Excipient, includes, but 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 dispersion that thing grows Agent, wetting agent or emulsifying agent, 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, salt solution, physiological saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers parenteral solutions, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers parenteral solutions.Non- transporter includes, but 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 not limited to the poly- second two of ethanol, 1,3-BDO, liquid Alcohol (such as Liquid Macrogol and PEG400), propane diols, glycerine, METHYLPYRROLIDONE, N, N- dimethylacetamides Amine and dimethyl sulfoxide.
Suitable antimicrobial or preservative include, but not limited to phenol, cresols, mercurial, phenmethylol, 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 not limited to sodium chloride, glycerine and glucose.Suitable buffer Include, but not limited to phosphate and citrate.Suitable antioxidant is including the sulfurous acid such as present invention description Hydrogen salt and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to procaine hydrochloride.Suitable suspending agent and point Powder is including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone such as present invention description. Suitable emulsifying agent includes those of present invention description, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene takes off 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 NaOH, hydrochloric acid, citric acid and lactic acid.Suitable complexing agent includes, but does not limit In cyclodextrin, including alpha-cyclodextrin, beta-schardinger dextrin, HP-β-CD, Sulfobutylether-beta-schardinger dextrin and sulfobutyl group Ether 7- beta-schardinger dextrins (CyDex,Lenexa,KS)。
The pharmaceutical composition that the present invention is provided can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multiple dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All of parenteral administration all must be aseptic, as known in the art with practice.
In some embodiments, pharmaceutical composition is provided with instant sterile solution.In other embodiments, Pharmaceutical composition is provided with aseptic dried soluble product, including freeze-dried powder agent and hypodermic tablet, and it is using preceding use Carrier is reconstructed.In other embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In other implementation In scheme, pharmaceutical composition dries insolubility product before being formulated into use with the aseptic of carrier reconstruct.Also at some In 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 postpone-, sustained release-, Pulse-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition can be configured to supensoid agent, solid, semisolid or thixotropic liquid, the reservoir administration as implantation. In some embodiments, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, and it is insoluble to body fluid But the outside polymeric membrane for allowing the active component in pharmaceutical composition to diffuse through is surrounded.
Suitable internal matrix include polymethyl methacrylate, poly- butyl methacrylate, plasticising or it is unplasticizied Polyvinyl chloride, plasticising nylon, plasticising PET, plasticising polyethylene terephthalate, natural rubber, Polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly- diformazan silica Alkane, silicone carbonate copolymer, hydrogel, collagen, the crosslinking of the ester of hydrophilic polymer such as acrylic acid and methacrylic acid The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and coach.
Suitable outside polymeric membrane includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Thing, ethylene/vinyl acetate copolymer, silicone rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second The copolymer of alkene, ethlyene dichloride and vinyl acetate, vinylidene chloride, ethene 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 to any dose to patient's inhalation Type, such as dry powder doses, aerosol, supensoid agent or liquid composite.In some embodiments, medicine group disclosed in this invention Compound can be configured to be suitable to the formulation with dry powder doses to patient's inhalation.In other embodiment, present invention institute is public The pharmaceutical composition opened can be configured to be suitable to the formulation by sprayer to patient's inhalation.By inhalation delivery to lung Dry powder composite generally comprises fine powdered compound disclosed in this invention and one or more fine powdered medicine Acceptable excipient on.It to be especially suitable for use as by those skilled in the art the pharmaceutically acceptable excipient of dry powder doses Know, it includes lactose, starch, mannitol and single-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding system It is standby to obtain.In general, compound can be by about 1 to 10 micron of D for (such as the micronizing) that size reduces50Value (for example, with Laser diffractometry measurement) define.
Can be by the way that be suspended or dissolved in compound disclosed in this invention to prepare in liquefied propellant by aerosol.It is adapted to Propellant include chlorohydrocarbon, hydro carbons and other liquid gas.Representational propellant includes：Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), HFC-134a (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.Aerosol comprising compound disclosed in this invention generally passes through Metered dose inhaler (MDI) is administered to patient.Such device dawn known to those skilled in the art
Aerosol can include pharmaceutically acceptable excipient that is extra, 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.
Being suitable for the pharmaceutical composition of cutaneous penetration can be prepared into discontinuous paster agent, it is intended that the epidermis with patient keeps It is in close contact the time of an elongated segment.For example, the delivering active ingredients from paster agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for the pharmaceutical composition of local administration can be formulated into ointment, cream, supensoid agent, lotion, pulvis, Solution, paste, gel, spray, aerosol or finish.For example, ointment, cream and gel can use water or oil Matrix, and suitable thickener and/or gel and/or solvent are configured.Such matrix can 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 gel 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 be prepared with water or oil matrix, and generally also contain one or more emulsifying agent, 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 Can be formulated with water or non-aqueous matrix comprising one or more dispersant, solubilizer, suspending agent or preservative.
Topical formulations can be administered using one or many daily by affected part；The impermeable plastic wound dressing for covering skin is preferential Used.Adhesiveness store system can realize continuous or extension administration.
Treatment eyes, or when other organs such as face and skin, can apply as the combination of topical ointment or cream Thing.When ointment is formulated as, 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 is provided and uses compound disclosed in this invention and medicine composite for curing, prevention, or is improved 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 influenceed Disorderly or by one or more protein kinase, 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 symptom of disorder.
FLT3 kinases can be wild type and/or the mutation of FLT3 kinases.
Jak kinase can be wild type and/or the mutation of JAK1, JAK2, JAK3 or TYK2 kinases.
In some embodiments, the present invention provides class compound disclosed in this invention or comprising presently disclosed The pharmaceutical composition of compound, for treating, preventing or improve by unsuitable JAK1 kinases behavior mediation or otherwise The disease of influence is disorderly or mediated by unsuitable JAK1 kinases behavior or the disease that otherwise influences or disorder One or more symptom.In other embodiments, the disease, disorder or disease or one or more symptom of disorder It is related to unsuitable JAK2 kinases behavior.Also in some embodiments, the one of the disease, disorder or disease or disorder Plant or various symptoms are related to unsuitable JAK3 kinases behavior.
In some embodiments, the present invention provides class 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 is disorderly or mediated by unsuitable FLT3 kinases behavior or the disease that otherwise influences or disorder One or more symptom.
In some embodiments, the present invention provides class 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 or disease that is disorderly or being mediated by unsuitable Aurora-A kinases behavior or otherwise influenceed that mode influences Or one or more symptom of disorder.In other embodiments, one kind of the disease, disorder or disease or disorder or Various symptoms are related to unsuitable Aurora-B kinases behavior.Also in some embodiments, the disease, disorder or disease Disease or one or more symptom of disorder are related to unsuitable Aurora C kinases behaviors.
" unsuitable jak kinase behavior " refer to occur deviate with particular patient normal jak kinase behavior JAK 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 comes from, for example, the overexpression or mutation of protein kinase and Caused inappropriate or uncontrolled behavior.Therefore, the present invention provides the method for treating these diseases and disorder.
Consistent with above description, such disease or disorder are included but is not limited to：Bone marrow proliferative diseases, for example 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's Hypotype, acute megakaryoblastic leukemia (AMKL)；Lymphoproliferative disease, such as ALL (ALL), bone Myeloma；Cancer includes incidence cancer, prostate cancer breast cancer, oophoroma, melanoma, lung cancer, brain tumor, cancer of pancreas and kidney；With The diseases associated with inflammation relevant with immunologic function disorder, immune deficiency, immunological regulation or disorder, autoimmune disease, tissue shifting Plant repulsion, graft versus host disease(GVH disease), wound healing, ephrosis, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, silver bits Disease, allergic rhinitis, IBD include Crohn disease and ulcerative colitis (UC), systemic loupus erythematosus (SLE), close Section inflammation, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD) and dry eyes synthesis Levy (or keratoconjunctivitis sicca (KCS)).
On the one hand, the present invention provides class compound disclosed in this invention or the medicine comprising 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, methods described include give effectively treatment illness amount or effectively prevention illness amount one or more medicine disclosed herein Compositions or compound.On the other hand, suffered from provided herein is one kind treatment or risky suffer from proliferative diseases, autologous exempt from The method of the mammal of epidemic disease, anaphylactia, inflammatory disease or graft rejection.
In a kind of method in terms for the treatment of, the present invention provides treatment and/or prevention is susceptible or suffering from proliferative diseases The method of mammal, methods described includes giving one or more medicine disclosed herein of effective therapeutic dose or effective preventive dose Compositions or compound.In particular instances, proliferative diseases are selected from cancer (for example, solid tumor such as uterine leio muscle Knurl or prostate cancer), polycythemia vera, primary thrombocytosis, myelofibrosis, leukaemia (for example, AML, CML, ALL or CLL) and Huppert's disease.
On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing proliferative diseases. In specific embodiment, proliferative diseases be 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 CLL) And Huppert's disease.
On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, the medicine for preparing treatment or prevention proliferative diseases.In particular instances, proliferative diseases are selected from cancer (for example, real Body knurl, leiomyosarcoma of uterus or prostate cancer), polycythemia vera, primary thrombocytosis, myleo Change, leukaemia (for example, AML, CML, ALL or CLL) and Huppert's disease.
On the other hand, the side of the mammal of autoimmune disease is susceptible or suffering from provided herein is treatment and/or prevention Method, methods described includes giving one or more pharmaceutical composition disclosed herein or the change of effective therapeutic dose or effective preventive dose Compound.In particular instances, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, wolf Sore ephritis, dermatomyositis, Sjogren syndrome, psoriasis, type i diabetes and inflammatory bowel disease.
On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing autoimmune disease. In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, wolf Sore ephritis, dermatomyositis, Sjogren syndrome, psoriasis, type i diabetes and inflammatory bowel disease.
On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, the medicine for preparing treatment or prevention autoimmune disease.In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, LN, dermatomyositis, Sjogren syndrome, psoriasis, I Patients with type Ⅰ DM and inflammatory bowel disease.
On the other hand, the method for the mammal of anaphylactia is susceptible or suffering from provided herein is treatment and/or prevention, Methods described includes giving one or more pharmaceutical composition disclosed herein or chemical combination of effective therapeutic dose or effective preventive dose Thing.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 class compound disclosed herein, for treating and/or preventing anaphylactia. In specific embodiment, anaphylactia be selected from respiratory anaphylactic disease, nasosinusitis, eczema and measles, food hypersenstivity and Insect venom allergies.
On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, the medicine for preparing treatment or prevention anaphylactia.In certain embodiments, anaphylactia is selected from respiratory tract Anaphylactia, nasosinusitis, eczema and measles, food hypersenstivity and insect venom allergies.
On the other hand, the method for the mammal of inflammatory disease, institute are susceptible or suffering from provided herein is treatment and/or prevention Stating method includes giving one or more pharmaceutical composition disclosed herein or compound of effective therapeutic dose or effective preventive dose. In certain embodiments, inflammatory disease is selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis And psoriasis arthropathica.
On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing inflammatory disease.In spy In fixed embodiment, inflammatory disease is selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis and silver Bits disease arthritis.
On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, the medicine for preparing treatment or prevention inflammatory disease.In certain embodiments, inflammatory disease be selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis and psoriasis arthropathica.
On the other hand, the method for the mammal of graft rejection, institute are susceptible or suffering from provided herein is treatment and/or prevention Stating method includes giving one or more pharmaceutical composition disclosed herein or compound of effective therapeutic dose or effective preventive dose. In particular instances, graft rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.
On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing graft rejection.In spy In fixed embodiment, graft rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.
On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, the medicine for preparing treatment or prevention graft rejection.In particular instances, graft rejection is organ-graft refection, tissue Graft rejection and cell transplant rejection.
On the other hand, it is especially used as treating and/or preventing disease medicament noted earlier as medicine provided herein is a class Compound disclosed herein.It is also provided with that compound manufacture treatment is disclosed herein and/or prevents the medicine of disease noted earlier Thing.
One special projects of this method include that the present invention for giving the study subject effective dose with inflammation discloses chemical combination For a period of time, the time is enough to reduce the level of inflammation of study subject to thing, and preferably terminates the process of the inflammation.The party The special embodiment of method includes giving with or being susceptible to suffer from that the present invention of tested patients' effective dose of bone rheumatoid arthritis is public Compound become civilized for a period of time, the time is enough to reduce respectively or prevent the arthritis of the patient, and preferably terminates institute State the process of inflammation.
Another special projects of this method include giving the present invention of the study subject effective dose with proliferative diseases For a period of time, the time is enough to reduce the hyperplasia level of study subject to open compound, and preferably terminates the increasing The process of growing property disease.The special embodiment of the method includes giving being disclosed herein for the tested patients' effective dose with cancer For a period of time, the time is enough to reduce respectively or prevent the cancer symptom of the patient to compound, and preferably terminates described The process of cancer.
Therapeutic alliance
The compounds of this invention can be administered as single active agent, or can be administered with other therapeutic agents, Including being defined 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, prevention or improves the method for disease or illness, including gives safe and effective amount The combination medicine of compound and one or more therapeutically active agent is disclosed comprising the present invention.In some embodiments, medicine is combined Thing includes one or two other therapeutic agents.
The example of other therapeutic agents includes including but is not limited to：Anticancer, including chemotherapeutics and antiproliferative；Antiinflammatory； With immunity regulatin remedy agent or immunodepressant.
On the other hand, the present invention is provided includes the product of the compounds of this invention and at least one other therapeutic agents, can prepare Into the combination simultaneously, separately or sequentially applied in the treatment.In some embodiments, treatment is directed to by one or more egg White kinases, such as treatment of the disease or symptom of the mediation of jak kinase, FLT3 kinases or Aurora A activity.Joint is prepared and provided Product include being present in same pharmaceutical composition the composition comprising compound and other therapeutic agents is disclosed herein, or with Compound disclosed herein and other therapeutic agents that multi-form is present, for example, medicine box.
On the other hand, the present invention provides a kind of medicine comprising compound disclosed herein and another or various therapeutic agents Composition.In some embodiments, pharmaceutical composition can be comprising pharmaceutically acceptable excipient, load as described above Body, adjuvant or solvent.
On the other hand, the present invention provides the medicine box comprising two kinds or more of drug alone composition, wherein at least one Pharmaceutical composition discloses compound comprising the present invention.In some embodiments, medicine box includes individually keeping the composition Instrument, such as container, separate bottle or separate paper tinsel box.The example of this kind of medicine box is blister package, is commonly used for package panel Agent, capsule etc..
Present invention also offers purposes of the compounds of this invention in the disease or symptom that treatment albumen kinase activity is mediated, Wherein patient previous (such as in 24 hours) is treated with other therapeutic agents.Present invention also offers other treatment Purposes of the agent in treatment albumen kinases, disease and symptom that such as jak kinase, FLT3 kinases and Aurora A activity are mediated, Wherein patient previous (such as in 24 hours) is treated with the compounds of this invention.
Compound disclosed herein can be applied as single-activity component or as such as adjuvant, applied jointly with other medicines With.The other medicines include that immunodepressant, immunomodulator, other antiinflammatories are for example of the same race different for treating or preventing Body or xenograft acute or chronic rejection, inflammatory, the medicine of autoimmune disease；Or chemotherapeutics, such as malignant cell Antiproliferative.For example, the present invention discloses compound and can combine with following active component：Calcium nerve element inhibitor, such as ring spore Rhzomorph A or FK506；MTOR inhibitors, such as rapamycin, 40-O- (2- hydroxyethyls)-rapamycin, CCI779, ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9；Ascosin with immunosuppressive properties, for example ABT-281, ASM981 etc.；Corticosteroid；Endoxan；Imuran；Methotrexate (MTX)；Leflunomide；Mizoribine；Wheat Examine phenolic acid or salt；Mycophenolate mofetil；15- deoxyspergualins or its immunosupress homologue, analog or derivative； Described in pkc inhibitor, such as WO 02/38561 or WO 03/82859, such as compound of embodiment 56 or 70；It is immune Suppression monoclonal antibody, the monoclonal antibody of such as leukocyte receptors, for example, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or its part；Other immunomodulatory compounds, such as with CTLA4's The restructuring binding molecule or its mutant of at least part of extracellular domain, the CTLA4 being for example connected with non-CTLA4 protein sequences is extremely Few extracellular portion or its mutant, such as CTLA4Ig (being for example 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 taxol, gemcitabine, cis-platinum, Doxorubicin or 5 FU 5 fluorouracil；Or anti-infective.
Compound is disclosed with other immunotherapeutic agent/immunomodulators, antiinflammatory, chemotherapy or anti-infective in the present invention In the case for the treatment of administering drug combinations, the immunodepressant of administering drug combinations, immunomodulator, antiinflammatory, chemotherapeutant or anti-sense The dosage for contaminating compound certainly can be according to used by combination medicine type, for example whether it is that steroidal or calcineurin suppress Agent, specific medicine used, illness to be treated etc. and change.
On the one hand, the present invention provides a kind of present invention that includes and discloses compound and β2The connection of-adrenoceptor agonists Close.β2The example of-adrenoceptor agonists includes salmeterol, salbutamol, Formoterol, salmefamol, Fei Nuote Sieve, carmoterol, Yi Tanteluo, naminterol, Clenbuterol, pirbuterol, Flerobuterol, reproterol, special sieve of promulgation, indenes Da Teluo, Terbutaline, and their salt, the xinafoate (1- hydroxy-2-naphthoic acids salt) of such as salmeterol, husky butylamine The sulfate or free alkali or the fumarate of Formoterol of alcohol.In some embodiments, long-acting beta2- adrenocepter Activator, for example, provide effective bronchiectasis up to 12 hours or the compound of longer time, is preferred.
β2- adrenoceptor 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, the meat of substitution Cinnamic acid, triphenylacetic acid, sulfamic acid, p-aminobenzene sulfonic acid, 3- (1- naphthyls) 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 that compound and corticosteroid are disclosed comprising the present invention.Suitably Corticosteroid refers to those oral and suction corticosteroids, and its has the prodrug of anti-inflammatory activity.Example sprinkles including methyl Ni Songlong, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), the α of-16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-17-[(4- methyl-1,3-thiazoles- 5- carbonyls) epoxide] -17 β of -3- oxo-androst -1,4- diene-thiocarboxylic acid S- fluorine methyl esters, 6 α, fluoro- 17 α of 9 α-two-[(2- furans Mutter carbonyl) epoxide]-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-16-thiocarboxylic acid S- fluorine methyl esters (furancarboxylic acids Fluticasone) ,-17 α of Alpha-Methyl-3- oxos of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-16-β of propionyloxy-androsta-1,4- diene-17- Thiocarboxylic acid S- (2- oXo-tetrahydro furans-3S- bases) ester, the α of-16 Alpha-Methyl-3- oxos of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-17- (2,2,3,3- tetramethyls cyclopropyl carbonyl) epoxide--17 β of androstane -1,4- diene-thiocarboxylic acid S- cyano methyl esters and 6 α, 9 α-two The fluoro- α of-16 Alpha-Methyl of 11 beta-hydroxy-17-β of (1- ethyls cyclopropyl carbonyl) epoxide-3- oxo-androst-1,4- diene-17-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- for 16 α, 17- for sieve fluoronaphthalene moral (rofleponide), ciclesonide (ciclesonide) Methyl] double (epoxides)] -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), the α of-16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-17-[(4- methyl-1,3-thiazole-5- carbonyls) epoxide]- - 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]-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-16-thiocarboxylic acid S- methyl fluorides ester, 6 α, 9 α-two are fluoro- The α of-16 Alpha-Methyl-3- oxos of 11 beta-hydroxy-17-(2,2,3,3- tetramethyls cyclopropyl carbonyl) epoxide-androstane-1,4- diene-17 β-thiocarboxylic acid S- cyano methyl esters and the α of-16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-17-(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, - 17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of fluoro- 17 α of 9 α-two-[(2- furanylcarbonyls) epoxide]-11 beta-hydroxy-16-sulphur For carboxylic acid S- methyl fluoride esters.
On the other hand, the present invention provides a kind of joint that compound and nonsteroidal GR activators are disclosed comprising the present invention. Have to Transcription inhibition selectivity (compared with transcriptional activation), can be used for therapeutic alliance with glucocorticoid agonist activity Nonsteroidal compound covered in the compound in following patent including those：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 04/026248th, 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, the present invention provides a kind of present invention that includes and discloses compound and nonsteroidal anti-inflammatory drug (NSAID's) 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 are closed Into 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 WO 93/13055, WO 98/ 30537th, the compound disclosed in WO 02/50021, WO 95/34534 and WO 99/62875.CCR3 inhibitor include those Compound disclosed in WO 02/26722.
In some embodiments, compound is disclosed the present invention relates to the present invention to suppress with phosphodiesterase 4 (PDE4) Application in the joint of agent, the especially application in inhalant dosage form.For the PDE4 specific inhibitors of this aspect of the present invention Can be known suppression PDE4 enzymes or be found be used as PDE4 inhibitor any compound, they be only PDE4 suppress Agent, is not to suppress other members, the compound of such as PDE3 and PDE5 in PDE families.Compound includes cis -4- cyano group -4- (3- Cyclopentyloxy -4- methoxyphenyls) hexamethylene -1- carboxylic acids, 2- carbomethoxy -4- cyano group -4- (3- cyclo propyl methoxies -4- two Fluorine methoxyphenyl) hexamethylene -1- ketone and cis-[4- cyano group -4- (3- cyclo propyl methoxy -4- difluoro-methoxies phenyl) ring Hexane -1- alcohol]；Also include that hexamethylene -1- carboxylic acids are (also referred to as cis -4- cyano group -4- [3- (ring propoxyl group) -4- methoxyphenyls] Xi Luosi) and its salt, ester, prodrug or physical form, it was in 09 month 1996 No. 03 United States Patent (USP) US 5,552,438 for authorizing Disclosed in, 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 that compound and anticholinergic are disclosed comprising the present invention.Cholinolytic Can agent example be those be used as muscarinic receptor antagonist compounds, particularly those as M1 or M3 receptor antagonists, M1/M3Or M2/M3Receptor dual antagonist or M1/M2/M3The compound of the general antagonist of acceptor.The example compound bag of inhalation Include ipratropium (for example, as bromide, CAS 22254-24-6, withFor trade name is sold), Oxygen support ammonium (for example, as bromide, CAS 30286-75-0) and tiotropium are (for example, as bromide, CAS 136310-93- 5, withFor trade name is sold)；What is be also interested in also has Revatropate (for example, as hydrobromic acid Salt, CAS 262586-79-8) and LAS-34273 disclosed in WO01/04118.The example compound of oral administration includes piperazine Logical sequence Xiping (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or its hydrobromate CAS 133099-07-7, WithFor trade name is sold), oxybutynin (CAS 5633-20-5, withIt is trade name Sell), terodiline (CAS 15793-40-5), Tolterodine (CAS 124937-51-5, or its tartrate CAS 124937-52-6, withFor trade name is sold), Austria is for ammonium (for example, as bromide, CAS 26095- 59-0, withFor trade name is sold), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, or its succinate CAS 242478-38-2, i.e. compound YM-905, with For trade name is sold).
On the other hand, the present invention provides a kind of joint that compound and H1 antagonists are disclosed comprising the present invention.H1 antagonists Example include, but 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 other realities Apply in scheme, the present invention provides a kind of joint that compound and H3 antagonists (and/or inverse agonist) are disclosed comprising the present invention.H3 The example of antagonist includes those compounds disclosed in WO 2004/035556 and WO 2006/045416.Can be used for and this United other histamine receptor antagonists of disclosure of the invention compound include H4 receptor antagonists (and/or inverse agonist), for example, exist Jablonowski et al.,J.Med.Chem.46:Compound disclosed in 3957-3960 (2003).
Another aspect, the present invention provides a kind of present invention that includes and discloses compound, with PDE4 inhibitor and β2- adrenaline The joint of receptor stimulating agent.
Also on the one hand, the present invention provides a kind of present invention that includes and discloses compound, suppresses with anticholinergic drug and PDE-4 The joint of agent.
Above-described joint easily can be prepared into pharmaceutical composition to use, therefore, including defined above group Conjunction 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 forms order of administration or can be administered simultaneously. In one embodiment, each compound component is administered simultaneously with the pharmaceutical dosage forms for combining.Known treatment agent be adapted 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, is controlled with other comprising compound disclosed by the invention Treat the joint of activating agent.
In some embodiments, the pharmaceutical composition that the present invention is provided discloses compound and di-phosphate ester comprising the present invention The joint of enzyme 4 (PDE4) inhibitor.
In other embodiments, the pharmaceutical composition that the present invention is provided discloses compound and β 2- kidneys comprising the present invention The joint of upper parathyrine receptor stimulating agent.
In other embodiments, the pharmaceutical composition that the present invention is provided discloses compound and cortex class comprising the present invention The joint of sterol.
In other embodiments, the pharmaceutical composition that the present invention is provided discloses compound and non-steroidal comprising the present invention The joint of class GR activators.
In other embodiments, the pharmaceutical composition that the present invention is provided discloses compound and cholinolytic comprising the present invention The joint of energy medicine.
In other embodiment, the pharmaceutical composition that the present invention is provided discloses compound and antihistamine comprising the present invention The joint of medicine.
In medical oncology field, combine that to carry out treating cancer patient be conventional means using different form of therapy.Including In section's oncology, being added to one or more of the present composition other co-therapies form 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.
The present invention discloses compound and can also be advantageously utilised in combination with other compounds, or and other therapeutic agents, especially During it is the combination of antiproliferative.Such antiproliferative includes, but 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 Compound；The compound and the compound of other anti-angiogenesis of targeting/reduction albumen or lipid kinase activity；Targeting, reduce or Suppress the compound of albumen or lipid phosphate esterase active；Gonadorelin excitomotor；Antiandrogen；Methionine aminopeptidase suppresses Agent；Diphosphonate；BRM；Antiproliferation antibodies；Heparanase inhibitors；The carcinogenic hypotype inhibitor of Ras；Telomere Enzyme inhibitor；Proteasome inhibitor；Treat the medicament of neoplastic hematologic disorder；Targeting, the compound for reducing or suppressing Flt-3 activity； Hsp90 inhibitor；TemozolomideAnd Calciumlevofolinate.
Term used herein " aromatase inhibitor ", refers to suppress the compound that estrogen is produced, that is, suppress substrate male Alkene diketone and testosterone change into 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, particularly 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.Good fortune Mei Tan (formestane) can be with commercially available, as trade mark isForm administration.Fadrozole (fadrozole) can be with commercially available, as trade mark isForm administration.Anastrozole (anastrozole) can be with With commercially available, as trade mark isForm administration.Letrozole (letrozole) can with commercially available, As trade mark is OrForm administration.Aminoglutethimide (aminoglutethimide) can be with Commercially available, such as trade mark is Form administration.The present invention includes aromatase inhibitor chemotherapeutic Combination 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 not limited to TAM (tamoxifen), fulvestrant (fulvestrant), Raloxifene And raloxifene hydrochloride (raloxifene hydrochloride) (raloxifene).TAM (tamoxifen) can With with commercially available, as trade mark isForm administration.Raloxifene hydrochloride (raloxifene Hydrochloride) can be with commercially available, as trade mark isForm administration.Fulvestrant (fulvestrant) can be with United States Patent (USP) US 4, the formulation disclosed in 659,516 or commercially available, such as trade mark isForm administration.Combination of the present invention including antiestrogenic chemotherapeutic is particularly useful for the treatment of ERs and is in Positive tumour, such as tumor of breast.
Term used herein " antiandrogen " refers to any material that can suppress male sex hormone biological action, and it is wrapped Include, but be not limited to, Bicalutamide (bicalutamide, trade name), its formulation can be according to United States Patent (USP) US 4,636,505 prepare.
Term used herein " Gonadorelin excitomotor " includes, but not limited to abarelix (abarelix), Ge She Rayleigh (goserelin) and goserelin acetate.Goserelin is disclosed in United States Patent (USP) US 4 in 100,274, can be with city Sell, such as trade mark is Form administration.Abarelix (abarelix) can be according to United States Patent (USP) Method disclosed in US 5,843,901 prepares formulation.
Term used herein " topoisomerase I inhibitor ", includes, but are not limited to TPT (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 of naphthalene (nemorubicin)；Anthraquinones mitoxantrone (mitoxantrone) and Losoxantrone (losoxantrone)；Podophillotoxines Etoposide (etoposide) and Teniposide (teniposide).Etoposide can be with commercially available, as trade mark isForm administration.Teniposide can be with commercially available, if trade mark is VM's Form is administered.Doxorubicin can be with commercially available, as trade mark isOr Form administration.Epirubicin can be with commercially available, as trade mark is Form administration.Idarubicin can be with 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, especially vincristine, 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 ForForm administration.Vincristine sulphate can be with commercially available, as trade mark is's Form is administered.Discodermolide can be obtained according to the method disclosed in United States Patent (USP) US 5,010,099.It is additionally included in WO 98/10121, United States Patent (USP) 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 With the Epothilones analog derivative disclosed in WO 00/31247, particularly preferred ebomycin A and/or B.
Term used herein " alkylating agent " includes, but not limited to endoxan (cyclophosphamide), different ring phosphorus Acid amides (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 be with commercially available , such 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 the 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] -2E-2- acrylamides and its can pharmaceutically connect The salt received.Especially include Vorinostat (SAHA).
Term " antineoplastic antimetabolite " includes, but 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 also 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/reduce albumen or lipid kinase activity or albumen or the active change of lipid phosphatase Compound, or other anti-angiogenesis compound " include, but not limited to protein tyrosine kinase and/or serine and/or Threonine inhibitor, or lipid kinase inhibitors, for example
A) target, reduce or suppress the compound of platelet derived growth factor receptor (PDGFR) activity；Targeting, reduction Or suppress the active compounds of PDGFR, the compound for especially suppressing pdgf receptor includes N- phenyl-2-pyrimidine-amine derivatives, Such as Imatinib (imatinib), SU101, SU6668, GFB-111 etc.；
B) target, reduce or suppress the active compound of fibroblast growth factor acceptor (FGFR)；
C) target, reduce or suppress the active compound of IGF-1-1 (IGF-1R)；Targeting, reduction Or suppress the active compounds of IGF-1R, especially suppressing the compound of IGF-1 receptor actives includes those in patent WO 02/ Compound disclosed in 092599；
D) compound of targeting, reduction or suppression Trk receptor tyrosine kinase family actives；
E) compound of targeting, reduction or suppression Axl family active；
F) compound of targeting, reduction or suppression c-Met receptor actives；
G) compound of targeting, reduction or suppression Kit/SCFR receptor tyrosine kinase activities；
H) target, reduce or suppress the active chemical combination of C-kit receptor tyrosine kinases (part in PDGFR families) Thing；Targeting, the compound for reducing or suppressing C-kit receptor tyrosine kinase family actives, especially suppress the change of c-Kit acceptors Compound, including Imatinib (imatinib) etc.；
I) target, reduce or suppress c-Abl families and their gene fusion products, such as change of BCR-Abl kinase activities Compound；Targeting, the compound for reducing or suppressing c-Abl family members and their Gene Fusion things include N- phenyl -2- pyrimidines - Amine derivative, such as Imatinib, PD180970, AG957, NSC 680410, the PD173955 from ParkeDavis
J) Raf family members in targeting, reduction or suppression 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 into Member, and/or cell cycle protein dependent kinase family (CDK) member activity compound；Particularly those are in United States Patent (USP) US 5,093, the staurosporine derivatives disclosed in 330, such as midostaurin (midostaurin)；More examples of compounds Also 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 suppress the active compound of protein tyrosine kinase inhibitor；Targeting, reduction suppress The compound of protein tyrosine kinase inhibitor activity includes GleevecOr tyrosine phosphorylation Inhibitor；Preferred low-molecular-weight (the Mr of tyrphostin<1500) compound, or its pharmaceutically acceptable salt, especially Its compound for being selected from the eyeball class of the eyeball class of benzyl allyl two or S- aryl sheet the third two or Double bottom thing quinolines, further selected from tyrosine Phosphorylation inhibitor A23/RG-50810, AG 99, tyrphostin AG 213, 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 suppress receptor tyrosine kinase epidermal growth factor receptor family (EGFR, ErbB2, The equal or heterodimer of ErbB3, ErbB4) activity compound；Targeting, reduction suppress Epidermal Growth Factor Receptor Family Compound refer in particular to suppress EGF receptor family member (such as EGF receptor, ErbB2, ErbB3, ErbB4, or can with EGF or The material that EGF associated ligands are combined) compound, albumen or antibody, is particularly 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 97/30034th, WO 97/49688 and WO 97/38983, WO 96/30347 (such as CP 358774), (such as chemical combination of WO 96/33980 Thing 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 the 7H- pyrrolo-es being disclosed in WO 03/013541-[2,3-d] pyrimidine derivatives.
Additionally, anti-angiogenic compounds include having other active mechanisms (for example, suppressing not with albumen or lipid kinase It is related) compound, such as ThalidomideAnd TNP-470.
The compound of targeting, reduction or suppression albumen or lipid kinase activity is the inhibitor of phosphatase -1, 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 not limited to Cox-2 inhibitor, and 5- is alkyl-substituted 2- fragrant aminos phenylacetic acid and its derivative, such as celecoxibRofecoxibEtoricoxib, Valdecoxib, or 5- alkyl -2- fragrant amino phenylacetic acids, such as 5- methyl -2- (the chloro- 6'- fluoroanilinos of 2'-) phenylacetic acids or reed Rice examines former times
Term used herein " diphosphonate " includes, but not limited to Etidronic Acid, Clodronate, Tiludronic Acid, handkerchief 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 name's Form is administered.Tiludronic Acid can be with commercially available, such as trade nameForm administration；Pamidronic acid (Pamidronic acid) can be with commercially available, such as trade name ArediaTM(AREDIATM) form administration；Alendronic acid Can be with commercially available, such as trade nameForm administration；Ibandronic acid can be with commercially available, such as business The name of an article isForm administration；Risedronic Acid can be with commercially available, such as trade nameForm administration；Zoledronic acid can be with commercially available, such as trade name's Form is administered.
Term " mTOR inhibitors " refers to suppress 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 target, reduce or suppress acetylsulfuric acid depolymerized heparin Compound.This term includes, but does not limit PI-88.
Term used herein " BRM " 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 suppress Ras carcinogenic activities compound, such as " farnesyl transferase inhibitor ", such as L-744832, DK8G557 or R115777(Zarnestra)。
Term used herein " telomerase inhibitor " refers to targeting, the compound for reducing or suppressing telomerase activation.Target To, reduce or suppress telomerase activation compound refer in particular to suppress telornerase receptor compound, such as telomere mycin.
Term used herein " methionine aminopeptidase inhibitor " refers to targeting, reduces or suppress methionine aminopeptidase activity Compound.The compound of targeting, reduction or suppression methionine aminopeptidase activity includes bengamide or derivatives thereof.
Term used herein " proteasome inhibitor " refers to targeting, reduces or the active chemical combination of protease inhibition body Thing.The compound of targeting, reduction or protease inhibition body activity includes PS-341 and MLN 341.
Term used herein " NMPI " or " MMP inhibitor " include, but not limited to glue Former albumen peptides and non-peptide inhibitor, such as tetracycline derivant, hydroxamic acid peptide inhibitor Batimastat (batimastat) With the equivalent homologue Marimastat (marimastat, BB-2516) of its oral bio, Pu Masita (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996。
Term used herein " being used for treating the reagent of neoplastic hematologic disorder " includes, but not limited to FMS- sample EGFR-TKs Inhibitor.Targeting, the compound for reducing or suppressing FMS- samples tyrosine kinase receptor (Flt-3R) activity；Interferon, 1-b-D- Arabinofuranosyl adenin cytimidine (ara-c) and bisulfan；With ALK inhibitor, such as targeting, reduction or suppression anaplastic lymphoma kinase Compound.
The compound of targeting, reduction or suppression FMS- samples tyrosine kinase receptor (Flt-3R) especially suppresses Flt-3 and receives The compound of body kinase families member, albumen or antibody, such as PKC412, midostaurin (midostaurin), staurosporin Derivative, SU11248 and MLN518.
Term used herein " HSP90 inhibitor " includes, but are not limited to target, reduce or suppress the endogenous of HSP90 The compound of atpase activity；The chemical combination for degraded by ubiquitin protein body enzymatic pathway, targetting, reduce or suppress HSP90 client proteins Thing.Targeting, the compound of the Endogenous ATP enzymatic activity for reducing or suppressing HSP90 refer in particular to suppress the Endogenous ATP of HSP90 The compound of enzymatic activity, albumen or antibody, for example, 17- allyl aminos, 17-AAG (17AAG), its The compound of his geldanamycin correlation, red shell rhzomorph and hdac inhibitor.
Term used herein " antiproliferation antibodies " includes, but 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 2 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 present invention can be disclosed compound and be used in combination with the leukemia therapy of standard, especially It is used in combination with the therapy treated for AML.Specifically, the present invention can be disclosed into compound to turn with such as farnesyl- Moving enzyme inhibitor and/or other is used for medicine such as daunorubicin, adriamycin, Ara-C, VP-16, Teniposide, rice that AML is treated Support anthraquinone, idarubicin, carboplatin and PKC412 administering drug combinations.
Compound disclosed by the invention can also be advantageously utilised in the combination of 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), TMP (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 medicine, qinghaosu, Arteflene (arteflene), Artemether, Artesunate, primaquine, suction NO, L-arginine, dipropyl Alkene triamine NONO esters (NO donor), Rosiglitazone (PPARy activators), activated carbon, hematopoietin, levamisol, And Malaridine.
Compound disclosed by the invention can also be advantageously used in the group of the combination or other therapeutic agents with other compounds In conjunction, for example, treat the other therapeutic agents of leishmaniasis, trypanosomiasis, toxoplasmosis and cerebral cysticercosis.Such medicament includes, but It is not limited to nivaquin, atovaquone-proguanil, Artemether-lumenfantrine, quinine sulfate, Artesunate, quinine, fortimicin (doxycycline), clindamycin (clindamycin), meglumine antimony (meglumine antimoniate), gluconic acid Antimony sodium (sodium stibogluconate), Miltefosine (miltefosine), ketoconazole (ketoconazole), pentamidine (pentamidine), amphotericin B (AmB), AmB liposomes, paromomycin (paromomycine), Eflornithine (eflornithine), nifurtimox (nifurtimox), suramin (suramin), melarsoprol (melarsoprol), sprinkle Ni Songlong (prednisolone), benzimidazole, sulphadiazine, pyrimethamine, synergistic sulfonamide methylisoxazole, radonil, Ah Miramycin (azitromycin), Atovaquone, dexamethasone, praziquantel, albendazole (albendazole), beta-lactam, FQNS medicine, macrolides medicine, aminoglycoside medicine, sulphadiazine and pyrimethamine.
Can be from classic " The as code name, the structure of common name or active component determined by trade name and its preparation (such as M.J.O ' Neil et al. compile ' The MerckIndex ', the 13rd to the current edition of Merck Index (Merck index) " Version, Merck Research Laboratories, 2001) or from database (such as Patents International (examples Such as IMS World Publications)) in know.
It is above-described, can with the present invention compound that compound is applied in combination be disclosed, can be by people in the art Member, prepares and is administered according to the method described in above-mentioned document.
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 sensitiveness weak ground.
" joint " represents the medicine box of the fixing joint in single dose unit form or the part for administering drug combinations, its In compound disclosed by the invention and joint companion can be in same time individual application or can be in certain time interval Inside apply respectively, joint companion shown cooperation, for example acted synergistically.As the term is employed herein " co-administered " Or " administering drug combinations " etc. are intended to include selected joint companion is applied to the single individuality (such as patient) for needing it, and anticipate It is intended to include that wherein material is without going through identical method of administration or the therapeutic scheme being administered simultaneously." medicine as the term is employed herein Joint " is represented and mixes or the resulting product of joint more than one active components, and both fixed connection including active component Close and also combine including on-fixed.Term " fixing joint " represents active component 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 " represents that active component is disclosed such as the present invention Compound, and joint companion as corpus separatum simultaneously, it is common or without special time limitation ground successively to patient's administration, its In the administering mode treatment levels of significance of two kinds of compounds are provided in patient's body.The latter applies also for HAART, For example apply three or more active component.
Treatment method
In some embodiments, treatment method disclosed by the invention includes giving safe and effective amount to patient in need The compounds of this invention or the pharmaceutical composition comprising the compounds of this invention.Each embodiment disclosed by the invention is included by right The present invention that patient in need gives safe and effective amount discloses compound or the drug regimen of compound is disclosed comprising the present invention Thing is come the method for the treatment of disease mentioned above.
In some embodiments, the present invention disclose compound or can comprising the of the invention pharmaceutical composition for disclosing compound To be administered by any suitable method of administration, including Formulations for systemic administration and local administration.Formulations for systemic administration includes oral administration, stomach Parenteral administration, cutaneous penetration and rectally.Typical parenteral refers to including the vein by injection or administered by infusion Interior, intramuscular and hypodermic injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, suction and nose Interior administration.In one embodiment, the present invention disclose compound or can comprising the of the invention pharmaceutical composition for disclosing compound Be administered orally.In other embodiments, the present invention discloses compound or the medicine of compound is disclosed comprising the present invention Composition can be inhalation.In a further embodiment, the present invention disclose compound or comprising it is of the invention compound is disclosed can Being intranasal administration.
In some embodiments, the present invention disclose compound or can comprising the of the invention pharmaceutical composition for disclosing compound With once daily, or according to dosage regimen, at the appointed time in section, in different time interval administrations several times.For example, Be administered once a day, twice, three times or four times.In some embodiments, it is administered once a day.In other embodiment In, it is taken twice daily.Can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.This The appropriate dosage regimen of disclosure of the invention compound or the pharmaceutical composition that compound is disclosed comprising the present invention depends on the compound Pharmacokinetic property, for example dilute, distribution and half-life period, these can be by determination of technical staff.Additionally, the present invention is disclosed Compound or comprising the present invention disclose compound pharmaceutical composition appropriate dosage regimen, including implementation the program it is lasting when Between, it is the order of severity of disease being treated, the age of patient under consideration and health, treated depending on treated disease The medical history of patient, while the factor in the range of technical staff's knowledge and experience such as the property of therapy, desired therapeutic effect. Such technical staff should also be understood that the reaction to dosage regimen for individual patient, or elapse individual patient over time When needing change, in order to be sufficiently accurate it may be desired to adjust suitable dosage regimen.
The present invention discloses compound other therapeutic agents can simultaneously, or before it or be afterwards administered with one or more. The compounds of this invention can be respectively administered with other therapeutic agents by identical or different method of administration, or therewith with medicine group Solvate form is administered.
For the individuality 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 components Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination be depend on individual species, body weight, the age and Individual instances, treated disease (disorder) or disease (disease) or its order of severity.Possesses the doctor of conventional technical ability Teacher, clinician or animal doctor can easily determine to prevent, treat or suppress disease (disorder) or disease (disease) development During required each active component effective dose.
Dose Characteristics cited above using favourable mammal (such as mouse, rat, dog, monkey) or its from Confirmed in the external and in vivo studies of body organ, tissue and sample.The present invention discloses compound with solution, such as aqueous solution form Use in vitro, it is also possible to such as suspension or the aqueous solution form enteral in vivo, it is parenteral, it is especially intravenous to use.
In some embodiments, it is about 0.1mg daily to about 2 that the present invention disclose the treatment effective dose of compound, 000mg.Its pharmaceutical composition should provide about 0.1mg to about 2,000mg compounds of dosage.In a particular In, the pharmaceutical dosage unit forms of preparation can provide about 1mg to about 2,000mg, about 10mg to about 1,000mg, and about 20mg is to about The combination of each main component in 500mg, or the main active or every dosage unit form of about 25mg to about 250mg.One In particular, the pharmaceutical dosage unit forms of preparation can provide about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg main active.
Additionally, compound disclosed by the invention can be administered with prodrug forms.In the present invention, the present invention discloses compound " prodrug " be that finally can in vivo discharge the functional derivatives that the present invention discloses compound when being administered to patient.In the past When medicine form gives compound disclosed by the invention, those skilled in the art can implement one kind in following manner and more than：(a) Change the internal onset time of compound；B () changes the internal acting duration of compound；C () changes the internal of compound Conveying is distributed；D () changes the internal solubility of compound；And (e) overcomes the side effect or other difficult points that compound faced. Typical functional derivatives for preparing prodrug, comprising in vivo chemically or enzyme the mode compound that cracks Variant.Comprising preparing these variants of phosphate, acid amides, ester, monothioester, carbonate and carbaminate to people in the art It is well-known for member.
General synthesis step
It is the description present invention, is listed below embodiment.But it is to be understood that the invention is not restricted to these embodiments, simply The method of the present invention is put into practice in offer.
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein substitution base definition such as formula (I) shown in.Following reaction scheme and embodiment are used to that this to be further illustrated The content of invention.
The professional of art will be recognized that：Chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds more of the invention, and be considered as in model of the invention for preparing other methods of compound of the invention Within enclosing.For example, the synthesis of the compound according to those non-illustrations of the invention can successfully by those skilled in the art Completed by method of modifying, such as appropriate protection interference group, by using other known reagents except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all of temperature is set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all not by being further purified when using, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao's purchase Can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether is dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is that drying is used in advance through anhydrous sodium sulfate.
Below reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb all suitable rubber stoppers beyond the Great Wall, substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopies are recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopies are with CDC13、 DMSO-d6、CD3OD or acetone-d6It is solvent (in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as with reference to mark It is accurate.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), dd (doublet of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant, is represented with hertz (Hz).
The condition determination of Algorithm (MS) data is：Level Four bar HPLC-M (the pillar models of Agilent 6120： Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Mobile phase：5%-95% (contains 0.1% The CH of formic acid3CN) in (H containing 0.1% formic acid2O the ratio in)), using electron spray ionisation (ESI), under 210nm/254nm, Detected with UV.
Use Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (the pillar types of pure compound Number：NOVASEP50/80mm DAC), detected with UV in 210nm/254nm.
The use of brief word below is through the present invention：
AcOH、HOAc、CH3COOH acetic acid
Ac2O acetic anhydrides
BOC, Boc tert-butoxycarbonyl
(Boc)2O di-tert-butyl dicarbonates
BH3.DMS borane dimethylsulf iotade
The double diphenyl phosphines of BINAP 1,1'- dinaphthalenes -2,2'-
N-BuOH n-butanols
CH2Cl2, DCM dichloromethane
CDC13Deuterochloroform
CH3I iodomethane
DIEA、DIPEA、i-Pr2NEt diisopropyl ethyl amines
DMF N,N-dimethylformamides
DMP dimethyl phthalates
DMAP DMAPs
DMSO dimethyl sulfoxide (DMSO)s
DHP 3,4- dihydropyran
PPTs 4- toluene sulfonic acide pyridines
Et3N, TEA triethylamine
EtOAc, EA ethyl acetate
EtOH ethanol
Et2O ether
EDCI 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
G grams
H hours
HATU 2- (7- azepine -1H- BTA -1- bases) -1,1,3,3- tetramethyls Base urea hexafluorophosphoric acid ester
HCl hydrochloric acid
HOAT 1- hydroxyl -7- azepine BTAs
KOH potassium hydroxide
KMnO4Potassium permanganate
K2CO3Potassium carbonate
LiCl lithium chlorides
LiHMDS, LHMDS bis- (trimethyl silicon substrate) lithium amide
LAH lithium aluminium hydrides
MeCN、CH3CN acetonitriles
MsCl methane sulfonyl chlorides
(NH4)2SO4Ammonium sulfate
NH4Cl ammonium chlorides
NaH sodium hydrides
NaBH3CN sodium cyanoborohydrides
Na2CO3Sodium carbonate
NaOH NaOH
Na2SO4Sodium sulphate
Na2S2O3Sodium thiosulfate
NaHCO3Sodium acid carbonate
NaOAc ammonium acetates
Ti(Oi-Pr)4The isopropyl ester of metatitanic acid four
NBS NBSs
MeOH methyl alcohol
ML, ml milliliter
Pd(OAc)2Palladium
Pd/C palladiums/carbon
PE petroleum ethers (60~90 DEG C)
PTSA p-methyl benzenesulfonic acid
PDC Pyridinium dichromates
RT, rt, r.t. room temperature
Rt retention times
Raney Ni Raney's nickels
THF tetrahydrofurans
TFAA TFAAs
TFA trifluoroacetic acids
TBAF tetrabutyl ammonium fluorides
Ti(Oi-Pr)4Four isopropyl titanates
TsCl 4- toluene sulfochlorides
The preparation present invention discloses the typical synthesis step of compound as shown in following 1~synthetic schemes of synthetic schemes 2.Remove Non- other explanation, each Z, Z1、R1、R3And R5With definition as described in the present invention, p is 0,1 or 2, q are 0,1,2 or 3, PG are to protect Shield group.
Synthetic schemes 1：
With such as formula (5) shown in structure the present invention the general synthesis that compound can be described by synthetic schemes 1 is disclosed Method is prepared, and specific steps refer to embodiment.In synthetic schemes 1, optionally substituted dichloro pyrimidine (1) with it is optionally substituted Heterocyclic compound (2) in alkali, such as in the presence of triethylamine, generation heteroaryl compound (3).Compound (3) with it is optionally substituted 4- aminopyrazole compounds (4) or its hydrochloride, in alkali, such as in the presence of diisopropyl ethyl amine, triethylamine, in higher temperatures The lower reaction of degree, obtain kinases inhibitor (5)。
Synthetic schemes 2：
With such as formula (9) or (10) shown in structure the present invention disclose compound can be described by synthetic schemes 2 one As synthetic method prepare, specific steps refer to embodiment.In synthetic schemes 2, substituted dichloro pyrimidine (1) and with guarantor Protect base optionally substituted heterocyclic compound (6) in alkali, such as in the presence of triethylamine, generate optionally substituted heteroaryl compound (7).Compound (7) with optionally substituted aminopyrazole compound (4) or its hydrochloride, in alkali, such as diisopropyl ethyl amine, three Ethamine or in acid, such as ethyl acetate solution of trifluoroacetic acid, hydrogen chloride, or under the catalytic action of suitable Pd catalyst, Reacting generating compound (8).Compound (8) in blocking group can in acid condition, such as trifluoroacetic acid, the acetic acid of hydrogen chloride Ethyl ester solution, or in the presence of hydrazine hydrate remove, obtain kinases inhibitor (9).Under suitable conditions to chemical combination Thing (9) in introduce different substitution bases, can obtain with formula (10) shown in structure kinases inhibitor.
Embodiment
The 6- of embodiment 1 ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) (methyl) amino) six Hydrogen furans simultaneously [3,2-b] furan-3-ol
Step 1) 6- (benzyloxy) hexahydro furyl simultaneously [3,2-b] furan-3-ol
At 0 DEG C, NaH (60% is suspended in Dormant oils, 3.28g, 82.1mmol) is suspended in DMF In (135mL), and it is added dropwise over the different Mountain of Pear alcohol (10.00g, 68.4mmol) being dissolved in DMF (10mL) Solution, after reaction solution is stirred 30 minutes at 0 DEG C, adds benzyl bromine (14.04g, 82.1mmol), and reaction solution then is moved into room Temperature, and be stirred overnight.Reactant mixture is concentrated under reduced pressure, gained residue is diluted with water (100mL), and uses ethyl acetate (200mL x 3) is extracted, and the organic layer of merging is washed, anhydrous sodium sulfate drying with saturated aqueous common salt (200mL x 3), and filtering is simultaneously Concentrated under reduced pressure, gained residue is purified through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1), obtains title compound Thing is yellow oil (10.36g, 64.1%).
MS(ESI,pos.ion)m/z:259.2[M+Na]+；
1H NMR(600MHz,CDCl3):δ (ppm) 7.37 (q, J=8.0Hz, 4H), 7.31 (m, 1H), 4.78 (d, J= 11.9Hz, 1H), 4.72 (t, J=4.4Hz, 1H), 4.58 (d, J=11.9Hz, 1H), 4.43 (d, J=4.2Hz, 1H), 4.32 (d, J=2.9Hz, 1H), 4.08 (td, J=7.2,4.7Hz, 1H), 4.01 (dd, J=10.1,3.4Hz, 1H), 3.96 (d, J= 10.1Hz, 1H), 3.87 (dd, J=8.7,6.8Hz, 1H), 3.62 (t, J=8.3Hz, 1H), 2.62 (m, 1H).
Step 2) 6- (benzyloxy) hexahydro furyl simultaneously [3,2-b] furans -3- bases -4- toluene sulfonic acide esters
At 0 DEG C, by 6- (benzyloxy) hexahydro furyl simultaneously [3,2-b] furan-3-ol (10.36g, 43.9mmol), three second Amine (22.16g, 219.0mmol) and DMAP (1.60g, 13.1mmol) are dissolved in dichloromethane (90mL), and Paratoluensulfonyl chloride (12.52g, 65.7mmol), reaction solution dislocation room temperature are added thereto to, and are stirred overnight.Reactant mixture It is quenched with water (100mL), and is extracted with dichloromethane (200mL x 3), organic phase saturated aqueous common salt (the 200mL x of merging 3) wash, then with anhydrous sodium sulfate drying, then filter and be concentrated under reduced pressure, gained residue is through silica gel column chromatography (petroleum ether/second Acetoacetic ester (v/v)=4/1) purifying, title compound is obtained for faint yellow solid (14.33g, 83.7%).
MS(ESI,pos.ion)m/z:408.2[M+NH4]+；
1H NMR(600MHz,CDCl3):δ (ppm) 7.82 (d, J=8.3Hz, 2H), 7.34 (m, 7H), 4.90 (d, J= 3.3Hz, 1H), 4.75 (d, J=11.8Hz, 1H), 4.70 (t, J=4.5Hz, 1H), 4.55 (m, 2H), 4.04 (m, 3H), 3.85 (dd, J=8.9,6.6Hz, 1H), 3.60 (dd, J=8.8,7.7Hz, 1H), 2.48 (s, 3H).
Step 3) N- benzyls -6- (benzyloxy) hexahydro furyl simultaneously [3,2-b] furans -3- amine
By 6- (benzyloxy) hexahydro furyl simultaneously [3,2-b] furans -3- bases 4- toluene sulfonic acides ester (14.33g, 36.7mmol) It is dissolved in benzylamine (20.00g, 186.6mmol), and is added thereto to LiCl (1.20g, 28.3mmol), reactant mixture liter Warm to 180 DEG C tube sealing reactions are concentrated under reduced pressure after 34 hours, and gained residue is diluted with water (100mL), and uses dichloromethane (100mL x 3) is extracted, and the organic phase of merging washed with saturated aqueous common salt (100mL x 3), then with anhydrous sodium sulfate drying, so After filter and be concentrated under reduced pressure, gained residue is purified through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1), is marked Topic compound is yellow oil (9.88g, 82.7%).
MS(ESI,pos.ion)m/z:326.2[M+H]+。
Step 4) N- benzyls -6- (benzyloxy)-N- methyl hexahydro furyl simultaneously [3,2-b] furans -3- amine
By N- benzyls -6- (benzyloxy) hexahydro furyl, simultaneously [3,2-b] furans -3- amine (9.88g, 30.36mmol) is dissolved in In formic acid (19mL), and formalin (37% [w/w], 2.96g, 36.4mmol) is added, reaction solution is stirred overnight at 110 DEG C Afterwards, it is concentrated under reduced pressure.Gained residue saturated aqueous sodium carbonate is adjusted to pH=8, is then extracted with ethyl acetate (100mL x 3) Take, the organic phase of merging is washed with water (100mL x 3) and saturated aqueous common salt (100mL) respectively, anhydrous sodium sulfate drying, filter And be concentrated under reduced pressure, gained residue is purified through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtains title compound Thing is yellow oil (4.77g, 46.4%).
MS(ESI,pos.ion)m/z:340.2[M+H]+。
Step 5) 6- (methylamino) hexahydro furyl simultaneously [3,2-b] furan-3-ol
By N- benzyls -6- (benzyloxy)-N- methyl hexahydro furyl, simultaneously [3,2-b] furans -3- amine (5.09g, 15mmol) is molten Solution is added thereto to Pd/C (1.0g, 10%wt) and hydrochloric acid (12M, 2mL) in ethanol (40mL), and reaction solution is placed in 5M Pa H2In autoclave, and be stirred overnight at 60 DEG C, then filter, gained filtrate obtains title compound through concentrated under reduced pressure It is yellow oil (2.12g, 88.9%).
MS(ESI,pos.ion)m/z:160.1[M+H]+。
Step) 6- ((2,5- dichloro pyrimidine -4- bases) (methyl) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol
By 2,4,5- trichloropyrimidines (484.9mg, 2.64mmol) and 6- (methyl) amino) hexahydro furyl simultaneously [3,2-b] furan - 3- alcohol (530.2mg, 3.33mmol) of muttering is dissolved in EtOH (30mL), is added thereto to Et3N (566.0mg, 5.59mmol), institute Reactant mixture is obtained to be stirred overnight at normal temperatures.Reactant mixture is concentrated under reduced pressure, gained residue is dissolved in ethyl acetate and water Mixed solvent (1/1 (v/v), 100mL) in, then with ethyl acetate (100mL x 3) extract, the organic phase saturation of merging Saline solution (100mL) is washed, and anhydrous sodium sulfate drying filters and is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=2/1) purifying, title compound is obtained for faint yellow solid (760.2mg, 94.0%).
MS(ESI,pos.ion)m/z:306.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)8.14(s,1H),4.87(m,1H),4.85(s,1H),4.62(m, 1H), 4.40 (m, 1H), 4.21 (m, 1H), 4.10 (m, 1H), 3.90 (dd, J=9.6,5.7Hz, 1H), 3.78 (dd, J=9.6, 5.1Hz,1H),3.51(s,1H),3.37(s,3H)。
Step 7) 6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) (methyl) amino) hexahydro Furans simultaneously [3,2-b] furan-3-ol
By 6- ((2,5- dichloro pyrimidine -4- bases) (methyl) amino) hexahydro furyl [3,2-b] furan-3-ol (342.2mg, 1.12mmol) it is suspended in n-BuOH (5mL) with 1- methyl isophthalic acids H- pyrazoles -4- amine hydrochlorates (185.0mg, 1.38mmol), to Wherein add DIPEA (358.8mg, 2.78mmol).Gained reaction system is warming up to 150 DEG C, and overnight, reaction mixes tube sealing reaction Thing is concentrated under reduced pressure, and gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=40/1), and it is shallow brown to obtain title compound Color solid (156mg, 38.0%).
MS(ESI,pos.ion)m/z:367.1[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)8.01(s,1H),7.65(s,1H),7.48(s,1H),6.52(s, 1H), 4.76 (m, 2H), 4.58 (m, 1H), 4.37 (m, 1H), 4.19 (t, J=7.9Hz, 1H), 4.03 (t, J=8.8Hz, 1H), 3.90 (m, 4H), 3.78 (dd, J=9.6,5.2Hz, 1H), 3.51 (s, 1H), 3.29 (s, 3H).
The 6- of embodiment 2 (methyl (2- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) amino) hexahydro furyl And [3,2-b] furan-3-ol
Step 1) 6- ((2- chlorine pyrimidine-4-yl) (methyl) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol
By 2,4,5- trichloropyrimidines (628.7mg, 4.22mmol) and 6- (methylamino) hexahydro furyl simultaneously [3,2-b] furan - 3- alcohol (0.87g, 5.46mmol) of muttering is dissolved in EtOH (50mL), is added thereto to Et3N (0.94g, 9.29mmol), gained is anti- Mixture is answered to be stirred overnight at normal temperatures.Reactant mixture is concentrated under reduced pressure, gained residue is dissolved in the mixed of ethyl acetate and water Bonding solvent (1/1 (v/v), 100mL), is then extracted, the organic phase saturated aqueous common salt of merging with ethyl acetate (100mL x 3) (100mL) is washed, and anhydrous sodium sulfate drying filters and is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EtOAc (v/ V)=1/2) purify, title compound is obtained for faint yellow solid (522.3mg, 37.2%).MS(ESI,pos.ion)m/z: 272.2[M+H]+；
1H NMR(400MHz,CDCl3):δ (ppm) 8.12 (d, J=6.1Hz, 1H), 6.43 (d, J=6.1Hz, 1H), 5.36 (s, 1H), 4.68 (t, J=4.6Hz, 1H), 4.63 (m, 1H), 4.39 (m, 1H), 4.10 (dt, J=18.1,8.3Hz, 2H), 3.84 (ddd, J=30.1,9.6,5.2Hz, 2H), 3.11 (s, 3H), 2.75 (d, J=5.6Hz, 1H).
Step 2) hexahydro furyl is simultaneously for 6- (methyl (2- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) amino) [3,2-b] furan-3-ol
By 6- ((2- chlorine pyrimidine-4-yl) (methyl) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol (358.0mg, 1.32mmol) it is dissolved in n-BuOH (5mL) with 1- methyl isophthalic acid H- pyrazoles -4- amine hydrochlorates, is added thereto to DIPEA (434.6mg,3.36mmol).Gained reaction system is warming up to 150 DEG C, and overnight, reactant mixture is concentrated under reduced pressure tube sealing reaction, institute Residue through silica gel column chromatography (DCM/MeOH (v/v)=10/1) purify, obtain title compound for brown solid (300mg, 68.4%).
MS(ESI,pos.ion)m/z:333.2[M+H]+；
1H NMR(400MHz,DMSO-d6):δ (ppm) 8.17 (d, J=6.0Hz, 1H), 7.97 (s, 1H), 7.62 (s, 1H), 6.41 (d, J=5.5Hz, 1H), 5.48 (d, J=3.2Hz, 1H), 5.12 (d, J=4.6Hz, 1H), 4.48 (s, 2H), 4.33 (d, J=3.6Hz, 1H), 4.21 (m, 2H), 3.82 (s, 3H), 3.75 (dd, J=8.2,6.0Hz, 1H), 3.61 (dd, J =8.0,6.7Hz, 1H), 3.16 (d, J=4.1Hz, 1H), 3.09 (s, 3H).
The 6- of embodiment 3 ((5- methyl -2- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) amino) hexahydro furan Mutter simultaneously [3,2-b] furan-3-ol
Step 1) 6- ((tetrahydrochysene -2H- pyrans -2- bases) epoxide) hexahydro furyl simultaneously [3,2-b] furan-3-ol
Hexahydro furyl simultaneously [3,2-b] furans -3,6- glycol (10.0g, 68.50mmol) are dissolved in DCM (150mL), often PPTs (1.7g, 6.85mmol) is added thereto under temperature, DHP (6.0g, 71.90mmol), 2 is slowly added to after adding thereto again Hour adds, and is stirred overnight under gained reactant mixture normal temperature.Reactant mixture is concentrated under reduced pressure, to being added water in gained residue (150mL), is extracted with ethyl acetate (150mL x 3), and the organic phase of merging is washed with saturated aqueous common salt (300mL), anhydrous sulphur Sour sodium is dried, and is filtered and is concentrated under reduced pressure, and gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=1/1), obtains title Compound is white solid (7.1g, 45%).
1H NMR(400MHz,CDCl3):δ(ppm)4.70-4.61(m,1H),4.58-4.53(m,1H),4.40-4.28 (m,1H),4.27-4.18(m,1H),4.05-.96(m,1H),3.93-3.83(m,1H),3.82-3.74(m,2H),3.52- 3.41 (m, 2H), 2.81 and 2.79 (d, J=7.2Hz, 1H), 1.84-1.72 (m, 1H), 1.71-1.60 (m, 1H), 1.59- 1.41(m,4H)。
Step 2) 6- ((tetrahydrochysene -2H- pyrans -2- bases) epoxide) tetrahydrofuran simultaneously [3,2-b] furans -3 (2H) -one
By 6- ((tetrahydrochysene -2H- pyrans -2- bases) epoxide) hexahydro furyl simultaneously [3,2-b] furan-3-ol (5.0g, 21.7mmol) it is dissolved in DCM (150mL), DMP (18.4g, 43.5mmol) is added thereto under normal temperature, is warming up to 30 DEG C of stirrings Overnight.Reactant mixture is concentrated under reduced pressure, to being added water in gained residue (150mL), is extracted with ethyl acetate (150mL x 3) Take, the organic phase of merging is washed with saturated aqueous common salt (300mL), and anhydrous sodium sulfate drying filters and is concentrated under reduced pressure, gained residual Thing is purified through silica gel column chromatography (PE/EtOAc (v/v)=2/1), obtains title compound for yellow oil (4.96g, 98%).
1H NMR(600MHz,CDCl3):δ (ppm) 4.90 and 4.73 (d, J=4.1Hz, 1H), 4.75-4.70 (m, 1H), 4.48-4.40 (m, 1H), 4.28 (d, J=4.2Hz, 1H), 4.11-4.00 (m, 2H), 4.00-3.91 (m, 1H), 3.89-3.82 (m,1H),3.81-3.63(m,1H),3.56-3.46(m,1H),1.88-1.74(m,1H),1.73-1.63(m,1H),1.62- 1.43(m,4H)。
Step 3) 6- ((tetrahydrochysene -2H- pyrans -2- bases) epoxide) hexahydro furyl simultaneously [3,2-b] furans -3- amine
By 6- ((tetrahydrochysene -2H- pyrans -2- bases) epoxide) tetrahydrofuran simultaneously [3,2-b] furans -3 (2H) -one (3.5g, 15.3mmol) it is dissolved in the methanol solution of ammonia (30mL, 7M), is slowly added to NaBH under normal temperature thereto4(1.16g, 30.6mmol).Added water thereto (50mL) after being stirred 10 hours under reactant mixture normal temperature, filtered, filter cake is with EtOAc (50mL) Washing, filtrate is extracted with EtOAc (80mL x 3), and the organic phase of merging is washed with saturated aqueous common salt (200mL), anhydrous sodium sulfate Dry, filter and be concentrated under reduced pressure, obtain title compound crude product for grease (3.6g, crude product).It is not purified, directly carry out Next step is reacted.
Step 4) 6- amino hexahydro furyl simultaneously [3,2-b] furan-3-ol hydrochloride
By 6- ((tetrahydrochysene -2H- pyrans -2- bases) epoxide) hexahydro furyl simultaneously [3,2-b] furans -3- amine (2.8g, 12.2mmol) it is dissolved in DCM (50mL), is added thereto to the ethyl acetate solution (15mL, 3.8M) of hydrogen chloride, gained reaction is mixed It is stirred overnight under compound normal temperature, is concentrated under reduced pressure, gained residue drying under reduced pressure at 60 DEG C obtains title compound crude product and is Brown oil (3.3g, crude product).Product is not purified, directly carries out next step reaction.
MS(ESI,pos.ion)m/z:146[M+H]+。
Step 5) 6- ((the chloro- 5- methylpyrimidines -4- bases of 2-) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol
By 6- amino hexahydro furyl, simultaneously [3,2-b] furan-3-ol hydrochloride (400mg, 2.20mmol) is suspended in n-BuOH In (6mL), the chloro- 5- methylpyrimidines (269mg, 1.65mmol) of 2,4- bis- and Et are added thereto to3N(1.00g,9.90mmol)。 Under the protection of gained reaction system nitrogen, 95 DEG C are warming up to, be stirred overnight.Reactant mixture decompression suction filtration, filter cake is with DCM (30mL) Washing, filtrate is washed with water (20mL) and saturated aqueous common salt (20mL), and, with anhydrous sodium sulfate drying, filtering is simultaneously for the organic layer of merging Concentrated under reduced pressure, gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=40/1), obtains title compound for yellow is solid Body (72mg, 16%).
MS(ESI,pos.ion)m/z:272[M+H]+；
1H NMR(400MHz,CDCl3):δ (ppm) 7.78 (s, 1H), 5.49 (d, J=6.8Hz, 1H), 4.79-4.63 (m, 2H), 4.53 (d, J=3.3Hz, 1H), 4.39 (d, J=3.1Hz, 1H), 4.29-4.23 (m, 1H), 4.00-3.93 (m, 1H), 3.93-3.87 (m, 1H), 3.35 (t, J=8.4Hz, 1H), 2.01 (s, 3H).
Step 6) 6- ((5- methyl -2- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) amino) hexahydro furyl And [3,2-b] furan-3-ol
By 6- ((the chloro- 5- methylpyrimidines -4- bases of 2-) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol (54mg, 0.20mmol) be suspended in n-BuOH (1mL), be added thereto to 1- methyl isophthalic acids H- pyrazoles -4- amine (32mg, 0.24mmol) and DIPEA (78mg, 0.60mmol) gained reaction systems are warming up to 150 DEG C, and tube sealing reaction is overnight.Reactant mixture is concentrated under reduced pressure, To being added water in gained residue (20mL), extracted with DCM (20mL x 3), the organic phase saturated aqueous common salt (30mL) of merging is washed Wash, anhydrous sodium sulfate drying, filter and be concentrated under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=20/1) Purifying, obtains title compound for white solid (46mg, 70%).
MS(ESI,pos.ion)m/z:333[M+H]+；
1H NMR(600MHz,CDCl3):δ(ppm)7.66(s,1H),7.63(s,1H),7.49(s,1H),7.04(br, 1H), 5.32 (d, J=6.2Hz, 1H), 4.76 (t, J=4.4Hz, 1H), 4.68-4.63 (m, 1H), 4.55 (d, J=3.7Hz, 1H), 4.40 (d, J=2.8Hz, 1H), 4.26 (t, J=8.0Hz, 1H), 4.02-3.97 (m, 1H), 3.96-3.91 (m, 1H), 3.86 (s, 3H), 3.40 (t, J=8.6Hz, 1H), 1.97 (s, 3H).
The 6- of embodiment 4 ((2- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) amino) hexahydro furyl simultaneously [3, 2-b] furan-3-ol
Step 1) 6- ((2- chlorine pyrimidine-4-yl) amino) hexahydro furyl simultaneously [3,2-b] furan-3-ol
6- amino hexahydro furyl [3,2-b] furan-3-ol hydrochloride (363mg, 2.0mmol) is suspended in EtOH (10mL) In, it is added thereto to 2,4- dichloro pyrimidines (298mg, 2.0mmol) and Et3N(1.01g,10.0mmol).Gained reaction system nitrogen Under gas shielded, stirring at normal temperature is overnight.Reactant mixture decompression suction filtration, filtrate decompression concentration, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=30/1) is purified, and obtains title compound for white solid (165mg, 32%).
MS(ESI,pos.ion)m/z:258[M+H]+；
1H NMR(600MHz,CDCl3):δ (ppm) 7.99 (d, J=7.1Hz, 1H), 7.93 (d, J=5.8Hz, 1H), 6.66 (d, J=5.9Hz, 1H), 5.31 (d, J=3.6Hz, 1H), 4.60 (t, J=4.1Hz, 1H), 4.50-4.42 (m, 1H), 4.41 (d, J=3.6Hz, 1H), 4.19-4.12 (m, 1H), 4.10 (s, 1H), 3.99 (t, J=8.0Hz, 1H), 3.81-3.77 (m,1H),3.75-3.71(m,1H)。
Step 2) 6- ((2- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) amino) hexahydro furyl simultaneously [3,2- B] furan-3-ol
By 6- ((2- chlorine pyrimidine-4-yl) amino) hexahydro furyl, simultaneously [3,2-b] furan-3-ol (354mg, 1.37mmol) hangs In floating on n-BuOH (3mL), be added thereto to 1- methyl isophthalic acids H- pyrazoles -4- amine (220mg, 1.65mmol) and DIPEA (531mg, 4.11mmol) gained reaction system is warming up to 150 DEG C, and overnight, reactant mixture is concentrated under reduced pressure tube sealing reaction, gained residue warp Silica gel column chromatography (DCM/MeOH (v/v)=30/1) is purified, and obtains title compound for white solid (120mg, 22%).
MS(ESI,pos.ion)m/z:319[M+H]+；
1H NMR(600MHz,CDCl3And CD3OD):δ(ppm)7.68(s,1H),7.56(s,1H),7.45(s,1H), 5.81 (d, J=5.5Hz, 1H), 4.66 (t, J=4.1Hz, 1H), 4.72-4.60 (m, 1H), 4.44 (d, J=3.6Hz, 1H), 4.21 (s, 1H), 4.11 (t, J=7.8Hz, 1H), 3.88-3.83 (m, 1H), 3.83-3.78 (m, 1H), 3.77 (s, 3H), 3.33-3.26(m,1H)。
The 2- of embodiment 5 ((6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) amino) hexahydros Furans simultaneously [3,2-b] furans -3- bases) epoxide) ethanol
Step 1) 6- (2- (benzyloxy) ethyoxyl) hexahydro furyl simultaneously [3,2-b] furan-3-ol
Under 0 DEG C and nitrogen protection, by hexahydro furyl simultaneously [3,2-b] furans -3,6- glycol (7.50g, 51.37mmol) hangs In floating over dry DMF (100mL), and (2.90g, 72.39mmol, 60% are suspended in mineral oil to be added thereto to sodium hydride In).Mixture is moved to and is stirred at room temperature 15 minutes, is subsequently adding 2- bromine oxethyls methylbenzene (12.26g, 56.97mmol), gained Mixture is heated to 115 DEG C of reactions overnight.After reaction terminates, reaction, gained mixture DCM is quenched with water (100mL) (300mL x 3) is extracted, and the organic phase of merging is with saturated common salt water washing (200mLx3), then uses anhydrous Na2SO4Dry, filtering, Then it is concentrated under reduced pressure, residue is purified through silica gel chromatograph column chromatography (EtOAc/PE (v/v)=1/2), it is palm fibre to obtain title compound Color grease (3.90g 27%).
MS(ESI,pos.ion)m/z:281.2[M+H]+；
1H NMR(400MHz,CDCl3):δ (ppm) 7.35 (m, 4H), 7.32-7.29 (m, 1H), 4.70 (t, J=4.4Hz, 1H), 4.58 (d, J=2.8Hz, 2H), 4.43 (d, J=4.2Hz, 1H), 4.30 (d, J=3.1Hz, 1H), 4.14-4.0 (m, 1H),4.01-3.85(m,4H),3.74-3.58(m,4H)。
Step 2) 6- (2- benzyloxies) ethyoxyl) hexahydro furyl simultaneously [3,2-b] furans -3- base methanesulfonates
Under nitrogen protection, by 6- (2- (benzyloxy) ethyoxyl) hexahydro furyl simultaneously [3,2-b] furan-3-ol (1.50g, 5.36mmol) it is suspended in dry DCM (20mL) solution, and is added thereto to triethylamine (1.20mL, 8.60mmol) and N, N- lutidines -4- amine (0.13g, 1.07mmol).Mixture is cooled to 0 DEG C, then be added dropwise methane sulfonyl chloride (0.50mL, 6.50mmol), gained mixture moved to and react at room temperature overnight.After having reacted, mixture is diluted with DCM (50mL), uses saturation Brine It (50mL), then use anhydrous Na2SO4Dry, and filter, be then concentrated under reduced pressure, residue is through silica gel chromatograph column chromatography (EtOAc/PE (v/v)=2/1) is purified, and obtains title compound for yellow oil (1.81g, 94%).
MS(ESI,pos.ion)m/z:359.1[M+H]+；
1H NMR(400MHz,CDCl3):δ (ppm) 7.39-7.29 (m, 5H), 5.13-5.08 (m, 1H), 4.74 (t, J= 4.5Hz, 1H), 4.69 (d, J=4.4Hz, 1H), 4.58 (d, J=1.4Hz, 2H), 4.19-4.08 (m, 3H), 4.00-3.93 (m,1H),3.92-3.85(m,1H),3.76-3.62(m,4H),3.07(s,3H)。
Step 3) 3- azidos -6- (2- (benzyloxy) ethyoxyl) hexahydro furyl simultaneously [3,2-b] furans
By 6- (2- (benzyloxy) ethyoxyl) hexahydro furyl simultaneously [3,2-b] furans -3- bases methanesulfonates (1.40g, 3.91mmol) it is suspended in DMF (15mL), and is added thereto to sodium azide (1.38g, 21.15mmol).Mixture is heated to 140 DEG C are reacted 48 hours.After having reacted, reactant mixture is filtered, filtrate is diluted with DCM (200mL), gained mixture is used and divided Other water (200mL x 3) and saturated aqueous common salt (100mL x 2) are washed, organic phase anhydrous Na2SO4Dry, and filter, then Be concentrated under reduced pressure to obtain crude product.Products therefrom is unprocessed to be directly used in next step reaction.
MS(ESI,pos.ion)m/z:278.0[M–N2+H]+。
Step 4) 2- ((6- amino hexahydro furyl simultaneously [3,2-b] furans -3- bases) epoxide) ethanol
Simultaneously [3,2-b] furans suspends 3- azidos -6- (2- (benzyloxy) ethyoxyl) hexahydro furyl that back is obtained In MeOH (20mL), and it is added thereto to Pa (OH)2/ C (10%, 0.31g).Mixture is anti-in atmosphere of hydrogen and at room temperature Should overnight.After having reacted, mixture is filtered, and washed with MeOH (20mL), then filtrate decompression is concentrated to give crude product, gained Product is unprocessed to be directly used in next step reaction.MS(ESI,pos.ion)m/z:190.1[M+H]+。
Step 5) 2- ((6- ((2,5- dichloro pyrimidine -4- bases) amino) hexahydro furyl simultaneously [3,2-b] furans -3- bases) epoxide) Ethanol
By 2,4,5- trichloropyrimidines (0.71g, 3.88mmol) are suspended in EtOH (20mL), and are added thereto to back 2- ((6- amino hexahydro furyl simultaneously [3,2-b] furans -3- bases) epoxide for obtaining) ethanol and triethylamine (1.10mL, 7.89mmol), mixture reacts overnight at room temperature.After having reacted, reactant mixture is concentrated under reduced pressure, residue is through silica gel column layer Analysis (DCM/MeOH (v/v)=50/1) purifying, obtains title compound for brown liquid (0.21g, three step gross production rates：16%)
MS(ESI,pos.ion)m/z:336.1[M+H]+。
Step 6) 2- ((6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) amino) hexahydro furans Mutter simultaneously [3,2-b] furans -3- bases) epoxide) secondAlcohol
By 2- ((6- ((2,5- dichloro pyrimidine -4- bases) amino) hexahydro furyl simultaneously [3,2-b] furans -3- bases) epoxide) ethanol (0.18g, 0.54mmol) is suspended in n-BuOH (5mL), and be added thereto to 1- methylpyrazole -4- amine hydrochlorates (0.15g, 1.10mmol) and N, N- diisopropylethylamine (0.28g, 2.18mmol).Mixture is placed in tube sealing, is then heated to 150 DEG C It is stirred overnight, is then concentrated under reduced pressure, residue is purified through silica gel chromatograph column chromatography (DCM/MeOH (v/v)=20/1), obtains title Compound is the liquid (42mg, 20%) of viscous brown.
MS(ESI,pos.ion)m/z:396.9[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.91(s,1H),7.66(s,1H),7.49(s,1H),6.75(s, 1H), 5.95 (d, J=6.1Hz, 1H), 4.72 (t, J=4.5Hz, 1H), 4.69-4.59 (m, 2H), 4.38-4.30 (m, 1H), 4.21-4.14 (m, 1H), 4.14-4.07 (m, 1H), 3.89 (s, 3H), 3.81-3.73 (m, 5H), 3.60 (t, J=8.4Hz, 1H)。
The chloro- N of the 5- of embodiment 64- (6- methoxyl groups hexahydro furyl simultaneously [3,2-b] furans -3- bases)-N2- (1- methyl isophthalic acid H- pyrroles Azoles -4- bases) pyrimidine -2,4- diamines
Step 1) 6- (benzyloxy) hexahydro furyl simultaneously [3,2-b] furan-3-ol
At 0 DEG C, sodium hydride (3.24g, 81.0mmol) is suspended in dry DMF (20mL), and be added thereto to six Hydrogen furans simultaneously [3,2-b] furans -3,6- glycol (10.1g, 69.1mmol).Mixture is stirred 1 hour at 0 DEG C, is subsequently adding Bromomethyl benzene (11.73g, 68.58mmol).Gained mixture is stirred at room temperature 4.5 hours.After having reacted, water is then used (50mL) is quenched reaction, and the water layer of separation is extracted with EtOAc (250mL x 3), and the organic phase of merging washes (50mL x with water 6), then anhydrous Na is used2SO4Dry, then filtering is concentrated under reduced pressure, and residue is through silica gel chromatograph column chromatography (PE/EtOAc (v/v)=2/ 1) purify, obtain title compound for pale yellow oil (8.1g, 50%).
MS(ESI,pos.ion)m/z:259.0[M+Na]+。
Step 2) 3- (benzyloxy) -6- methoxyl groups hexahydro furyl simultaneously [3,2-b] furans
By 6- (benzyloxy) hexahydro furyl, simultaneously [3,2-b] furan-3-ol (8.1g, 34mmol) is dissolved in acetonitrile (100mL) In, and it is added thereto to NaOH (4.12g, 103mmol) and iodomethane (9.76g, 68.8mmol).Mixture is heated to 45 DEG C stirring 8 hours.After reaction terminates, it is concentrated under reduced pressure, and residue is diluted with EtOAc (500mL), is filtered to remove solid.Filtrate Use H2O (50mL x 3) is washed, then uses anhydrous Na2SO4Dry, then filtering is concentrated under reduced pressure, obtain title compound for yellow Grease (7.84g, 91.4%).
MS(ESI,pos.ion)m/z:251.0[M+H]+.
Step 3) 6- methoxyl groups hexahydro furyl simultaneously [3,2-b] furan-3-ol
By 3- (benzyloxy) -6- methoxyl groups hexahydro furyl, simultaneously [3,2-b] furans (7.84g, 31.3mmol) is dissolved in EtOH In (80mL), and it is added thereto to Pd/C (10%, 812mg).Reaction solution stirs 2 under 1 hydrogen of atmospheric pressure under normal temperature My god, the solid in mixture is then filtered to remove, gained filtrate decompression is concentrated, it is residue obtained through silica gel column chromatography (PE/ EtOAc (v/v)=1/1) purifying, title compound is obtained for colorless oil (4.53g, 90.3%).
MS(ESI,pos.ion)m/z:161.2[M+H]+；
1H NMR(600MHz,DMSO-d6):δ (ppm) 4.78 (d, J=6.5Hz, 1H), 4.39 (d, J=4.4Hz, 1H), 4.33 (t, J=4.6Hz, 1H), 4.09 (ddd, J=7.8,6.5,1.5Hz, 1H), 3.84 (d, J=9.8Hz, 1H), 3.78 (d, J=4.0Hz, 1H), 3.75 (dd, J=9.8,3.9Hz, 1H), 3.71 (dd, J=8.4,6.5Hz, 1H), 3.31 (t, J= 8.1Hz,1H),3.26(s,3H)。
Step 4) 6- methoxyl groups hexahydro furyl simultaneously [3,2-b] furans -3- base methanesulfonates
By 6- methoxyl groups hexahydro furyl, simultaneously [3,2-b] furan-3-ol (1.03g, 6.43mmol) is dissolved in dry DCM In (30mL), and it is added thereto to triethylamine (1.3mL, 9.4mmol) and methane sulfonyl chloride (0.58mL, 7.5mmol).Reaction solution It is stirred at room temperature 6 hours.After having reacted, with the NaHCO of saturation3(50mL) is quenched reaction, gained mixture EtOAc (80mL x 3) is extracted, the organic phase anhydrous Na of merging2SO4Dry, then filtering is concentrated under reduced pressure, and residue is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) is purified, and obtains title compound for colorless oil (1.1g, 71.9%).
MS(ESI,pos.ion)m/z:239.2[M+H]+。
Step 5) 3- nitrine -6- methoxyl groups hexahydro furyl simultaneously [3,2-b] furans
By 6- methoxyl groups hexahydro furyl, simultaneously [3,2-b] furans -3- bases methanesulfonates (1.1g, 4.6mmol) is dissolved in DMF In (25mL), and it is added thereto to sodium azide (1.66g, 25.5mmol).Reaction solution be heated to 140 DEG C react 12 hours, instead After having answered, the NaHCO of reactant mixture saturation3The aqueous solution dilutes (50mL), and gained mixture is extracted with EtOAc (80mL x 3) Take, the organic phase of merging is washed, anhydrous Na with water (30mL x 5)2SO4Dry, refilter, be then concentrated under reduced pressure to obtain title compound Thing is faint yellow solid (0.85g, 99.4%).
Step 6) 6- methoxyl groups hexahydro furyl simultaneously [3,2-b] furans -3- amine
By 3- nitrine-methoxyl group hexahydro furyl, simultaneously [3,2-b] furans (0.85g, 4.6mmol) is dissolved in MeOH (50mL) In, and it is added thereto to Pd/C (10%, 94.5mg).Reaction solution is stirred overnight at room temperature under a hydrogen for atmospheric pressure, then Filtering, is then concentrated under reduced pressure, and residue is through silica gel column chromatography (DCM/MeOH (0.02M NH3) (v/v)=25/1) purifying, marked Topic compound is colorless oil (380mg, 52.1%).
MS(ESI,pos.ion)m/z:160.3[M+H]+。
Step 7) the chloro- N- of 2,5- bis- (6- methoxyl groups hexahydro furyl simultaneously [3,2-b] furans -3- bases) pyrimidine -4- amine
By 6- methoxyl groups hexahydro furyl, simultaneously [3,2-b] furans -3- amine (380mg, 2.3872mmol) is dissolved in EtOH In (25mL), and triethylamine (967.4mg, 9.560mmol) and 2 are added thereto to, 4,5- trichloropyrimidines (526.2mg, 2.869mmol).Reaction solution is stirred at room temperature 4 hours, is then concentrated under reduced pressure, residue obtained through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purify, obtain title compound for white solid (490mg, 67.2%).
MS(ESI,pos.ion)m/z:305.9[M+H]+；
1H NMR(400MHz,CDCl3):δ (ppm) 8.09 (s, 1H), 5.51 (d, J=6.7Hz, 1H), 4.71-4.61 (m, 3H), 4.05 (dd, J=10.0,4.4Hz, 1H), 3.97-3.87 (m, 4H), 3.42 (s, 3H).
Step 8) the chloro- N of 5-4- (6- methoxyl groups hexahydro furyl simultaneously [3,2-b] furans -3- bases)-N2- (1- methyl isophthalic acid H- pyrazoles- 4- yls) pyrimidine -2,4- diamines
By the chloro- N- of 2,5- bis- (6- methoxyl groups hexahydro furyl simultaneously [3,2-b] furans -3- bases) pyrimidine -4- amine (430mg, 1.4046mmol), diisopropylethylamine (546.7mg, 4.23mmol) and 1- methylpyrazole -4- amine hydrochlorates (283.3mg, 2.12mmol) it is dissolved in n-BuOH (10mL), reaction solution is warming up to 150 DEG C, and then tube sealing reaction 23 hours is concentrated under reduced pressure, Residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=50/1), obtains the crude product of title compound for white solid, slightly Product acetone recrystallization, obtains title compound for white solid (220mg, 42.6%).
MS(ESI,pos.ion)m/z:366.9[M+H]+；
1H NMR(600MHz,CDCl3):δ(ppm)7.97(s,1H),7.92(s,1H),7.41(s,1H),7.11(s, 1H), 5.24 (d, J=6.1Hz, 1H), 4.76 (s, 1H), 4.67 (d, J=3.9Hz, 1H), 4.59 (t, J=5.3Hz, 1H), 4.08 (dd, J=10.1,4.6Hz, 1H), 3.99 (dd, J=10.3,4.9Hz, 1H), 3.96-3.92 (m, 3H), 3.89 (s, 3H),3.42(s,3H)。
The N of embodiment 74- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- bases) the chloro- N of -5-2- (1- methyl isophthalic acid H- pyrazoles- 4- yls) pyrimidine -2,4- diamines
Step 1) 6- hydroxyls hexahydro furyl simultaneously [3,2-b] furans -3- bases 4- toluene sulfonic acide esters
By hexahydro furyl, simultaneously [3,2-b] furans -3,6- glycol (10.00g, 68.4mmol) is dissolved in dichloromethane (60mL) In, and pyridine (1.08g, 13.7mmol) is added thereto to, mixture is cooled to 0 DEG C, adds 4- toluene sulfonyl chlorides (15.66g,82.1mmol).Reactant mixture is stirred 30 minutes at 0 DEG C, is then moved to and is stirred overnight at room temperature, then uses dichloromethane Alkane (250mL) dilutes, and gained mixture uses 1M hydrochloric acid (300mL), water (300mL) and saline solution (300mL) to wash respectively.It is organic Mutually use anhydrous Na2SO4Dry, be then concentrated under reduced pressure, residue is purified through silica gel column chromatography (EtOAc/PE (v/v)=2/1), is obtained Title compound is colorless oil (10.24g, 49.8%).
MS(ESI,pos.ion)m/z:301.2[M+H]+；
1H NMR(400MHz,CDCl3):δ (ppm) 7.79 (d, J=8.3Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 4.84 (dd, J=11.5,6.3Hz, 1H), 4.62 (t, J=4.7Hz, 1H), 4.34 (d, J=4.3Hz, 1H), 4.24 (s, 1H), 4.10-4.06 (m, 1H), 3.84 (d, J=2.0Hz, 2H), 3.80 (dd, J=9.6,6.3Hz, 1H), 3.65 (dd, J=9.6, 6.6Hz,1H),2.42(s,3H)。
Step 2) 2- (6- hydroxyls hexahydro furyl simultaneously [3,2-b] furans -3- bases) isoindoline -1,3- diketone
By simultaneously [3,2-b] furans -3- bases 4- toluene sulfonic acides ester (10.24g, the 34.1mmol) dissolving of 6- hydroxyls hexahydro furyl In DMSO (60mL), and it is added thereto to (1,3- dioxoisoindolin -2- bases) potassium (8.21g, 44.3mmol).Reaction is mixed Then compound is down to room temperature in 130 DEG C and stirred under nitrogen atmosphere, and is poured into water, gained mixture dichloromethane (300mL x 3) is extracted, and the organic phase of merging is washed, anhydrous Na with water (100mL x 3)2SO4Dry, be then concentrated under reduced pressure, it is residual Slag through silica gel column chromatography (EtOAc/PE (v/v)=1/1) purify, obtain title compound for white solid (2.35g, 25.0%).
MS(ESI,pos.ion)m/z:276.0[M+H]+；
1H NMR(400MHz,CDCl3):δ (ppm) 7.86 (dd, J=5.4,3.1Hz, 2H), 7.74 (dd, J=5.5, 3.0Hz, 2H), 5.17 (dd, J=4.3,2.2Hz, 1H), 4.84-4.74 (m, 2H), 4.44-4.35 (m, 1H), 4.17 (t, J= 8.5Hz, 1H), 4.06 (dd, J=10.1,3.3Hz, 1H), 3.97-3.85 (m, 2H).
Step 3) 6- (1,3- dioxoisoindolin -2- bases) hexahydro furyl simultaneously [3,2-b] furans -3- base methanesulfonates
By 2- (6- hydroxyls hexahydro furyl simultaneously [3,2-b] furans -3- bases) isoindoline -1,3- diketone (2.35g, 8.54mmol) it is dissolved in dichloromethane (40mL), and is added thereto to triethylamine (1.30g, 12.8mmol) and N, N- diformazan Yl pyridines -4- amine (209.2mg, 1.7mmol).Mixture is cooled to 0 DEG C, and in N2Protection is lower to add methane sulfonyl chloride (0.8mL,10.0mmol).Gained mixture is stirred 30 minutes at 0 DEG C, is then moved to and is stirred overnight at room temperature.After having reacted, mix Compound is diluted with dichloromethane (100mL), then is washed with the hydrochloric acid (100mL) of 1M, water (100mL) and saline solution (100mL) respectively Wash, use anhydrous Na2SO4Dry, be then concentrated under reduced pressure, it is residue obtained pure through silica gel column chromatography (MeOH/DCM (v/v)=1/200) Change, obtain title compound for white solid (2.35g, 77.9%).
MS(ESI,pos.ion)m/z:353.9[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.87-7.85(m,2H),7.79-7.71(m,2H),5.16-5.15 (m,2H),5.08-5.07(m,1H),4.88-4.80(m,1H),4.26-4.19(m,1H),4.17-4.10(m,2H),3.96- 3.91(m,1H),3.09(s,3H)。
Step 4) 2- (6- nitrine hexahydro furyl simultaneously [3,2-b] furans -3- bases) isoindoline -1,3- diketone
By 6- (1,3- dioxoisoindolin -2- bases) hexahydro furyl simultaneously [3,2-b] furans -3- base methanesulfonates (2.80g, 7.9mmol) is dissolved in DMF (60mL), and is added thereto to sodium azide (2.16g, 33.2mmol).Reaction is mixed Compound is stirred 23 hours at 140 DEG C, then is diluted with dichloromethane (100mL).Gained mixture water (100mL x 3) is washed Wash, then use anhydrous Na2SO4Dry, be then concentrated under reduced pressure, obtain crude product.Crude product is not purified to be directly used in next step reaction.
Step 5) 2- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- bases) isoindoline -1,3- diketone
By 2- (6- nitrine hexahydro furyl simultaneously [3,2-b] furans -3- bases) isoindoline -1,3- diketone (previous step crude product) It is dissolved in MeOH (70mL), and is added thereto to 10%Pd (OH)2/C(240mg,0.17mmol).Reactant mixture is in room temperature And stirred under nitrogen atmosphere is overnight, then filters, then filtrate decompression is concentrated, obtain crude product.The not purified direct use of crude product In next step reaction.
MS(ESI,pos.ion)m/z:275.0[M+H]+。
Step 6) 2- (6- ((2,5- dichloro pyrimidine -4- bases) amino) hexahydro furyl simultaneously [3,2-b] furans -3- bases) iso-indoles Quinoline -1,3- diketone
By 2,4,5- trichloropyrimidines (1.45g, 7.9mmol) are dissolved in MeOH (40mL), and are added thereto to triethylamine (970mg, 9.6mmol) and 2- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- bases) isoindoline -1,3- diketone (previous steps Crude product).Reactant mixture is stirred at room temperature overnight, and is then concentrated under reduced pressure, residue obtained through silica gel column chromatography (EtOAc/PE (v/v)=1/3) purify, obtain title compound for white solid (450mg, three step gross production rates：13.5%).
MS(ESI,pos.ion)m/z:421.1[M+H]+；
1H NMR(600MHz,CDCl3):δ(ppm)8.07(s,1H),7.90-7.85(m,2H),7.79-7.73(m,2H), 5.14-5.13(m,1H),5.00-4.98(m,1H),4.91-4.86(m,1H),4.76-4.68(m,1H),4.36-4.29(m, 2H),4.13-4.07(m,1H),3.65-3.62(m,1H)。
Step 7) 2- (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) amino) hexahydro furans Mutter simultaneously [3,2-b] furans -3- bases) isoindoline -1,3- diketone
By 2- (6- ((2,5- dichloro pyrimidine -4- bases) amino) hexahydro furyl simultaneously [3,2-b] furans -3- bases) isoindoline - 1,3- diketone (370.0mg, 0.88mmol) and 1- methyl isophthalic acids H- pyrazoles -4- amine hydrochlorates (354.2mg, 2.65mmol) are dissolved in N-BuOH (10mL), and it is added thereto to DIPEA (683.1mg, 5.29mmol).Reactant mixture is stirred overnight at 150 DEG C, Then it is concentrated under reduced pressure, residue is through silica gel column chromatography (MeOH/CH2Cl2(v/v)=1/30) purify, it is red to obtain title compound Solid (140.0mg, 33.1%).
MS(ESI,pos.ion)m/z:482.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.90(s,1H),7.88-7.86(m,2H),7.76-7.74(m,2H), 7.67 (s, 1H), 7.46 (s, 1H), 6.73 (s, 1H), 5.89 (d, J=7.5Hz, 1H), 5.16-5.14 (m, 1H), 4.99- 4.96 (m, 1H), 4.87 (td, J=7.6,2.2Hz, 1H), 4.67-4.60 (m, 1H), 4.32 (t, J=8.5Hz, 1H), 4.28- 4.22 (m, 1H), 4.08-4.04 (m, 1H), 3.87 (s, 3H), 3.63 (t, J=8.9Hz, 1H).
Step 8) N4- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- bases) the chloro- N of -5-2- (1- methyl isophthalic acid H- pyrazoles -4- Base) pyrimidine -2,4- diamines
By 2-, (hexahydro furyl is simultaneously for 6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) amino) [3,2-b] furans -3- bases) isoindoline -1,3- diketone (140.0mg, 0.29mmol) is dissolved in EtOH (5mL), and to it Middle addition hydrazine hydrate (198.6mg, 2.94mmol).Reactant mixture is stirred at room temperature 4 hours, is then concentrated under reduced pressure, gained Residue is through silica gel column chromatography ((7M NH3MeOH solution)/DCM (v/v)=1/20) purifying, obtain title compound for white Solid (65.0mg, 63.6%).
MS(ESI,pos.ion)m/z:351.9[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.89(s,1H),7.65(s,1H),7.47(s,1H),6.50(s, 1H), 5.94 (s, 1H), 4.76-4.73 (m, 1H), 4.60-4.57 (m, 1H), 4.40 (d, J=4.1Hz, 1H), 4.24-4.20 (m, 1H), 4.00 (dd, J=9.2,4.4Hz, 1H), 3.87 (s, 3H), 3.80 (d, J=9.1Hz, 1H), 3.62 (d, J= 4.1Hz,1H),3.50-3.46(m,1H)。
The N- of embodiment 8 (6- ((the chloro- 2- of 5- ((1- methyl isophthalic acid H- pyrazoles -4- bases) amino) pyrimidine-4-yl) amino) hexahydros Furans simultaneously [3,2-b] furans -3- bases)) methylsulfonamides
By N4- (6- amino hexahydro furyl simultaneously [3,2-b] furans -3- bases) the chloro- N of -5-2- (1- methyl isophthalic acid H- pyrazoles -4- bases) Pyrimidine -2,4- diamines (57.0mg, 0.16mmol) is dissolved in dichloromethane (5mL), and is added thereto to triethylamine (26.2mg, 0.26mmol) and N, N- lutidines -4- amine (4.1mg, 0.03mmol).Mixture is down to 0 DEG C, is subsequently adding Methylsufonyl chloride (28.3mg, 0.25mmol).Reactant mixture stirs 30min at 0 DEG C, then moves to and is stirred overnight at room temperature, It is concentrated under reduced pressure again, residue obtained to be purified through silica gel column chromatography (MeOH/DCM (v/v)=1/30), it is white to obtain title compound Solid (28.0mg, 40.2%).
MS(ESI,pos.ion)m/z:430.2[M+H]+；
1H NMR(400MHz,CDCl3):δ(ppm)7.90(s,1H),7.62(s,1H),7.48(s,1H),6.56(s, 1H),5.81(s,1H),4.80-4.78(m,1H),4.70-4.67(m,1H),4.64-4.59(m,1H),4.28-4.24(m, 1H),4.09-4.07(m,2H),3.94-3.88(m,1H),3.87(s,3H),3.51-3.46(m,1H),3.05(s,3H)。
Biologic test
The LC/MS/MS systems of analysis include the serial vacuum degassing furnace of Agilent 1200, binary syringe pump, orifice plate from Dynamic sampler, post insulating box, charged spray ionizes the Agilent G6430 three-level level Four bar mass spectrographs in (ESI) source.Quantitative analysis Carried out under MRM patterns, the parameter of MRM conversions is as in Table A：
Table A
Many reaction detection scannings 490.2→383.1
Fragmentation voltage 230V
Capillary voltage 55V
Dryer temperature 350℃
Atomizer 40psi
Drier flow velocity 10L/min
Analysis uses Agilent XDB-C18,2.1x 30mm, 3.5 μM of posts to inject 5 μ L samples.Analysis condition：Mobile phase It is 0.1% aqueous formic acid (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient 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 Terminate
Additionally, also have the series LC/MS/MS spectrometers of Agilent 6330 for what is analyzed, equipped with G1312A binary note Penetrate pump, G1367A automatic samplers and G1314C UV detectors；LC/MS/MS spectrometers use ESI radioactive sources.Use titer Suitable cation model treatment and MRM conversions are carried out to each analyte carries out optimal analysis.Used during analyzing Capcell MP-C18 posts, specification is：100x 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 into polypropylen tubes duplicate hole to be incubated.The typical mixed liquor that is incubated includes people or big Rat hepatic microsome (0.5mg protein/mL), target compound (5 μM) and NADPH (1.0mM) potassium phosphate that cumulative volume is 200 μ L (PBS, 100mM, pH value are 7.4), compound to be dissolved in DMSO to buffer solution, and are diluted using PBS, make its final The concentration of DMSO solution is 0.05%.And be incubated in the water-bath communicated with air at 37 DEG C, preincubate is mixed for 3 minutes backward Albumen is added in conjunction liquid and starts reaction.At different time points (0,5,10,15,30 and 60min), the ice-cold second of same volume is added Nitrile terminating reaction.Sample at -80 DEG C in preserving until carrying out LC/MS/MS analyses.
Concentration of the compound in people or rat liver microsomes mixtures incubated is determined by the method for LC/MS/MS 's.The range of linearity of concentration range is determined by each test-compound.
It is parallel to be incubated experiment and use the microsome of denaturation as negative control, it is incubated at 37 DEG C, react when different Between point (0,15 and 60 minute) terminate.
Dextromethorphan (70 μ Μ) is incubated as positive control at 37 DEG C, reaction different time point (0,5,10, 15,30 and 60 minutes) terminate.All include positive and negative control sample in each assay method, to ensure that microsome is incubated The integrality of system.
Additionally, stability data of the compound of the present invention in people or rat liver microsomes can also be obtained by tests below Arrive.People or rat liver microsomes are placed in into duplicate hole in polypropylen tubes to be incubated.Typical mixtures incubated includes people or rat Hepatomicrosome (ultimate density：0.5mg albumen/mL), compound (ultimate density：1.5 μM) and K- that cumulative volume is 30 μ L buffering Solution (EDTA containing 1.0mM, 100mM, pH 7.4).Compound is dissolved in DMSO, and is diluted with K- cushioning liquid, made The ultimate density of DMSO is 0.2%.After preincubate 10 minutes, 15 μ L NADPH (ultimate densities are added：2mM) carry out enzymatic anti- Should, whole experiment is carried out in 37 DEG C of incubation tube.At different time points (0,15,30 and 60 minute), 135 μ L acetonitriles are added (containing IS) terminating reaction.It is centrifuged 10 minutes with 4000rpm, except deproteinized, collects supernatant, is analyzed with LC-MS/MS.
In above-mentioned experiment, ketanserin (1 μM) is selected as positive control, is incubated at 37 DEG C, reacts in the different time Point terminates for (0,15,30 and 60 minute).All include positive control sample in each assay method, to ensure that microsome is incubated body The integrality of system.
Data analysis
For each reaction, concentration (as a percentage) of the compound in people or rat liver microsomes are incubated is pressed With respect to the plotted as percentage of zero time point, internal CLint CL is inferred with thisint(ref.:Naritomi Y, Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324.).Referring to table 1, table 1 is compound provided in an embodiment of the present invention in people to result With the experimental result of stability in rat liver microsomes.
The experimental result of the compound provided in an embodiment of the present invention stability in people and rat liver microsomes of table 1
∞:Infinity, ND:Do not measure
As shown in Table 1, when in the compounds of this invention being incubated in into people and rat liver microsomes, compound table of the present invention Reveal appropriate stability.
The medicine of embodiment B mouse, rat, dog and monkey after intravenous injection and oral quantitatively the compounds of this invention is for power Learn and evaluate
Pharmacokinetic of the present invention to the compounds of this invention in mouse, rat, dog or monkey body is commented Estimate.The compounds of this invention is with the aqueous solution or the aqueous solution of 2%HPMC+1% Tween-80s, the saline solution of 5%DMSO+5%, 4% MC or capsule form are administered.It is administered for intravenous injection, animal gives the dosage of 1 or 2mg/kg.For oral dose (p.o.), rat and mouse are 5 or 10mg/kg, and dog and monkey are 10mg/kg.It is 0.25,0.5,1.0,2.0 at time point, Blood (0.3mL) is taken within 3.0,4.0,6.0,8.0,12 and 24 hours, and is centrifuged 10 minutes under 3,000 or 4,000rpm.Collect blood Slurry solution, and analyzed until carrying out above-mentioned LC/MS/MS in being preserved at -20 DEG C or -70 DEG C.Result is this hair referring to table 2, table 2 Experimental result of medicine of the compound that bright embodiment is provided in rat body for feature.
Experimental result of medicine of the compound provided in an embodiment of the present invention of table 2 in rat body for feature
As shown in Table 2, when the compound intravenous injection administration for the present invention being provided or oral administration, chemical combination of the present invention Thing shows good pharmacokinetic property, including preferably absorbs, preferable half-life period (T1/2) and preferable oral bio Availability (F).
Embodiment C Kinase activity assays
The present invention discloses compound can be evaluated as the effectiveness of kinases inhibitor by following experiment.
The general description of kinase assay
Kinase assay by detect mix γ-33The myelin basic protein (MBP) of P-ATP is come what is completed.Prepare 20 μ g/ MBP (Sigma#M-1891) trishydroxymethylaminomethane buffer salt solution (TBS of ml；50mM Tris pH 8.0,138mM NaCl, 2.7mM KCl), white 384 orifice plate (Greiner) of associativity high is coated with, per the μ L of hole 60.4 DEG C, it is incubated 24h.Use afterwards 100 μ L TBS board-washings 3 times.Kinase reaction is in kinase buffer liquid (the 5mM Hepes pH 7.6,15mM that cumulative volume is 34 μ L NaCl, 0.01% bovine serum albumin(BSA) (Sigma#I-5506), 10mM MgCl2, 1mM DTT, 0.02%TritonX-100) in Carry out.Compound is dissolved in DMSO, is added in each hole, the ultimate density of DMSO is 1%.Twice of each data determination, often The measure of individual compound is at least tested twice.Such as, the ultimate density of enzyme is 10nM or 20nM.Addition does not have markd ATP (10 μM) and γ-33The ATP of P marks is (per hole 2x 106Cpm, 3000Ci/mmol) start reaction.Reaction is shaken at room temperature Carry out 1 hour.The 384 orifice plates PBS of 7x, is subsequently adding the scintillation solution of the μ L of every hole 50.Counted with Wallac Trilux Device testing result.To those of ordinary skill in the art, this is only the one kind in numerous detection methods, and other methods are also Can.
The IC that above-mentioned test method can be inhibited50And/or inhibition constant Ki。IC50It is defined as under test conditions, suppression Make compound concentration during 50% enzymatic activity.Made comprising 10 curves of concentration point, estimation using the extension rate of 1/2log IC50Value by following compound concentration (for example, make a typical curve：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] (specific activity about 500cpm/pmol, concentration determines according to demand) be incubated under conditions of existing. Start reaction after adding MgATP mixtures.40 minutes are incubated at room temperature afterwards, and it is anti-to terminate to be added thereto to 3% phosphoric acid solution Should.The reaction solution of 10 μ L is distributed on P30 filters in mottled, and was cleaned 3 times in 5 minutes with 75mM phosphoric acid, and Preservation in methanol solution is put into before dry and scinticounting at once.
JAK2(h)
JAK2 (h) in 8mM MOPS pH 7.0,0.2mM EDTA, 100 μM KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC, 10mM magnesium acetate and [γ-33P-ATP] (specific activity is about 500cpm/pmol, concentration determines according to demand) exist under conditions of be incubated.Start reaction after adding MgATP mixtures. 40 minutes are incubated at room temperature afterwards, are added thereto to 3% phosphoric acid solution and are carried out terminating reaction.It it is in mottled point by the reaction solution of 10 μ L It is distributed on P30 filters, and was cleaned 3 times in 5 minutes with 75mM phosphoric acid, and first is put at once with before scinticounting drying Preserved in alcoholic solution.
JAK3(h)
JAK3 (h) is in 8mM MOPS pH 7.0,0.2mM EDTA, 500 μM of GGEEEEYFELVKKKK, 10mM magnesium acetates [γ-33P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) be incubated under conditions of existing.Add Start reaction after MgATP mixtures.40 minutes are incubated at room temperature afterwards, are added thereto to 3% phosphoric acid solution and are carried out terminating reaction.Will The reaction solution of 10 μ L is distributed on P30 filters in mottled, and clean 3 times in 5 minutes with 75mM phosphoric acid, and drying with Preservation in methanol solution is put into before scinticounting at once.
TYK2(h)
TYK2 (h) is in 8mM MOPS pH 7.0,0.2mM EDTA, 250 μM of GGMEDIYFEFMGGKKK, 10mM magnesium acetates [γ-33P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) be incubated under conditions of existing.Add Start reaction after MgATP mixtures.40 minutes are incubated at room temperature afterwards, are added thereto to 3% phosphoric acid solution and are carried out terminating reaction.Will The reaction solution of 10 μ L is distributed on P30 filters in mottled, and clean 3 times in 5 minutes with 75mM phosphoric acid, and drying with Preservation in methanol solution is put into before scinticounting at once.
FLT3(h)
FLT3 (h) in 8mM MOPS pH 7.0,0.2mM EDTA, 50 μM of EAIYAAPFAKKK, 10mM magnesium acetates and [γ-33P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) be incubated under conditions of existing.Add Start reaction after MgATP mixtures.40 minutes are incubated at room temperature afterwards, are added thereto to 3% phosphoric acid solution and are carried out terminating reaction.Will The reaction solution of 10 μ L is distributed on P30 filters in mottled, and clean 3 times in 5 minutes with 75mM phosphoric acid, and drying with Preservation in methanol solution is put into before scinticounting at once.
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] (specific activity about 500cpm/pmol, concentration determines according to demand) incubated under conditions of existing Educate.Start reaction after adding MgATP mixtures.40 minutes are incubated at room temperature afterwards, are added thereto to 3% phosphoric acid solution to terminate Reaction.The reaction solution of 10 μ L is distributed on P30 filters in mottled, and was cleaned 3 times in 5 minutes with 75mM phosphoric acid, and Preserved in being put into methanol solution at once before dry and scinticounting.
Aurora-B(h)
Aurora-B (h) in 8mM MOPS pH 7.0,0.2mM EDTA, 30 μM of AKRRRLSSLRA, 10mM magnesium acetates and [γ-33P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) be incubated under conditions of existing.Add Start reaction after MgATP mixtures.40 minutes are incubated at room temperature afterwards, are added thereto to 3% phosphoric acid solution and are carried out terminating reaction.Will The reaction solution of 10 μ L is distributed on P30 filters in mottled, and clean 3 times in 5 minutes with 75mM phosphoric acid, and drying with Preservation in methanol solution is put into before scinticounting at once.
Kinase assay in the present invention be completed by Millipore companies of Britain (Millipore UK Ltd, Dundee Technology Park,Dundee DD21SW,UK)。
In addition, the kinase activity of compound can be by KINOMEscanTMDetection, this detection is to be based on using active sites Point guidance type Competition binding assay method quantitative determination compound.The experiment is carried out by being combined with three kinds of compounds, i.e. DNA marks Note enzyme, fixed ligand and detection compound, the competition energy of qPCR detection compounds and fixed ligands is carried out by DNA marker Power.
Major part experiment is all the T7 bacteriophage bacterium that kinases mark is cultivated from escherichia coli host derived from BL21 bacterial strains Strain, after being in the Escherichia coli of exponential phase with T7 phage-infects, lysate is centrifuged to bacteriolyze for 32 DEG C of oscillation incubations Filtering removal cell fragment, remaining kinases carries out qPCR detections in going to HEK-293 cells with DNA marker.Streptavidin After coated particle is with biotinylated smaller ligand room temperature treatment 30min, affine resin can be produced for kinase assay.Match somebody with somebody After body particle is closed through unnecessary biotin, through confining liquid (SEABLOCKTM(Pierce), 1% bovine serum albumin(BSA), 0.05% Polysorbas20,1mM DTT) the uncombined part of cleaning, reduces non-specific binding.By the combination buffer (20% in 1x SEABLOCKTM, 0.17x PBSs, 0.05% polysorbas20,6mM DTT) in combine kinases, part 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 1h is swung, adds lavation buffer solution (1x PBSs, 0.05% polysorbas20) to clean affine particle, add wash-out slow After fliud flushing resuspended (1x PBSs, 0.05% polysorbas20,0.5 μM of non-biotinylated affinity ligand), shaken at room temperature 30min is incubated, the concentration of kinases in eluent is detected by qPCR.It is in the U.S. that kinase activity described in text is determined The KINOMEscan of DiscoveRx companies (Albrae St.Fremont, CA 94538, USA)TMDepartment, is measured.
Kinase activity assays result referring to table 3 and table 4, table 3 for compound provided in an embodiment of the present invention JAK1 and JAK2 kinase assay results, table 4 is tried for Aurora-A, Aurora-B and FLT3 kinases of compound provided in an embodiment of the present invention Test result.
JAK1 the and JAK2 kinase assay results of the compound provided in an embodiment of the present invention of table 3
NT：Test
Aurora-A, Aurora-B and FLT3 kinase assay result of the compound provided in an embodiment of the present invention of table 4
NT：Test
From table 3 and table 4, compound of the present invention in kinase assay to JAK1, JAK2, Aurora-A, Aurora-B and FLT3 kinases generally shows preferable activity.
Finally it should be noted that also other modes are used for implementing the present invention.Correspondingly, embodiments of the invention are To illustratively illustrate, but be not limited to content described in the invention, it is also possible to be made within the scope of the present invention Modification or the equivalents added in the claims.All publications or patent cited in the present invention all will be used as this hairs Bright bibliography.

Claims (17)

1. a kind of compound, it is the pharmaceutically acceptable salt of the compound shown in formula (I) or compound shown in formula (I),
Wherein,
Z isWherein, X and X ' are each independently O, and Z is optionally by 1 R3Group is replaced；
Z1It is H or C1-C6Alkyl；
A is pyrazolyl, and it is optionally by 1 R5Group is replaced；
W is N；
R1It is H, F, Cl, Br, I, C1-C6Alkyl or C1-C6Haloalkyl；
R3It is H, OH, NH2、C1-C6Alkyl, C1-C6Alkoxy ,-O (CR7R8)n-ORcOr-N (Rc) S (=O)mR6；
R5It is C1-C6Alkyl；R6It is C1-C6Alkyl or C1-C6Haloalkyl；
Each R7And R8It is separately H or C1-C6Alkyl；
RcIt is H or C1-C6Alkyl；
M is 1 or 2；With
N is 1,2,3 or 4.
2. compound according to claim 1, wherein, RcIt is H or C1-C4Alkyl.
3. compound according to claim 1, wherein, A is
4. compound according to claim 1, wherein, Z1It is H, methyl, ethyl, n-propyl or isopropyl.
5. compound according to claim 1, wherein, R1It is H, F, Cl or C1-C4Alkyl.
6. compound according to claim 1, wherein, R3It is H, OH, NH2、C1-C4Alkoxy ,-O (CR7R8)n-ORcOr-N (Rc) S (=O)mR6。
7. compound according to claim 1, wherein, R6It is C1-C4Alkyl or C1-C4Haloalkyl.
8. compound according to claim 1, the structure with one of：
Or its pharmaceutically acceptable salt.
9. a kind of pharmaceutical composition, it includes the compound described in claim 1-8 any one.
10. pharmaceutical composition according to claim 9, wherein further comprising pharmaceutically acceptable excipient, carrier, Adjuvant, solvent or combinations thereof.
11. pharmaceutical composition according to claim 9 or 10, wherein further including therapeutic agent, the therapeutic agent is selected from Chemotherapeutics, antiproliferative, phosphodiesterase 4 inhibitors, beta-2-adrenoreceptor agonists, corticosteroid, nonsteroidal GR It is activator, anticholinergic drug, antihistamine, anti-inflammatory reagent, immunodepressant, immunomodulator, athero- for treating artery The medicine of hardening, the medicine for treating pulmonary fibrosis and combinations thereof.
Compound described in 12. claim 1-8 any one or claim 9-11 any one described pharmaceutical composition are in system Purposes in standby medicine, the medicine is used to preventing, process, treat or mitigating protein kinase mediated disease.
13. purposes according to claim 12, wherein the disease that the protein kinase mediated disease is JAK- to be mediated, The disease of FLT3- mediations, disease, proliferative diseases, autoimmune disease, anaphylactia, the inflammatory disease of Aurora- mediations Disease, graft rejection, myelofibrosis, COPD, asthma, psoriasis, type i diabetes, eczema or measles.
14. purposes according to claim 13, wherein, the proliferative diseases are cancer, polycythemia vera, original Hair property piastrenemia, acute myelocytic leukemia, chronic granulocytic leukemia or ALL；
The autoimmune disease is systemic loupus erythematosus, skin lupus erythematosus, LN, Sjogren syndrome or class Rheumatic arthritis；
The anaphylactia is respiratory anaphylactic disease, food hypersenstivity or insect venom allergies；
The inflammatory disease is LN, dermatomyositis, nasosinusitis, inflammatory bowel disease, rheumatoid arthritis, juvenile form joint Scorching or psoriasis arthropathica.
15. purposes according to claim 14, wherein, the inflammatory bowel disease is Crohn disease.
Compound described in 16. claim 1-8 any one or claim 9-11 any one described pharmaceutical composition are in system Purposes in standby medicine, the medicine is used for the activity of regulatory protein kinases.
17. purposes according to claim 16, wherein the protein kinase is jak kinase, FLT3 kinases, Aurora A Or combinations thereof.
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