CN104926794B

CN104926794B - Substituted heteroaryl compound and combinations thereof and purposes

Info

Publication number: CN104926794B
Application number: CN201510114757.8A
Authority: CN
Inventors: 习宁; 李敏雄; 李晓波; 张涛; 吴彦君
Original assignee: Add And Open Up Scientific Co; Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2014-03-17
Filing date: 2015-03-16
Publication date: 2017-12-05
Anticipated expiration: 2035-03-16
Also published as: CN104926824B; CN104926794A; CN104926795A; CN104926795B; CN104926824A

Abstract

The invention provides heteroaryl compound of one kind substitution and combinations thereof and their purposes.Described compound be formula (I) shown in compound or formula (I) shown in compound stereoisomer, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug.Present invention also offers the pharmaceutical composition for including the compound, described compound and pharmaceutical composition can be with the activity of regulatory protein kinases, for preventing, handling, treating 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 kind of noval chemical compound as kinase activity inhibitor, prepare them Method, the pharmaceutical composition comprising the compound and the compound and its pharmaceutical composition treating a variety of different diseases Application in disease.More specifically, compound of the present invention can be used 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, is catalyzed the phosphorylation of target proteins matter substrate.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 acceptors 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 a kind of highly relevant serine/threonine kinase, and it is mitotic crucial tune Agent is saved, the accurate and equal separation (segtion) for the genomic material from mother cell to daughter cell is required.Aurora The member of kinase families includes the 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( Can still there are different (Richard D.Carvajal, et al., Clin Cancer Res., 2006,12 (23) greatly each other:6869- 6875；Daruka Mahadevan,et al.,Expert Opin.Drug Discov.,2007,2(7):1011-1026).

Aurora-A generally expresses and adjusted the cell cycle events occurred from the phase in late period S through the M phases, 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 The separation of heart body (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.), the Chromosomal arrangement on equatorial plate (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 from G2 through M phases Aurora-A protein level and kinase activity, its peak activity is in the prometaphase.Once activation, Aurora-A mediates its multiple functions, conversion by including centrosome protein (centrosomin) interaction with various substrates 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), (Murata-Hori M, et are adhered in protein localization to kinetochore and centromere, correct micro-pipe-centromere al.,Curr Biol.2002,12:894-899), and 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 biology 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, show 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 to contaminate The unstability and aneuploidy of colour solid.The Aurora-B of mitosis point main function 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 Qualitative and tumour occur (Weaver BA, et al., Cancer Cell, 2005,8:7-12).

Aurora-A overexpressions are the tumorigenic required features of Aurora-A- inductions.It is overexpressed in tool Aurora-A Cell in, mitotic feature be 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 entered from mid-term Exhibition causes many chromosome separation defects to the later stage.Cytokinesis will not occur for these cells, and develop other cell Cycle, polyploidy and progressive chromosome instability (Anand S, et al., Cancer Cell, 2003,3:51-62).

Verified Aurora is overexpressed and a variety of malignant proliferative disorders, such as the carcinoma of the rectum, breast cancer, lung cancer, cancer of pancreas, preceding Row gland cancer, carcinoma of urinary bladder, head and neck cancer, cervix cancer, oophoroma, liver cancer and stomach cancer etc., it is closely related, excite exploitation and be used 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 Into the centerbody separation defect and cytokinesis failure (Marumoto T, et al., J of, monopole mitotic spindle 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, the biology orientation that can not realize chromosome, cytokinesis Failure (Goto H, et al., J Biol Chem., 2003,278:8526-8530；Severson AF,et al.,Curr Biol.,2000,10:1162-1171).The repetitive cycling for not including the abnormal mitosis of cytokinesis causes huge more times Property and ultimately result 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 it is more preferable (Ditchfield C, et al., J Cell Biol., 2003,161:267-280), so as to target Aurora can be realized to selectivity inside 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 the activity in xenograft models still shows that rational treatment refers to clinical tolerability Number.On the premise of preclinical antitumor activity and tumor-selective potentiality, several Aurora As have been developed at present and have been 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 forms, and includes extracellular ligand-binding domain of five immunoglobulin class structure compositions, 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)。

FLT3 part 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 the soluble form tyrosine kinase activity of energy activated receptor simultaneously stimulate the 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 kind signal transduction pathway, such as the signal transducer and activator (STAT5), RAS/ mitogens of transcription 5 Protein kinase (RAS/MAPK), phosphoinositide 3-kinase (PI3K), the Src of original activation be of the same race and glue protogene (SHC), contains SH2 inositol -5- phosphatases (SHIP) and the cytoplasmic tyrosine phosphoric acid with 2 Src- homologys 2 (SH2) domains (SHP2) Enzyme, its breed in cell, played 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 in placenta, sexual gland and brain expression (Maroc N, et al., Oncogene, 1993,8:909- 918) and in immune response play a significant role (deLapeyriere O.et al., Leukemia, 1995,9:1212- 1218)。

FLT3 also with the hemopoietic system dysfunction before malignant proliferative lesion, such as piastrenemia, true property blood platelet Bone is obtained before increase disease, myelofibrosis (MF), chronic idiopathic myelofibrosis (IMF), polycythemia (PV), canceration Marrow hyperplasia exception syndrome, hematologic malignancies include, but not limited to leukaemia, (NHL), lymphogranulomatosis (also known as Hodgkin lymphoma) and myeloma, such as, acute lymphatic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), CNL (CNL), it is closely related.Acute myeloid leukaemias (AML) of the FLT3 in 70-100% In, and in the ALL (ALL) of high percentage with it is each it is horizontal be overexpressed (Griffin JD, et al., Haematol J.,2004,5:188-190).In primitive cell crisis, it is also in the smaller of chronic myelogenous leukemia (CML) It is overexpressed in hypotype.Research has shown that B pedigree leukaemias ALL and AML continually co-express 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).In addition, FLT3L is in langerhans cell histiocytosis and Patients with SLE cell serum with high-level table Reach, further show that the dendritic cells Signal Regulation of FLT3 and autoimmune disease is extremely closely related.

Increasing evidence shows that polytype leukaemia and myeloproliferative syndrome have the prominent of EGFR-TK Become.FLT3 mutation are one of body changes most frequent 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 is lacked 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 in JM domains, which replicates (ITD) mutation, to be contributed in AML About 17-34% FLT3 Activating mutations.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 be confined to JM domains.However, in different patients, there is change its length and position Change.These repetitive routines can be used for destroying 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 ground has the recurrence of FLT3 mutation or obstinate AML patient as some or all Monotherapy reached clinical test.Generally, these as shown by data FLT3 is to be used for AML and other relevant diseases for developing 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.JAK families adjust and are related to the cell of immune response in the propagation that cell factor relies on Played an important role in function.Cell factor is combined with their acceptor, causes receptor dimerization, can so promote JAKs phases Mutual phosphorylation, it can also promote cytokine receptor internal specific tyrosine motif phosphorylation.Identify 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：JAK1 (Janus kinases -1), (Janus swashs 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 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) interaction, induces IL-2 receptor families, IL-4 receptor families, and gp130 receptor families send signal.It is to I The signal of type (IFN-α/β) and II types (IFN-γ) interferon, and the IL-10 family members by II cytokines 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 kinases is demonstrated to the sign of the tissue from JAK1 knock-out mices and led in IFN, IL-IO, IL-2/IL-4 and IL-6 Key effect in road.

JAK1 expression in cancer cell can promote individual cells atrophy, potentially them is fled from tumour, be transferred to body Other positions of body.By the cell factor of JAK1 transduction signals, its horizontal raising involves substantial amounts of immune and inflammation disease Disease.JAK1 or JAK family kinase inhibitors can be used for adjusting or treat these diseases (Kisseleva et al., 2002, Gene 285:1-24；Levy et al.,2005,Nat.Rev.Mol.Cell Biol.,3:651-662).Target the people of IL-6 paths Resource monoclonal antibody (Torr pearl monoclonal antibody Tocilizumab) ratifies to be used to treat moderate to severe rheumatoid pass by EU Committee Save inflammation (Scheinecker et al., 2009, Nat.Rev.Drug Discov.8:273-274).

JAK2 and II cytokines receptor family (such as interferon receptors), GM-CSF receptor families, gp130 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 disease disease such as polycythemia vera, primary thrombocytosis and idiopathic myelofibrosis, generally deposit (JAK2V617F) is mutated in the JAK2 of acquired activation.The situation that the JAK2 albumen of mutation can stimulate in no 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 is only with being present in IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokine receptor complex Public gamma cells factor acceptor chain is related.JAK3 is mainly expressed in immunocyte, and the tyrosine phosphorus for passing through interleukin-2-receptor Acidifying activation, transduction signal.Because JAK3 is limited to express in candidate stem cell more, relative to other JAKs, it is in cell factor Effect in signal transduction is stricter.JAK3 mutation can cause severe combined immunodeficiency (SCID) (O'Shea et al.,2002,Cell,109(suppl.):S121-S131).Effect based on it in lymphocyte is adjusted, targeting JAK3 and The path of JAK3 mediations has been used for treating immunosupress indication (for example, graft rejection and rheumatoid arthritis) (Baslund et al.,2005,Arthritis&Rheumatism 52:2686-2692；Changelian et al., 2003,Science 302:875-878)。

TYK2 and IFN-α, IL-6, IL-10 to IL-12 signal transductions are related.Biochemical research and knock out mice Disclose 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 infection.Opposite, resistance allergy can be improved, autologous exempt from by suppressing TYK2 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 shared p40 subunits of targeting IL-12 and IL-23 cell factors Monoclonal antibody (Ustekinumab), for treat moderate to severe plaque psoriasis (Krueger et al., 2007, N.Engl.J.Med.356:580-92；Reich et al.,2009,Nat.Rev.Drug Discov.8:355-356).This Outside, target IL-12 and IL-23 paths antibody carried out be used 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 Escape to many propagation and cancer associated processes, including cell cycle progression, apoptosis, angiogenesis, infiltration, transfer and immune system Keep away (Haura et al., Nature Clinical Practice Oncology, 2005,2 (6), 315-324；Verna et al.,Cancer and Metastasis Reviews,2003,22,423-434).In addition, JAK/STAT signal paths are to making The generation and differentiation of hemocytoblast, proinflammatory and anti-inflammatory dual regulation, and immune response play an important role (O'Sullivan et al.,Molecular Immunology 2007,44:2497)。

Therefore, all four members of JAK/STAT 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 cell factor swashs using various various forms of JAK Enzyme (O'Sullivan et al., Mol.Immunol, 2007,44:2497；Murray J.,Immunol,2007,178: 2623), in antagonism family different choice jak kinase, lead to treat the related disease of the specific cells factor or JAK/STAT The disease of variability or polymorphism correlation is probably useful in road.

Rheumatoid arthritis (RA) is a kind of autoimmune disease characterized by chronic joint inflammation.Take JAK suppressions The patient with rheumatoid arthritis of preparation shows the 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 make specific JAK sub- The micromolecular inhibitor of type inactivation can not only mitigate RA clinical symptoms, can also suppress those and promote being permitted for RA disease progressions Undue regulation (" the Inhibitors of JAK for the treatment of rheumatoid of more proinflammatory cytokines arthritis:rationale and clinical data.”Clin.Invest.(2012)2(1),39–47)。

STAT3 or STAT5 sustained activation has been proved to be present in many entity human tumours, including lacteal tumor, pancreas Knurl, prostate tumor, ovarioncus and liver cancer, while exist 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 comes from it is each STAT3 (Mohamad Bassam Sonbol, Belal Firwana, Ahmad in the human tumor cell line of kind entity tumor Zarzour,Mohammad Morad,Vishal Rana and Ramon V.Tiu“Comprehensive review of JAK inhibitors in myeloproliferative neoplasms.”Therapeutic Advances in Hematology 2013,4(1),15-35；Hedvat M,Huszar D,Herrmann A,Gozgit J M,Schroeder A,Sheehy A,et al.“The JAK2inhibitor AZD1480potently blocks Stat3signaling and oncogenesis in solid tumors.”Cancer Cell2009；16(6):487–97.).Therefore, jak kinase is suppressed Treatment to these diseases plays beneficial effect.

Know clearly, kinases inhibitor gathers 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, immunodepressant that it can be as 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 other treatment caused by immune response (for example, fash, contact dermatitis or diarrhoea), etc..This Compound, composition and the method for invention description directly correspond to these needs and other purposes.

Abstract of invention

Suppress the invention provides one kind, adjust and/or regulate and control one or more protein kinases, as jak kinase, FLT3 swash The compound of enzyme and Aurora A activity, for treating proliferative diseases, autoimmune disease, anaphylactia, inflammatory disease Disease, graft rejection and their complication.Present invention provides the method for preparing these compounds, 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, change of the invention 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, and the Kinase Selectivity of optimization, in pharmacokinetic trial in animal body Show good absorption and higher bioavilability.In addition, the compounds of this invention also has more excellent membrane permeability, fit In local administration, and dissolubility is preferable, therefore has more excellent druggability.

Specifically：

On the one hand, the present invention relates to the alloisomerism of compound shown in compound or formula (I) of the one kind as 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 C₇-C₁₂Spiral shell bicyclic alkyl, C₇-C₁₂Condensed-bicyclic alkyl, 7-12 atom composition The miscellaneous bicyclic group of spiral shell or the 7-12 former molecular miscellaneous bicyclic alkyl of fusion, wherein, Z is optionally by 1,2,3,4 or 5 R³Group Substituted；

Z¹For H, C₁-C₁₂Alkyl, C₃-C₁₂Cycloalkyl or 3-12 former molecular heterocyclic radical, wherein, Z¹Optionally by 1, 2nd, 3,4 or 5 R⁴Group is substituted；

A is indazolyl or Pyrazolopyridine base, wherein, A is optionally by 1,2,3,4 or 5 R⁵Group is substituted；

W is N；

R¹For 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-OR^c、-(CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-OC (=O) R⁶、-O(CR⁷R⁸)_n-R⁶、-N(R^c) C (=O) R⁶、-(CR⁷R⁸)_nC (=O) OR^c、-(CR⁷R⁸)_nC (=O) NR^aR^b,-C (=NR^c)NR^aR^b、-N(R^c) C (=O) NR^aR^b、-N(R^c)S (=O)_mR⁶Or-S (=O)₂NR^aR^b, wherein, R¹Optionally by 1,2,3,4 or 5 R⁹Group is substituted；

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-OR^c、-(CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-S (=O)₂R⁶,-OC (=O) R⁶、-O(CR⁷R⁸)_n-R⁶、-O(CR⁷R⁸)_n-OR^c、-N(R^c) C (=O) R⁶、-(CR⁷R⁸)_nC (=O) OR^c、- (CR⁷R⁸)_nC (=O) NR^aR^b,-C (=NR^c)NR^aR^b、-N(R^c) C (=O) NR^aR^b、-N(R^c) S (=O)_mR⁶Or-S (=O)₂NR^aR^b, or two adjacent R³, and together with the atom that they are connected, form C₃-C₁₂Cycloalkyl or 3-12 atom composition Heterocycloalkyl, wherein, above-mentioned each substituent is individually optionally by 1,2,3,4 or 5 R⁹Group is substituted；

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-C₁₂Aryl, 3-12 former molecular heterocyclic radical ,- (C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical), 5-12 former molecular heteroaryl ,-(CR⁷R⁸)_n-OR^c、- (CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-OC (=O) R⁶、-O(CR⁷R⁸)_n-R⁶、-N(R^c) C (=O) R⁶、-(CR⁷R⁸)_nC (=O) OR^c、-(CR⁷R⁸)_nC (=O) NR^aR^b,-C (=NR^c)NR^aR^b、-N(R^c) C (=O) NR^aR^b、-N(R^c) S (=O)_mR⁶Or-S (= O)₂NR^aR^b, wherein, above-mentioned each R⁴And R⁵Individually optionally by 1,2,3,4 or 5 R⁹Group is substituted；

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 substituted；

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 that they are connected, form C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocycle Base or 5-12 former molecular heteroaryl groups, wherein, above-mentioned each substituent is individually optionally by 1,2,3,4 or 5 R⁹Base Group is substituted；

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 R^a、R^bAnd R^cIt 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 heteroaryl or-(C₁-C₄Alkylene Base)-(5-10 former molecular heteroaryl), or R^aAnd R^b, and together with the nitrogen-atoms being connected with them, form 3-8 atom The heterocyclyl groups of composition, wherein, above-mentioned each substituent 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 substituent of alkyl amino is substituted；

Each m independently is 1 or 2；With

Each n independently is 0,1,2,3 or 4.

In other embodiments, Z C₈-C₁₁Spiral shell bicyclic alkyl, C₈-C₁₀Condensed-bicyclic alkyl, 8-11 atom group Into the miscellaneous bicyclic group of spiral shell or the 8-10 former molecular miscellaneous bicyclic alkyl of fusion, wherein, Z is optionally by 1,2,3 or 4 R³Group Substituted.

In some embodiments, Z¹For H, C₁-C₆Alkyl, C₃-C₆Cycloalkyl or 3-6 former molecular heterocyclic radical, its In, Z¹Optionally by 1,2 or 3 R⁴Group is substituted.

In other embodiments, R¹For H, F, Cl, CN, N₃、C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆ Haloalkyl, C₁-C₆Alkoxy, C₃-C₆Cycloalkyl, 3-6 former molecular heterocyclic radical ,-(CR⁷R⁸)_n-OR^c、-(CR⁷R⁸)_n- NR^aR^b,-C (=O) R⁶、-(CR⁷R⁸)_nC (=O) NR^aR^bOr-S (=O)₂NR^aR^b, wherein, R¹Optionally by 1,2 or 3 R⁹Group Substituted.

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-OR^c、-(CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-S (=O)₂R⁶、-O(CR⁷R⁸)_n-R⁶、-O(CR⁷R⁸)_n-OR^c、-N(R^c) C (=O) R⁶、-(CR⁷R⁸)_nC (=O) NR^aR^b、-N(R^c) C (=O) NR^aR^b、-N(R^c) S (=O)_mR⁶Or-S (=O)₂NR^aR^b, or two adjacent R³, and together with the atom that they are connected, shape Into C₃-C₆Cycloalkyl or 3-6 former molecular heterocycloalkyl, wherein, above-mentioned each substituent is individually optionally by 1,2 or 3 Individual R⁹Group is substituted.

In other 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), the molecular heteroaryl of 5-6 original ,- (CR⁷R⁸)_n-OR^c、-(CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-OC (=O) R⁶、-O(CR⁷R⁸)_n-R⁶、-N(R^c) C (=O) R⁶、- (CR⁷R⁸)_nC (=O) OR^c、-(CR⁷R⁸)_nC (=O) NR^aR^b、-N(R^c) S (=O)_mR⁶Or-S (=O)₂NR^aR^b, wherein, each R⁴And R⁵ Individually optionally by 1,2 or 3 R⁹Group is substituted.

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, each R⁶It is independent Optionally by 1,2 or 3 R⁹Group is substituted.

In other 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 form C together with the carbon atom being connected with them₃-C₆Cycloalkyl, phenyl, 3-6 former molecular heterocycle Base or 5-6 former molecular heteroaryl groups, wherein, above-mentioned each substituent is individually optionally by 1,2 or 3 R⁹Group is taken Generation.

In some 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 forms 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 R^a、R^bAnd R^cIt 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 heteroaryl or- (C₁-C₂Alkylidene)-(5-6 former molecular heteroaryl), or R^aAnd R^b, and together with the nitrogen-atoms being connected with them, formed 3-6 former molecular heterocyclyl groups, wherein, above-mentioned each substituent 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 substituent of alkyl amino is substituted.

In some embodiments, Z is following subformula：

Or their stereoisomer, wherein, each X, X ', X²And X³It is separately CH₂, NH or O, condition be to work as X² When being O, X³It is not O；Each minor structure or its stereoisomer shown in formula (Z-1)~(Z-54) are individually optionally by 1,2 or 3 R³Group is substituted.

In other embodiments, A is following subformula：

Wherein, the minor structure shown in formula (M), (N), (Q) or (T) is individually optionally by 1,2 or 3 R⁵Group is substituted.

In some embodiments, Z¹For H, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

In other embodiments, R¹For 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-OR^c、-(CR⁷R⁸)_n- NR^aR^b,-C (=O) R⁶、-(CR⁷R⁸)_nC (=O) NR^aR^bOr-S (=O)₂NR^aR^b, wherein, R¹Optionally by 1,2 or 3 R⁹Group Substituted.

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-OR^c、-(CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-S (=O)₂R⁶、-O(CR⁷R⁸)_n-R⁶、-O(CR⁷R⁸)_n-OR^c、-N(R^c) C (=O) R⁶、-(CR⁷R⁸)_nC (=O) NR^aR^b、-N(R^c) S (=O)_mR⁶ Or-S (=O)₂NR^aR^b, wherein, each R³Individually optionally by 1,2 or 3 R⁹Group is substituted.

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 substituted.

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 further is 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, handle, 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 other embodiments, protein kinase mediated disease of the present invention is proliferative diseases, autologous exempted from Epidemic disease, anaphylactia, inflammatory disease or graft rejection.

In other embodiments, protein kinase mediated disease of the present invention is cancer, polycythemia vera Disease, primary thrombocytosis, it is acute myelocytic leukemia, ALL, myelofibrosis, acute Myelocytic leukemia, chronic granulocytic leukemia, ALL, COPD, asthma, it is System property lupus erythematosus, skin lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren syndrome, psoriasis, type i diabetes, exhale Inhale road anaphylactia, nasosinusitis, eczema, measles, food hypersenstivity, insect venom allergies, inflammatory bowel disease, Crohn disease, class wind Wet arthritis, juvenile arthritis, psoriasis arthropathica, organ-graft refection, tissue transplantation rejection or cell transplantation row Reprimand.

On the other hand, the purposes the present invention relates to compound disclosed by the invention or pharmaceutical composition in medicine 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 method for preparation, separation and the purifying of the compound included the present invention relates to formula (I).

Biological results show that compound provided by the invention can be used as preferable kinases inhibitor.

Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they Be not in contradiction.In addition, 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 make more specific complete description below.

Detailed description of the invention book

Definition and general terms

It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation enclosed.This Invention is intended to cover all 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.The one of document, patent and the similar material combined Or more it is different from the application or in the case of contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be defined by the application.

It will further be appreciated that some features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also be provided in combination in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with arbitrarily suitable sub-portfolio in single embodiment.

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 versions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.In addition, 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 is obvious conflict unless otherwise indicated or in context, article " one " used herein, " one (kind) " " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to has more than one Component be taken into account in the embodiment of the embodiment and use or use.

Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by It is people to try object.

Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.

Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded from otherwise Content.

" stereoisomer " refers to there is identical chemical constitution, but the spatially different change of arrangement mode of atom or group Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..

" chirality " be with its mirror image can not overlapping property molecule；And " achirality " refer to can be with overlapping with its mirror image Molecule.

" enantiomter " refers to that two of a compound can not isomers that is overlapping but being 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 mixes Compound can be operated such as electrophoresis and chromatogram, such as HPLC by high resolution analysis to separate.

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, which have, rotates the plane of linearly polarized light Ability.When describing optically active compound, 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 rotated for linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix is (+) or d compound is dextrorotation.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or stereospecificity when, It 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, such as (R)-, (S)-or (R, S)-configuration be present.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of there is at least 50% enantiomeric excess, at least at least 60% enantiomeric excess, 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 one in possible isomers or they Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits .Chiral synthon or chiral reagent can be used to prepare for optically active (R)-or (S)-isomers, or be torn open using routine techniques Point.If compound contains a double bond, substituent may be E or Z configurations；If contain dibasic cycloalkanes in compound Base, the substituent 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 Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production 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(2^ndEd.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)。

What term " dynamic isomer " or " tautomeric form " referred to have different-energy can build (low by low 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, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include by proton migration the mutual inversion of phases that carries out, 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 carried 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.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one 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 substituted by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of 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 of structure it is specific Substituent is substituted.Unless otherwise indicated, the group of a substitution can have a substituent to may replace group is each Position substituted.When more than one position can be substituted by the one or more selected from specific group in given structural formula Base is substituted, then substituent with identical or different can substitute in each position.

Term " unsubstituted ", represent specified group without substituent.

Term " optionally by ... substitutes ", use can be exchanged with term " unsubstituted or by ... .. substitutes ", i.e., The structure is unsubstituted or substituted by one or more substituents of the present invention, substituent bag of the present invention Include, but be not limited to D, F, Cl, Br, I, CN, N₃、-CN、-NO₂、-OH、-SH、-NH₂,-C (=O) CH₂CN、-(CR⁷R⁸)_n-OR^c、- (CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-S (=O)₂R⁶,-OC (=O) R⁶、-O(CR⁷R⁸)_n-R⁶、-O(CR⁷R⁸)_n-OR^c、-N(R^c)C (=O) R⁶、-(CR⁷R⁸)_nC (=O) OR^c、-(CR⁷R⁸)_nC (=O) NR^aR^b,-C (=NR^c)NR^aR^b、-N(R^c) C (=O) NR^aR^b、- N(R^c) S (=O)_mR⁶,-C (=O) NR^aR^b, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, cycloalkanes Base, heterocyclic radical, aryl and heteroaryl etc., wherein, R⁶、R⁷、R⁸、R^a、R^b、R^c, m and n there is definition as described in the present invention.

In addition, it is necessary to explanation, unless otherwise explicitly point out, used describing mode in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, it both may be used To refer in different groups, do not influence mutually, can also represent in phase between expressed specific option between same-sign In same group, do not influenceed mutually between expressed specific option between same-sign.

In each several part of this specification, the substituent that the present invention discloses compound discloses according to radical species or scope.It is special Do not point out, the present invention includes each independent sub-combinations thereof of each member of 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 present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.If for example, the structure needs linking group and for being somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then is 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 ", expression contain 1 to 20 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group, wherein, the substituent institute that the alkyl group can be described optionally by one or more present invention Substitution.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In 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 Optionally it can be substituted by the substituent that one or more present invention describe.

The example of alkyl group includes, but is not limited to, methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-propyl (n- Pr、-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i-Bu ,- CH₂CH(CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), 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..

Term " alkylidene " represents to remove from the straight or branched alkyl of saturation the saturation obtained by two hydrogen atoms 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 " represents the straight or branched monovalent hydrocarbon containing 2-12 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 substituent stated is substituted, and it includes " cis " and " tans " positioning, 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 includes, but is not limited to, vinyl (- CH =CH₂), pi-allyl (- CH₂CH=CH₂) etc..What the alkenyl group can be described optionally by one or more present invention Substituent is substituted.

Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 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 substituent stated is substituted.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 includes, 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, it is former to contain 1-4 carbon for alkoxy base Son；In other embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally by one The substituent that individual or multiple present invention describe is substituted.

The example of alkoxy base includes, 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 " represent alkyl, and alkenyl or alkoxy base are by one Individual or multiple halogen atoms are substituted, and such example includes, but is not limited to, trifluoromethyl, trifluoromethoxy etc..

Term " carbocylic radical " or " carbocyclic ring " represented containing 3-12 carbon atom, monovalent or multivalence nonaromatic saturation Or unsaturated monocyclic, the bicyclic or three-ring system in part.It is double that carbon bicyclic group includes spiral shell carbon bicyclic group, fusion carbon bicyclic group and bridge carbon Ring group, suitable carbocylic radical group include, 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 monovalent or multivalence saturation 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, include C₇-C₁₂Spiral shell bicyclic alkyl, C₇-C₁₂Condensed-bicyclic alkyl and C₇-C₁₂Bridge bicyclic alkyl；In other reality Apply in scheme, cycloalkyl C₈-C₁₁Cycloalkyl, include C₈-C₁₁Spiral shell bicyclic alkyl and, C₈-C₁₁Condensed-bicyclic alkyl and C₈-C₁₁It is thick Close bicyclic alkyl.The group of naphthene base can be independently unsubstituted or by one or more substituent described in the invention Substituted.

Term " heterocyclic radical " and " heterocycle " are used interchangeably here, 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 be optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can be optionally 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 substituted by one or more substituents described in the invention.

In some embodiments, heterocyclic radical is 3-8 former molecular heterocyclic radical, refer to include 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 substituents described in the invention Generation.

In other embodiments, heterocyclic radical is 3-6 former molecular heterocyclic radical, refers to include 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.The former molecular heterocyclyl groups of described 3-6 can be optional Ground is substituted by one or more substituents described in the invention.

In other embodiments, heterocyclic radical is 7-12 former molecular heterocyclic radical, is referred to former comprising 7-12 ring Son, monovalent or multivalence, the miscellaneous bicyclic group of the undersaturated spiral shell of saturation or part, the miscellaneous bicyclic group of fusion 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 be 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 radical 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 The individual molecular heterocyclyl groups of original optionally can be substituted by one or more substituents described in the invention.

In other embodiment, heterocyclic radical is the 7-12 former molecular miscellaneous bicyclic group of spiral shell, is referred 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 be 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 former molecular miscellaneous bicyclic group of spiral shell of described 7-12 includes 7- The miscellaneous bicyclic group of spiral shell of 12 molecular saturations of original is (i.e.：The 7-12 former molecular miscellaneous bicyclic alkyl 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 former molecular miscellaneous bicyclic group group of spiral shell of described 7-12 can be optionally by this one or more hair Bright described substituent is substituted.

Also in other embodiments, heterocyclic radical is the 8-11 former molecular miscellaneous bicyclic group of spiral shell, refers to include 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 be 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 former molecular miscellaneous bicyclic group of spiral shell of described 8-11 includes 8- The miscellaneous bicyclic group of spiral shell (the 8-11 former molecular miscellaneous bicyclic alkyl of spiral shell) and the undersaturated spiral shell in part of 11 molecular saturations of original 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 former molecular miscellaneous bicyclic group group of spiral shell of described 8-11 can be optionally by one or more described in the invention Substituent substituted.

Also in other embodiment, heterocyclic radical is the 7-12 former molecular miscellaneous bicyclic group of fusion, refers to include 7- 12 annular atoms, unit price or multivalence, saturation or part is undersaturated, the nonaromatic miscellaneous bicyclic group of fusion, wherein at least One annular atom is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, the 7-12 former molecular miscellaneous bicyclic group of fusion can be carbon Base or nitrogen base, and-CH₂- group can be 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.The former molecular fusion of described 7-12 is miscellaneous bicyclic Base includes the miscellaneous bicyclic group of fusion of 7-12 former molecular saturation (i.e.：The 7-12 former molecular miscellaneous bicyclic alkyl of fusion) and The undersaturated miscellaneous bicyclic group of fusion in part.The example of the 7-12 former molecular miscellaneous bicyclic group of fusion 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- The molecular miscellaneous bicyclic group group of fusion of 12 originals optionally can be taken by one or more substituents described in the invention Generation.

Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " and " condensed ring radical " are used interchangeably here, 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 substituent thereon).

Term " loop coil base ", " loop coil ", " spiral shell bicyclic group " or " spiral shell is bicyclic " are used interchangeably here, refer to unit price or more Valency, the undersaturated member ring systems of saturation or part, one of ring is originating from specific ring carbon atom on another ring.For example, As described by following formula a, the member ring systems (ring B and B ') of a saturation are 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 " loop coil " 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 substituents described in the invention Substituted.

Term " Heterocyclylalkyl " refers to that the saturation of the unit price containing 3-12 annular atom or multivalence is monocyclic, bicyclic or three rings System, 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 be 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 substituent of invention is substituted.

In some embodiments, Heterocyclylalkyl is 7-12 former molecular Heterocyclylalkyl, is referred to containing 7-12 ring Atom, monovalent or multivalence, the miscellaneous bicyclic alkyl of spiral shell, the miscellaneous bicyclic alkyl of fusion or the miscellaneous bicyclic alkyl of bridge of saturation, 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 be 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 substituents described in the invention are substituted.

In some embodiments, Heterocyclylalkyl is 3-6 former molecular Heterocyclylalkyl, is referred to former containing 3-6 ring Son, monovalent or multivalence, the heterocyclic radical of saturation, wherein at least one annular atom is selected from nitrogen, sulphur or oxygen atom.Unless say in addition Bright, Heterocyclylalkyl can be carbon-based or nitrogen base, and-CH₂- group can be 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.The former molecular heterocycloalkyl of described 3-6 can be retouched optionally by one or more present invention The substituent stated is substituted.

In other embodiments, Heterocyclylalkyl is the 7-12 former molecular miscellaneous bicyclic alkyl of spiral shell, is referred to containing 7- 12 annular atoms, unit price or multivalence, the saturation miscellaneous bicyclic alkyl of spiral shell, wherein at least one annular atom be selected from nitrogen, sulphur or oxygen Atom.Unless otherwise indicated, Heterocyclylalkyl can be carbon-based or nitrogen base, and-CH₂- group can be optionally by-C (=O)-replaces 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..The former molecular spiral shell of described 7-12 is miscellaneous Bicycloalkyl radicals optionally can be substituted by one or more substituents described in the invention.

In other embodiments, Heterocyclylalkyl be 7-12 it is former it is molecular condense miscellaneous bicyclic alkyl, refer to containing 7-12 annular atom, unit price or multivalence, the saturation miscellaneous bicyclic alkyl of fusion, wherein at least one annular atom be 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 example of the 7-12 former molecular miscellaneous bicyclic alkyl of fusion 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.The former molecular miscellaneous bicycloalkyl radicals of fusion of described 7-12 can be optionally by this one or more hair Bright described substituent is substituted.

In other embodiments, Heterocyclylalkyl be 8-10 it is former it is molecular condense miscellaneous bicyclic alkyl, refer to containing 8-10 annular atom, unit price or multivalence, the miscellaneous bicyclic alkyl of fusion of saturation, wherein at least one annular atom is selected from nitrogen, sulphur Or oxygen atom.Unless otherwise indicated, the 8-10 former molecular miscellaneous bicyclic alkyl of fusion can be carbon-based or nitrogen base, and-CH₂- Group can be 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 example of the 8-10 former molecular miscellaneous bicyclic alkyl of fusion includes, but unlimited 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 former molecular miscellaneous bicycloalkyl radicals of fusion can be with Optionally substituted by one or more substituents 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 the molecular carbocylic radical group of 10 originals.

Used term is " undersaturated " in the present invention represents to contain one or more degrees of unsaturation in group.

Term " hetero atom " refers to O, S, N, P and Si, includes the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the 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 (NR in the pyrrolidinyl substituted as N-).

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 to contain 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 include 3-7 original 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 ", which exchanges, to be used.The example of aromatic yl group can include phenyl, naphthyl and anthryl.The aromatic yl group can with individually optional Substituted by one or more substituents described in the invention.

Term " heteroaryl " represents to contain 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 more Individual hetero atom, each of which member ring systems include 5-7 former molecular ring, and have one or more tie points and molecule remaining Part is connected.Term " heteroaryl " can exchange use with term " hetero-aromatic ring " or " heteroaromatics ".In some embodiment party In case, heteroaryl is comprising 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-12. In other embodiments, heteroaryl is to be formed comprising 1,2,3 or 4 heteroatomic 5-10 atom for being independently selected from O, S and N Heteroaryl.Also in some embodiments, heteroaryl is to include 1,2,3 or 4 heteroatomic 5-6 for being independently selected from O, S and N The individual molecular heteroaryl of original.The heteroaryl groups are optionally taken by one or more substituents described in the invention Generation.The example of heteroaryl groups includes, 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 that comprising at least two hetero atoms and wherein at least one be 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.

Term " carboxyl ", no matter it is single use or is used in conjunction with other terms, such as " carboxyalkyl ", expression-CO₂H；Term " carbonyl ", no matter it is single use or is 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 substituted by one or two alkyl group.Some of embodiments are 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 includes, but is not limited to, N- methylaminos, N- ethylaminos, N, N- Dimethylamino, N, N- lignocaines etc..

Term " fragrant amino " represents that amino group is substituted by one or two aromatic yl group, and such example includes, but It is not limited to N- phenylaminos.Some of embodiments are that the aromatic ring in fragrant amino can be further substituted.

Term " aminoalkyl " includes the C substituted by one or more amino₁-C₁₀Straight or branched alkyl group.Its In some embodiments be that aminoalkyl is the C substituted by one or more amino groups₁-C₆" aminoalkyl of lower level ", Such example includes, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.

As described in the invention, the member ring systems formed in substituent one key connection of picture to the ring at center are (such as formula b institutes Show) represent substituent any commutable position in the member ring systems and can substitute.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, a connecting key be connected to formed on the center of ring member ring systems (as shown in formula h, its In, X and X ' they are 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 represented 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 substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected with amino group to block Or the feature of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, t-butyl formate (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent of base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refers to that the substituent of carboxyl is used for blocking or protect the feature of carboxyl, in general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description of group in general 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, represent a compound and be converted into compound shown in formula (I) in vivo. Such conversion is hydrolyzed or is that precursor structure is influenceed through enzymatic conversion in blood or tissue in blood by pro-drug.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C₁-C₂₄) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.Completely begged on pro-drug 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 Adopt as stating and experimentally characterized.Such product can be by, by aoxidizing, being reduced, water to drug compound The methods of solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc., obtains.Correspondingly, the present invention includes compound Metabolite, including by the present invention compound metabolite caused by a period of time is fully contacted with mammal.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:It is 1-19. described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, 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 obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C₁-C₄Alkyl)₄Salt.The present invention, which is also intended to contemplate, to be appointed The quaternary ammonium salt that the compound for the group what includes N is formed.Water-soluble or oil-soluble or dispersion product can be by quaternized Effect obtains.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises 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, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.

Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (slow down or prevent 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 (such as stablizing perceptible symptom) or physiologically (such as stablizes body Parameter) or above-mentioned two aspects regulation disease or illness.In other embodiments, " treatment " refers to prevention or delay 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 as caused by tissue damaged or destruction responds, 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 the infection of pathogenic organism and virus and non-infectious mode, such as heart Wound or Reperfu- sion after muscle infarction or apoplexy, to the immune response and autoimmune response of exotic antigen.Therefore, this can be used 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 classical response, autoimmune disease and the delayed type hypersensitivity, DTH to exotic antigen Response (cell-mediated by T-).The repulsion of chronic inflammatory disease, transplanting solid tissue and organ is (such as kidney and bone-marrow transplantation Repel) and graft versus host disease (GVHD) be other examples of specific system of defense inflammatory reaction.

" autoimmune disease " used in the present invention refers to and body fluid or cell-mediated to body itself component response The set of any disease of related tissue damage.

" allergy " used in the present invention refers to that any symptom, histologic lesion or the function of organization that produce allergy lose.Such as " arthritis disease " used in the present invention refers to any characterized by being attributable to various etiologic etiological arthritis damages Disease." dermatitis " refers to the disease of skin characterized by being attributable to various etiologic etiological scytitises as used in the present invention Extended familys in any one." graft rejection " refers to lose 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.The treatment method of the present invention includes being used for the method for treating the disease related to inflammatory cell activation.

Term " cancer " and " cancer " refer to or described the physiology in patient generally characterized by cell growth out of control Illness." tumour " includes one or more cancer cells.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 Uterine cancer, salivary-gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, carcinoma of vulva, thyroid gland Cancer, liver cancer (hepatic carcinoma), cancer of anus, carcinoma of penis and head and neck cancer.

The description of the compound of the present invention

The invention discloses a kind of novel compound, protein kinase activity, particularly jak kinase, FLT3 can be used as to swash The inhibitor of enzyme and Aurora A activity.Compound as kinases inhibitor can be used for treatment and unsuitable albumen Kinase activity, particularly unsuitable jak kinase, FLT3 kinases and the related disease of Aurora A activity, such as treatment with Prevention is related to the disease of jak kinase, FLT3 kinases and the Aurora A mediation of signal path.Such disease includes proliferative Disease, autoimmune disease, anaphylactia, inflammatory disease, graft rejection and their complication.Especially, it is of the invention Compound can be used for treating 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, lupus nephritis, dermatomyositis, dry synthesis Sign, 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 one or more protein kinases is shown with stronger suppression is lived Property.

Z¹For H, C₁-C₁₂Alkyl, C₃-C₁₂Cycloalkyl or 3-12 former molecular heterocyclic radical, wherein, work as Z¹When not being H, Z¹Optionally by 1,2,3,4 or 5 R⁴Group is substituted；

W is N；

R¹For 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-OR^c、-(CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-OC (=O) R⁶、-O(CR⁷R⁸)_n-R⁶、-N(R^c) C (=O) R⁶、-(CR⁷R⁸)_nC (=O) OR^c、-(CR⁷R⁸)_nC (=O) NR^aR^b,-C (=NR^c)NR^aR^b、-N(R^c) C (=O) NR^aR^b、-N(R^c)S (=O)_mR⁶Or-S (=O)₂NR^aR^b, 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 substituted；

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-OR^c、-(CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-S (=O)₂R⁶,-OC (=O) R⁶、-O(CR⁷R⁸)_n-R⁶、-O(CR⁷R⁸)_n-OR^c、-N(R^c) C (=O) R⁶、-(CR⁷R⁸)_nC (=O) OR^c、- (CR⁷R⁸)_nC (=O) NR^aR^b,-C (=NR^c)NR^aR^b、-N(R^c) C (=O) NR^aR^b、-N(R^c) S (=O)_mR⁶Or-S (=O)₂NR^aR^b, or two adjacent R³, and together with the atom that they are connected, form C₃-C₁₂Cycloalkyl or 3-12 atom composition Heterocycloalkyl, wherein, above-mentioned each substituent, be not H, F, Cl, Br, I, NO₂, CN and N₃When, individually optionally by 1,2, 3rd, 4 or 5 R⁹Group is substituted；

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-C₁₂Aryl, 3-12 former molecular heterocyclic radical ,- (C₁-C₄Alkylidene)-(3-12 former molecular heterocyclic radical), 5-12 former molecular heteroaryl ,-(CR⁷R⁸)_n-OR^c、- (CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-OC (=O) R⁶、-O(CR⁷R⁸)_n-R⁶、-N(R^c) C (=O) R⁶、-(CR⁷R⁸)_nC (=O) OR^c、-(CR⁷R⁸)_nC (=O) NR^aR^b,-C (=NR^c)NR^aR^b、-N(R^c) C (=O) NR^aR^b、-N(R^c) S (=O)_mR⁶Or-C (=O) NR^aR^b, wherein, as above-mentioned each R⁴And R⁵It is not H, F, Cl, Br, I, NO₂, CN and N₃When, each R⁴And R⁵Respectively optionally by 1,2,3, 4 or 5 R⁹Group is substituted；

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 not being H, Each R⁶Individually optionally by 1,2,3,4 or 5 R⁹Group is substituted；

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 that they are connected, form C₃-C₁₂Cycloalkyl, C₆-C₁₂Aryl, 3-12 former molecular heterocycle Base or 5-12 former molecular heteroaryl groups, wherein, above-mentioned each substituent, it is not H, F, Cl, Br, I, NO₂, CN and N₃When, Individually optionally by 1,2,3,4 or 5 R⁹Group is substituted；

Each R^a、R^bAnd R^cIt 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 heteroaryl or-(C₁-C₄Alkylene Base)-(5-10 former molecular heteroaryl), or R^aAnd R^b, and together with the nitrogen-atoms being connected with them, form 3-8 atom The heterocyclyl groups of composition, wherein, above-mentioned each substituent, not for H when, 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 substituent institute of alkyl amino Substitution；

Each m independently is 1 or 2；With

Each n independently is 0,1,2,3 or 4.

In other embodiments, Z is following subformula：

In some embodiments, Z¹For H, C₁-C₆Alkyl, C₃-C₆Cycloalkyl or 3-6 former molecular heterocyclic radical, its In, work as Z¹When not being H, Z¹Optionally by 1,2 or 3 R⁴Group is substituted.

In other embodiments, Z¹For H, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

In some embodiments, A is following subformula：

In some embodiments, R¹For 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-OR^c、-(CR⁷R⁸)_n- NR^aR^b,-C (=O) R⁶、-(CR⁷R⁸)_nC (=O) NR^aR^bOr-S (=O)₂NR^aR^b, wherein, work as R¹It is not H, F, Cl, N₃During with CN, R¹Optionally by 1,2 or 3 R⁹Group is substituted.

In other embodiments, R¹For 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-OR^c、-(CR⁷R⁸)_n- NR^aR^b,-C (=O) R⁶、-(CR⁷R⁸)_nC (=O) NR^aR^bOr-S (=O)₂NR^aR^b, wherein, work as R¹It is not H, F, Cl, N₃During with CN, R¹Optionally by 1,2 or 3 R⁹Group is substituted.

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-OR^c、-(CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-S (=O)₂R⁶、-O(CR⁷R⁸)_n-R⁶、-O(CR⁷R⁸)_n-OR^c、-N(R^c) C (=O) R⁶、-(CR⁷R⁸)_nC (=O) NR^aR^b、-N(R^c) C (=O) NR^aR^b、-N(R^c) S (=O)_mR⁶Or-S (=O)₂NR^aR^b, or two adjacent R³, and together with the atom that they are connected, shape Into C₃-C₆Cycloalkyl or 3-6 former molecular heterocycloalkyl, wherein, above-mentioned each substituent, it is not H, F, Cl, NO₂、CN And N₃When, individually optionally by 1,2 or 3 R⁹Group is substituted.

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-OR^c、-(CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-S (=O)₂R⁶、-O(CR⁷R⁸)_n-R⁶、-O(CR⁷R⁸)_n-OR^c、-N(R^c) C (=O) R⁶、-(CR⁷R⁸)_nC (=O) NR^aR^b、-N(R^c) S (=O)_mR⁶ Or-S (=O)₂NR^aR^b, wherein, work as R³It is not H, F, Cl, NO₂, CN and N₃When, each R³Individually optionally by 1,2 or 3 R⁹Group Substituted.

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), the molecular heteroaryl of 5-6 original ,- (CR⁷R⁸)_n-OR^c、-(CR⁷R⁸)_n-NR^aR^b,-C (=O) R⁶,-OC (=O) R⁶、-O(CR⁷R⁸)_n-R⁶、-N(R^c) C (=O) R⁶、- (CR⁷R⁸)_nC (=O) OR^c、-(CR⁷R⁸)_nC (=O) NR^aR^b、-N(R^c) S (=O)_mR⁶Or-S (=O)₂NR^aR^b, 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 substituted.

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 substituted.

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 For H when, each R⁶Individually optionally by 1,2 or 3 R⁹Group is substituted.

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 form C together with the carbon atom being connected with them₃-C₆Cycloalkyl, phenyl, 3-6 former molecular heterocycle Base or 5-6 former molecular heteroaryl groups, wherein, above-mentioned each substituent, it is not H, F, Cl, Br, I, NO₂, CN and N₃When, Individually optionally by 1,2 or 3 R⁹Group is substituted.

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 forms 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 R^a、R^bAnd R^cIt 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 heteroaryl or- (C₁-C₂Alkylidene)-(5-6 former molecular heteroaryl), or R^aAnd R^b, and together with the nitrogen-atoms being connected with them, formed 3-6 former molecular heterocyclyl groups, wherein, above-mentioned each substituent, not for H when, individually optionally by 1,2 or 3 independence Selected from F, Cl, CN, N₃、OH、NH₂、C₁-C₄Alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy or C₁-C₄The substituent of alkyl amino Substituted.

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 production Thing, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.

The present invention disclose compound can contain asymmetry or chiral centre, therefore can different stereoisomer forms deposit .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 The part of the present invention.

In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and disclose compound as the present invention and be included in the invention.When Spatial chemistry is expressed the wedge-shaped line of reality (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body clearly and defines 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 Its mammal treated is compatible chemically and/or in toxicology.In other embodiments, the salt is not necessarily pharmacy Upper acceptable salt, can be used to prepare and/or purify 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, such as 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 of salt can be obtained by its derivative to be included such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.

The organic acid of 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 that salt can be obtained by its derivative includes, such as the metal of the I races of ammonium salt and periodic table to XII races. 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.

The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalescence or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate etc.) reaction, or by making the free alkali form and chemistry of these compounds It is prepared by the suitable acid reaction of metered amount.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in appropriate cases, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts：Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.

In addition, compound disclosed by the invention including their salt, with their hydrate forms or can also include it The form of solvent (such as ethanol, DMSO, etc.) obtains, 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 provides, which is also intended to, represents these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the formula that there is the compound of isotope enrichment the present invention to provide is described, except one or more Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In radio isotope be present, such as³H、¹⁴C and¹⁸F those compounds, or non radioactive isotope wherein be present, such as²H and¹³C.The compound of such isotope enrichment can be used for metabolism research (to 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 Single photon emission computed tomography (SPECT), or available 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.

In addition, 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 increase or volume requirements reduce or therapeutic index obtains improving band Come.It should be appreciated that the deuterium in the present invention is counted as the substituent 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 substituent of the compounds of this invention is designated as deuterium, The compound has at least 3500 (at each specified D-atoms 52.5% deuterium incorporation), at least for each D-atom specified 4000 (60% deuterium incorporations), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7 The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) The factor.The pharmaceutically useful solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution₂O, acetone-d₆、 DMSO-d₆Those solvates.

On the other hand, the present invention relates to the intermediate for preparing compound shown in formula (I).

On the other hand, the present invention relates to the method for preparation, separation and the purifying of compound shown in formula (I).

On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In 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 treatment by one or more protein kinases, as jak kinase, FLT3 kinases and The disease of Aurora A regulation or the method for disorder, the present invention that the treatment method includes giving mammal effective dose are 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, the present invention relates to compound disclosed by the invention or pharmaceutical composition to prepare treatment disease or disorder 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 are used for the activity of regulatory protein kinases.

Pharmaceutical composition, preparation and the administration of the compounds of this invention

The present invention provides a kind of pharmaceutical composition, and it includes 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 body protein kinase.

It is used to treat it will also be appreciated that some compounds of the present invention can exist in a free form, 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 patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.

Drug pharmaceutical compositions disclosed by the invention can prepare and be packaged as (bulk) form in bulk, wherein extractable safety 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 prepare and be packaged as unit dosage forms, wherein each physically discrete unit contains formula (I) institute of safe and effective amount The compound shown.When being prepared with unit dosage forms, pharmaceutical composition disclosed by the invention can generally contain, for example, 0.5mg to 1g, Or 1mg to 700mg or 5mg to 100mg compound disclosed by the invention.

" pharmaceutically acceptable excipient " means related to form of administration or pharmaceutical composition uniformity used in the present invention Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other into Split-phase is held, and the interaction of the effect of disclosing compound of the invention can be substantially reduced during avoiding that patient be administered and can be caused not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, every kind of excipient must be pharmaceutically acceptable, example Such as, there is sufficiently high purity.

Suitable pharmaceutically acceptable excipient can be different according to selected specific formulation.In addition, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.For example, it may be selected to can help to produce equal one dosage type low temperature Some pharmaceutically acceptable excipient.It may be selected to can help to some pharmaceutically acceptable figurations for producing stabilizer type Agent.May be selected to help to carry when patient be administered or transport it is of the invention disclose compound from an organ of body or partly to Another organ of body or partial some pharmaceutically acceptable excipient.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, stably 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 in preparation existing 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 select the suitable of the appropriate amount for the present 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 The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Known technology, the respective content of these documents are incorporated by reference into the present invention.Except any such as because producing any undesirable life Thing acts on, or with interaction occurs for any other composition in harmful way and pharmaceutically acceptable composition and 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 present invention relates to the technique for preparing pharmaceutical composition, described pharmaceutical composition to include the present invention Open compound and pharmaceutically acceptable excipient, carrier, assistant agent, solvent or combinations thereof, it is each that the technique includes mixing Kind composition.The pharmaceutical composition of compound is disclosed comprising the present invention, can be mixed under such as environment temperature and atmospheric pressure to make It is standby.

Compound disclosed by the invention is usually formulated as being suitable for the formulation that patient is administered by required approach.Example Such as, formulation includes the formulation that those are suitable for following method of administration：(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) local administration, for example, it is 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.

Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the material bag for being resistant to hydrochloric acid in gastric juice effect but dissolving or being disintegrated in intestines 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 surrounds Piece, it can be beneficial to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of material.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses and sweet tablet identical general characteristic.It is multiple Tabletting is by the compressed tablets of more than one press cycles preparation, including multilayer tablet and pressed coated or dry coating tablet.

Tabules can be by one kind that powder, crystallization or granular active component are single or are described with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colouring agent.Fumet and sweetener are particularly useful when forming chewable tablets and lozenge.

Pharmaceutical composition provided by the invention can be provided with soft capsule or hard shell capsules, and it can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section Fill in another section, therefore enclose active component completely.Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shell, It is plastified by adding glycerine, sorbierite or similar polyalcohol.Soft gelatin shell can include 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 Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and supensoid agent in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active component.

Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in 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 The acetal of receiving, such as two (low alkyl group) acetals of low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With with one or more 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 preservative can also be included.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.

Other useful liquid and semisolid dosage form include, but are not limited to include active component provided by the invention and two level 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, can be by the dosage unit preparations microencapsulation of oral administration.It can also be prepared into extending or tieing up The composition of release is held, such as by the way that microparticle material to be coated or be embedded in polymer, wax or the like.

Combination of oral medication provided by the invention can also be carried in the form of liposome, micella, microballoon or nanometer system For.Micella formulation can be prepared with the method that U.S.Pat.No.6,350,458 is described.

Pharmaceutical composition provided by the invention can be provided with the granule and pulvis of non-effervesce or effervesce, to be reconstructed into Liquid dosage form.The pharmaceutically acceptable carrier and excipient used in non-effervescent or pulvis can include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier and excipient used in effervescent or pulvis can wrap Include organic acid and carbon dioxide source.

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.In addition, compound disclosed in this invention can with reality A kind of Biodegradable polymeric used in the control release of existing medicine combines, for example, PLA, poly-epsilon-caprolactone, poly- Hydroxybutyric acid, poe, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and the crosslinking of hydrogel or amphiphilic block are total to Polymers.

Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.

Pharmaceutical composition provided by the invention can with will not to damage other active components of expected therapeutic action common Prepare, or with supplement expected from the material co-formulation that acts on.

Pharmaceutical composition provided by the invention can be by injecting, being transfused or be implanted into parenteral, for local or complete Body is administered.As the parenteral that uses of the present invention include intravenous, intra-arterial, intraperitoneal, intrathecal, intra-ventricle, in urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.

Pharmaceutical composition provided by the invention can be configured to any formulation suitable for parenteral, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such formulation can according to known to the technical staff in pharmaceutical science field conventional method come prepare (referring to Remington:The Science and Practice of Pharmacy, ibid).

Be intended for parenteral pharmaceutical composition can include one or more pharmaceutically acceptable carriers and Excipient, include, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resist micro- life The preservative of thing growth, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and scattered 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 Oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, the middle chain of 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 polyethylene glycol 400), 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 as describing the present invention 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 as describing the present invention. Suitable emulsifying agent includes those that the present invention describes, 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 sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitable complexing agent includes, but unlimited In cyclodextrin, including alpha-cyclodextrin, beta-schardinger dextrin, hydroxypropyl-β-cyclodextrin, Sulfobutylether-beta-schardinger dextrin and sulfobutyl group Ether 7- beta-schardinger dextrins (CyDex,Lenexa,KS)。

Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multiple dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art with practice.

In some embodiments, pharmaceutical composition is provided with instant sterile solution.In other embodiments, Pharmaceutical composition is provided with sterile dried soluble product, including freeze-dried powder agent and hypodermic tablet, and it is used before use Carrier reconstructs.In other embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In other implementation In scheme, pharmaceutical composition is formulated into the sterile dry insolubility product reconstructed before use with carrier.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 delay-, 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, the hydrogel of ester of hydrophilic polymer such as acrylic acid and methacrylic acid, collagen, crosslinking The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and coach.

Suitable 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 Alkene, the copolymer of 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.Pass through inhalation delivery to lung Dry powder composite generally comprises fine powdered compound disclosed in this invention and one or more fine powdered medicines Acceptable excipient on.Pharmaceutically acceptable excipient be especially suitable for dry powder doses is those skilled in the art institute 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, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D₅₀Value (for example, with Laser diffractometry measurement) define.

Aerosol can be prepared by the way that compound disclosed in this invention is suspended or dissolved in liquefied propellant.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 Patient is administered metered dose inhaler (MDI).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 the physical stability of preparation, improve valve characteristic, improve dissolubility, Or improve taste.

Discontinuous paster agent can be prepared into by being suitable for the pharmaceutical composition of cutaneous penetration, it is intended that be kept with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from paster agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).

The pharmaceutical composition for being suitable for locally being administered 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 configure.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 use water or oil matrix to prepare, and generally also contain one or more emulsifying agents, stabilizer, disperse Agent, suspending agent or thickener.

Externally-applied powder can be molded in the presence of arbitrarily suitable powder matrix such as talcum powder, lactose or starch.Drops It can be formulated with the water comprising one or more dispersants, solubilizer, suspending agent or preservative or non-aqueous matrix.

Topical formulations can be by being administered using one or many daily in affected part；The impermeable plastic wound dressing for covering skin is preferential Used.Adhesiveness store system can realize administration that is continuous or extending.

Eyes are treated, or when other organs such as face and skin, the combination as topical ointment or cream can be applied Thing.When being formulated as ointment, compound disclosed in this invention can be used together with paraffin or water-soluble ointment matrix.Or Person, compound disclosed in this invention can be configured to cream together with Oil-in-water emulsifiable paste agent matrix or oil-in-water base.

The purposes of the compounds of this invention and composition

The present invention, which provides, uses compound disclosed in this invention and medicine composite for curing, prevention, or improves by one kind Or multiple protein kinases, such as jak kinase (including JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (also referred to as FLK-2) or The disease or disorderly that Aurora A (including Aurora-A, Aurora-B and Aurora C) behavior is mediated or otherwise influenceed Disorderly or by one or more protein kinases, such as jak kinase (including JAK1, JAK2, JAK3 and TYK2 kinases), FLT3 kinases (also referred to as FLK-2) or Aurora A (including Aurora-A, Aurora-B and Aurora C) behavior mediation or otherwise The method of the disease of influence or one or more symptoms 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 a kind of 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 or disorder are mediated or the disease that otherwise influences or disorder by unsuitable JAK1 kinases behavior One or more symptoms.In other embodiments, the disease, disorder or disease or one or more symptoms of disorder It is related to unsuitable JAK2 kinases behavior.Also in some embodiments, the one of the disease, disorder or disease or disorder Kind or a variety of symptoms are related to unsuitable JAK3 kinases behavior.

In some embodiments, the present invention provides a kind of compound disclosed in this invention or comprising presently disclosed The pharmaceutical composition of compound, for treating, preventing or improve by unsuitable FLT3 kinases behavior mediation or otherwise The disease of influence or disorder are mediated or the disease that otherwise influences or disorder by unsuitable FLT3 kinases behavior One or more symptoms.

In some embodiments, the present invention provides a kind of compound disclosed in this invention or comprising presently disclosed The pharmaceutical composition of compound, mediated for treating, preventing or improve by unsuitable Aurora-A kinases behavior or with other Disease that mode influences or disorder or the disease for being mediated or otherwise being influenceed by unsuitable Aurora-A kinases behavior Or disorderly one or more symptoms.In other embodiments, one kind of the disease, disorder or disease or disorder or A variety of symptoms are related to unsuitable Aurora-B kinases behavior.Also in some embodiments, the disease, disorder or disease Disease or disorderly one or more symptoms are related to unsuitable Aurora C kinases behaviors.

" unsuitable jak kinase behavior " refers to that the JAK for occurring to deviate with particular patient normal jak kinase behavior swashs 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, which provides, treats these diseases and disorderly method.

Consistent with above description, such disease or disorder include but is not limited to：Bone marrow proliferative diseases, such as very Property polycythemia (PCV), essential thrombocythemia, idiopathic myelofibrosis (IMF)；Leukaemia, such as medullary system Leukaemia includes chronic myelogenous leukemia (CML), the CML forms of resistance to Imatinib, acute myeloid leukemia (AML) and AML'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, nephrosis, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, silver bits Disease, allergic rhinitis, IBD include Crohn disease and ulcerative colitis (UC), systemic loupus erythematosus (SLE), closed Save 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 a kind of compound disclosed in this invention or includes the medicine of presently disclosed compound Compositions, for preventing and/or treating the proliferative diseases, autoimmune disease, anaphylaxis of mammal (including mankind) Disease, inflammatory disease or graft rejection.

On the other hand, the present invention provides a kind for the treatment of and suffered 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 medicines disclosed herein Compositions or compound.On the other hand, suffer from provided herein is one kind treatment or risky suffer from proliferative diseases, autologous exempt from Epidemic disease, anaphylactia, inflammatory disease or graft rejection mammal method.

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 include giving effective therapeutic dose or one or more medicines disclosed herein of 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 a kind of 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 a kind of compound disclosed herein, or the drug regimen of compound disclosed herein is included Thing, the medicine of proliferative diseases is treated or prevented for preparing.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 include giving effective therapeutic dose or one or more pharmaceutical compositions disclosed herein of effective preventive dose or change 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 a kind of 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 a kind of compound disclosed herein, or the drug regimen of compound disclosed herein is included Thing, the medicine of autoimmune disease is treated or prevented for preparing.In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, lupus nephritis, 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 the one or more pharmaceutical compositions disclosed herein or chemical combination for giving 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 a kind of 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 a kind of compound disclosed herein, or the drug regimen of compound disclosed herein is included Thing, the medicine of anaphylactia is treated or prevented for preparing.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 State one or more pharmaceutical compositions disclosed herein or compound that method includes giving 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 a kind of 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 Consider disease arthritis to be worth doing.

On the other hand, provided herein is a kind of compound disclosed herein, or the drug regimen of compound disclosed herein is included Thing, the medicine of inflammatory disease is treated or prevented for preparing.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 State one or more pharmaceutical compositions disclosed herein or compound that method includes giving 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 a kind of 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 a kind of compound disclosed herein, or the drug regimen of compound disclosed herein is included Thing, the medicine of graft rejection is treated or prevented for preparing.In particular instances, graft rejection is organ-graft refection, tissue Graft rejection and cell transplant rejection.

On the other hand, provided herein is one kind as medicine it is especially used as treating and/or prevents disease medicament noted earlier 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.

The present invention that one special projects of this method include giving the study subject effective dose with inflammation discloses chemical combination For a period of time, the time is enough the level of inflammation for reducing study subject to thing, and preferably terminates the process of the inflammation.The party The present invention that the special embodiment of method includes giving the tested patients' effective dose for suffering from or being susceptible to suffer from bone rheumatoid arthritis is public Compound become civilized for a period of time, the time is enough the arthritis for reducing or preventing the patient respectively, 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 hyperplasia that the time is enough to reduce study subject is horizontal, and preferably terminates the increasing for open compound The process of growing property disease.The special embodiment of this method includes giving being disclosed herein for tested patients' effective dose with cancer For a period of time, the time is enough the cancer symptom for reducing or preventing the patient respectively to compound, and preferably described in termination The process of cancer.

Therapeutic alliance

The compounds of this invention can be used as single active agent to be administered, 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 the method for improving disease or illness, including gives safe and effective amount The combination medicine of compound and one or more therapeutically active agents is disclosed comprising the present invention.In some embodiments, medicine is combined Thing includes one or two kinds of 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 provides the product for including the compounds of this invention and at least one other therapeutic agent, can prepare Into the combination simultaneously, separately or sequentially applied in the treatment.In some embodiments, treatment is directed to by one or more eggs White kinases, such as the treatment of the disease or symptom of jak kinase, FLT3 kinases or Aurora A activity mediation.Prepared by joint provides Product include being present in comprising the composition that compound and other therapeutic agents are disclosed herein in same pharmaceutical composition, or with Compound and other therapeutic agents are disclosed herein existing for multi-form, for example, medicine box.

On the other hand, the present invention provides a kind of comprising the medicine that compound and another or a variety of therapeutic agents is disclosed herein Composition.In some embodiments, pharmaceutical composition can include pharmaceutically acceptable excipient, load as described above Body, adjuvant or solvent.

On the other hand, the present invention provides the medicine box for including two kinds or more of drug alone composition, wherein at least one Pharmaceutical composition includes the present invention and discloses compound.In some embodiments, medicine box includes individually keeping the composition Instrument, such as container, separated bottle or separated 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 mediates, Wherein patient previously with other therapeutic agents treated by (such as in 24 hours).Present invention also offers other treatment Purposes of the agent in treatment albumen kinases, the disease and symptom that are mediated such as jak kinase, FLT3 kinases and Aurora A activity, Wherein patient previously with the compounds of this invention treated by (such as in 24 hours).

Compound disclosed herein can be used as single-activity component to apply or be used as such as adjuvant, be applied jointly with other medicines With.The other medicines include, immunodepressant, immunomodulator, other antiinflammatories, such as 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 combined with following active component：The plain inhibitor of calcium nerve, such as ring spore Rhzomorph A or FK506；MTOR inhibitors, for example, rapamycin, 40-O- (2- hydroxyethyls)-rapamycin, CCI779, ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9；Ascosin with immunosuppressive properties, such as ABT-281, ASM981 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； Pkc inhibitor, such as described in WO 02/38561 or WO 03/82859, such as the compound of embodiment 56 or 70；It is immune Suppress monoclonal antibody, such as the monoclonal antibody of leukocyte receptors, for example, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or its part；Other immunomodulatory compounds, such as with CTLA4's The restructuring binding molecule or its mutant of at least part extracellular domain, such as the CTLA4 being connected with non-CTLA4 protein sequences is extremely Few extracellular portion or its mutant, such as CTLA4Ig (such as being named as ATCC 68629) or its mutant, such as LEA29Y； Adhesion molecule inhibitor, such as LFA-1 antagonists, the antagonists of ICAM-1 or -3, VCAM-4 antagonists or VLA-4 antagonists；Or Chemotherapeutics, such as taxol, gemcitabine, cis-platinum, Doxorubicin or 5 FU 5 fluorouracil；Or anti-infective.

In the present invention, compound and other immunotherapeutic agent/immunomodulators, antiinflammatory, chemotherapy or anti-infective are disclosed In the case for the treatment of administering drug combinations, immunodepressant, immunomodulator, antiinflammatory, chemotherapeutant or the anti-sense of administering drug combinations The dosage for contaminating compound certainly can be according to the type of combination medicine used, such as whether it is that steroidal or calcineurin suppress Agent, specific medicine, illness to be treated etc. used 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, such as xinafoate (1- hydroxy-2-naphthoic acids salt), the husky butylamine of salmeterol The sulfate or free alkali of alcohol or the fumarate of Formoterol.In some embodiments, long-acting beta₂- adrenocepter Activator, such as effective bronchiectasis is provided up to 12 hours or the compound of longer time, it is preferable.

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 present invention that includes and discloses compound and the joint of corticosteroid.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, 9 α-two fluoro- 17 α-[(2- furans Mutter carbonyl) epoxide]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-thiocarboxylic acid S- fluorine methyl esters (furancarboxylic acids Fluticasone) ,-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- by 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.Preferable 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, fluoro- 17 α of 6 α, 9 α-two-[(2- furanylcarbonyls) oxygen Base]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-thiocarboxylic acid S- methyl fluorides ester, 6 α, 9 α-two are fluoro- 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 present invention that includes and discloses compound and the joint of nonsteroidal GR activators. To Transcription inhibition with selectivity (compared with transcriptional activation), available for therapeutic alliance with glucocorticoid agonist activity Nonsteroidal compound includes those compounds covereding in following patent：WO 03/082827、WO 98/54159、WO 04/005229、WO 04/009017、WO 04/018429、WO 03/104195、WO 03/082787、WO 03/082280、WO 03/059899、WO 03/101932、WO 02/02565、WO 01/16128、WO 00/66590、WO 03/086294、WO 04/026248th, 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.NSAID's example includes nasmil, sodium nedocromil (nedocromil sodium), phosphodiesterase (PDE) inhibitor (such as theophylline, PDE4 inhibitor or mixed type PDE3/PDE4 inhibitor), leukotriene antagonist, leukotriene close 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 with phosphodiesterase 4 (PDE4) to suppress Application in the joint of agent, the application especially in inhalant dosage form.PDE4 specific inhibitors for this aspect of the present invention It can be known suppression PDE4 enzymes or be found any compound as PDE4 inhibitor, they are only that PDE4 suppresses Agent, it is not to suppress other members in PDE families, such as PDE3 and PDE5 compound.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 cis -4- cyano group -4- [3- (ring propoxyl group) -4- methoxyphenyls] hexamethylene -1- carboxylic acids are included (also referred to as 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 authorized 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 present invention that includes and discloses compound and the joint of anticholinergic.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, with() sold for trade name), Oxygen support ammonium (for example, as bromide, CAS 30286-75-0) and tiotropium are (for example, as bromide, CAS 136310-93- 5, with() sold for trade name)；Be also interested in also have Revatropate (for example, as hydrobromate, 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, withSold for trade name), oxybutynin (CAS 5633-20-5, with() sold for trade name Sell), terodiline (CAS 15793-40-5), Tolterodine (CAS 124937-51-5, or its tartrate CAS124937- 52-6, with() sold for trade name), Austria for ammonium (for example, as bromide, CAS 26095-59-0, withSold for trade name), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, Or its succinate CAS 242478-38-2, i.e. compound YM-905, with() sold for trade name).

On the other hand, the present invention provides a kind of present invention that includes and discloses compound and the joint of H1 antagonists.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 present invention that includes and discloses compound and the joint of H3 antagonists (and/or inverse agonist).H3 The example of antagonist includes the compound thoseed disclosed in WO 2004/035556 and WO 2006/045416.Available for this Other united histamine receptor antagonists of disclosure of the invention compound include H4 receptor antagonists (and/or inverse agonist), such as 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 can easily be prepared into pharmaceutical composition to use, therefore, including defined above group Close and represent 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 of combination.Known treatment agent is 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 comprising compound disclosed by the invention with other Treat the joint of activating agent.

In some embodiments, pharmaceutical composition provided by the invention includes the present invention and discloses compound and di-phosphate ester The joint of enzyme 4 (PDE4) inhibitor.

In other embodiments, pharmaceutical composition provided by the invention includes the present invention and discloses compound and β 2- kidneys The joint of upper parathyrine receptor stimulating agent.

In other embodiments, pharmaceutical composition provided by the invention includes the present invention and discloses compound and cortex class The joint of sterol.

In other embodiments, pharmaceutical composition provided by the invention includes the present invention and discloses compound and non-steroidal The joint of class GR activators.

In other embodiments, pharmaceutical composition provided by the invention includes the present invention and discloses compound and cholinolytic The joint of energy medicine.

In other embodiment, pharmaceutical composition provided by the invention includes the present invention and discloses compound and antihistamine The joint of medicine.

In internal medicine oncology, combine that to carry out treating cancer patient be conventional means using different form of therapy.Inside In section's oncology, being added to one or more other co-therapies forms of the present composition can be, for example, performing the operation, putting Treatment, chemotherapy, single transduction inhibitor or conditioning agent (for example, kinase inhibitor or conditioning agent) and/or monoclonal antibody.

The present invention, which discloses compound, can also be advantageously utilised in combination with other compounds, or and other therapeutic agents, especially It is in 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 of the compound of targeting/reduction albumen or lipid kinase activity and other anti-angiogenesis；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；Temozolomide ()；And Calciumlevofolinate.

Term used herein " aromatase inhibitor ", refers to suppress compound caused by estrogen, that is, it is male to suppress substrate 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 is() form administration.Fu Mei Smooth (formestane) can be with commercially available, as trade mark is() form administration.Fadrozole (fadrozole) can be with commercially available, as trade mark isForm administration.Anastrozole (anastrozole) can be with With commercially available, as trade mark is() form administration.Letrozole (letrozole) can with commercially available, As trade mark is() orForm administration.Aminoglutethimide (aminoglutethimide) can be with Commercially available, 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 is() form administration.Raloxifene hydrochloride (raloxifene Hydrochloride) can be with commercially available, as trade mark is() form administration.Fulvestrant (fulvestrant) can be or commercially available with United States Patent (USP) US 4, the formulation disclosed in 659,516, 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 4,100,274, can be with city Sell, 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 ", include, 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 is() form administration.Topology is replaced Health can be with commercially available, as trade mark is() form 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 name()；Daunomycin (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 is() form 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 is() or() form administration.Epirubicin can be with commercially available, as trade mark is( ) form administration.Idarubicin can be with commercially available, as trade mark is() form administration.Rice support anthracene Quinone can be with commercially available, as trade mark is() form 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 is() form administration.Docetaxel can be with With commercially available, as trade mark is() form 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 obtain 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, if trade mark is cancer() form administration.Ifosfamide can with commercially available, As trade mark is() form administration.

Term " histon deacetylase (HDAC) inhibitor " or " hdac inhibitor " 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 it can pharmaceutically connect The salt received.Especially include Vorinostat (SAHA).

Term " antitumor 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 For() form administration.Gemcitabine can be with commercially available, as trade mark is() Form is administered.This term also includes monoclonal antibody Herceptin (trastuzumab), can be with commercially available, as trade mark is() form 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 is() form Administration.

Term used herein " the change of targeting/reduction albumen or lipid kinase activity or albumen or lipid phosphatase activity Compound, or the compound of other anti-angiogenesis " include, but not limited to protein tyrosine kinase and/or serine and/or Threonine inhibitor, or lipid kinase inhibitors, such as

A) target, reduce or suppress the compound of platelet derived growth factor receptor (PDGFR) activity；Targeting, reduce Or suppress the compound of PDGFR activity, especially suppressing the compound of 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, reduce Or suppress the compound of IGF-1R activity, especially suppressing the compound of IGF-1 receptor actives includes those in patent WO 02/ Compound disclosed in 092599；

D) targeting, reduction or the compound for suppressing Trk receptor tyrosine kinase family actives；

E) targeting, reduction or the compound for suppressing Axl family active；

F) targeting, reduction or the compound for suppressing c-Met receptor actives；

G) targeting, reduction or the compound for suppressing 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 the 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) target, Raf family members in 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 the compound of cell cycle protein dependent kinase family (CDK) member activity；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；A kind of or QAN697 (P13K suppressions Preparation)；

K) target, reduce or suppress the active compound of protein tyrosine kinase inhibitor；Targeting, reduce or suppress Protein tyrosine kinase inhibitor activity compound include Gleevec () or tyrosine phosphorylation Inhibitor；The preferred low molecule amount (Mr of tyrphostin<1500) compound, or its pharmaceutically acceptable salt, especially It is selected from the compound of 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, ErbB3, ErbB4 equal or heterodimer) activity compound；Targeting, reduce or 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 combine) 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 0564409, WO 99/03854, EP 0520722、EP 0566226、EP 0787722、EP 0837063、US 5,747,498、WO 98/10767、WO 97/ 30034th, WO 97/49688 and WO 97/38983, WO 96/30347 (such as CP358774), (such as compound ZD of WO 96/33980 1839), WO 95/03283 (such as compound ZM105180), Herceptin (Trastuzumab), Cetuximab, Iressa, special sieve It is triumphant, 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.

In addition, anti-angiogenic compounds include having other active mechanisms (for example, with albumen or lipid kinase suppressing not It is related) compound, such as Thalidomide () and TNP-470.

Targeting, reduction or the compound of suppression albumen or lipid kinase activity are the inhibitor of phosphatase -1, and phosphatase 2A presses down 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, as celecoxib (), rofecoxib (), etoricoxib, cut down Ground is examined former times, or 5- alkyl -2- fragrant amino phenylacetic acids, such as 5- methyl -2- (the chloro- 6'- fluoroanilinos of 2'-) phenylacetic acids or reed rice Examine former times

Term used herein " diphosphonate " includes, but not limited to Etidronic Acid, Clodronate, Tiludronic Acid, pa rice phosphine Acid, alendronic acid, ibandronic acid, Risedronic Acid and zoledronic acid.Etidronic Acid can be with commercially available, such as trade name() form administration.Clodronate can be with commercially available, such as trade name() 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 Aredia^TM(AREDIA^TM) form administration；Alendronic acid Can be with commercially available, such as trade name() form administration；Ibandronic acid can be with commercially available, such as Trade name() form administration；Risedronic Acid can be with commercially available, such as trade name() form administration；Zoledronic acid can be with commercially available, such as trade name() Form administration.

Term " mTOR inhibitors " refers to suppress mammal rapamycin (mTOR) target protein have antiproliferative activity Compound, such as sirolimus (sirolimus,), everolimus (CERTICAN^TM), CCI-779 and ABT578。

Term used herein " heparanase inhibitors " refers to, targets, reduces or suppress acetylsulfuric acid depolymerized heparin Compound.This term includes, but unlimited 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 target, reduced Or suppress the compound of Ras carcinogenic activities, such as " farnesyl transferase inhibitor ", such as L-744832, DK8G557 or R115777(Zarnestra)。

Term used herein " telomerase inhibitor " refers to the compound for targetting, reducing or suppressing telomerase activation.Target Refer in particular to suppress the compound of telornerase receptor, such as telomere mycin to, the compound that reduces or suppress telomerase activation.

Term used herein " methionine aminopeptidase inhibitor " refers to target, reduce 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 target, reduces or the chemical combination of protease inhibition body activity 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, tetracycline derivant, such as hydroxamic acid peptide inhibitor Batimastat (batimastat) With its equivalent homologue Marimastat (marimastat, BB-2516) of oral bio, Pu Masita (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996。

Term used herein " reagent for being used for treating 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, reduce or suppress anaplastic lymphoma kinase Compound.

Targeting, reduce or suppress FMS- samples tyrosine kinase receptor (Flt-3R) compound especially suppress Flt-3 by The compound of body kinase families member, albumen or antibody, such as PKC412, midostaurin (midostaurin), staurosporin Derivative, SU11248 and MLN518.

Term used herein " HSP90 inhibitor " includes, but are not limited to target, reduce or suppress HSP90 endogenous The compound of atpase activity；The chemical combination degraded by ubiquitin protein body enzymatic pathway, targetted, reduce or suppress HSP90 client proteins Thing.Targeting, the compound for the Endogenous ATP enzymatic activity for reducing or suppressing HSP90 refer in particular to suppress HSP90 Endogenous ATP 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 (HERCEPTIN^TM), toltrazuril Monoclonal antibody-DM1, Tarceva (TARCEVA^TM), bevacizumab (AVASTIN^TM), Rituximab (), PR064553 (anti-CD40) and 2C4 antibody.Antibody means complete monoclonal antibody, polyclonal antibody, complete by least two The multi-specificity antibody and antibody fragment (as long as they have desired bioactivity) that whole antibody is formed.It is thin for acute marrow For the treatment of born of the same parents' sample leukaemia (AML), the leukemia therapy that the present invention can be disclosed to compound and standard is used in combination, especially It is with being used in combination for the therapy that AML is treated.Specifically, the present invention can be disclosed to compound with such as farnesyl- to turn Move enzyme inhibitor and/or other are used for medicine such as daunorubicin, adriamycin, Ara-C, VP-16, Teniposide, rice that AML is treated Hold in the palm anthraquinone, idarubicin, carboplatin and PKC412 administering drug combinations.

Compound disclosed by the invention can also be advantageously utilised in combination with other compounds or with other therapeutic agents In combination, especially other anti-malarial agents.Such anti-malarial agents include, but are not limited to chloroguanide (proguanil), Chlorproguanil (chlorproguanil), 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 combination with other compounds or the group of other therapeutic agents In conjunction, such as 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, Fluoroquinolones medicine, macrolides medicine, aminoglycoside medicine, sulphadiazine and pyrimethamine.

The structure of active component and its preparation can be from classic " The determined by code name, common name or trade name Merck Index (Merck index) " current edition (such as M.J.O ' Neil et al. compile ' The MerckIndex ', the 13rd Version, Merck Research Laboratories, 2001) or from database (such as Patents International (examples Such as IMS World Publications)) in know.

It is above-described, the compound that compound is applied in combination can be disclosed with the present invention, can be by people in the art Member, prepare and be 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 fixing joint in single dose unit form or the medicine box of 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.Term " co-administered " as used herein Or " administering drug combinations " etc. are intended to include to be applied to selected joint companion needs its single individual (such as patient), and anticipate It is intended to include wherein material without going through identical method of administration or the therapeutic scheme being administered simultaneously.Term " medicine as used herein Joint " represents that more than one active components are mixed to or combined resulting product, and both fixed connection including active component Closing, which also includes on-fixed, combines.Term " fixing joint " represents active component compound for example disclosed by the invention, and joint companion It is administered simultaneously in the form of single entities or dosage in patient.Term " on-fixed joint " represents that active component discloses such as the present invention Compound, and joint companion as corpus separatum simultaneously, it is common or limit ground without special time successively patient is administered, its In the administering mode treatment levels of significance of two kinds of compounds is provided in patient's body.The latter applies also for HAART, Such as using three or more active components.

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 pharmaceutical composition comprising the compounds of this invention.Each embodiment disclosed by the invention include by pair 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, to treat the method for disease mentioned above.

In some embodiments, the present invention discloses compound or can comprising the pharmaceutical composition of the invention 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 by injection or administered by infusion, including vein 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 discloses compound or can comprising the pharmaceutical composition of the invention 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 To be intranasal administration.

In some embodiments, the present invention discloses compound or can comprising the pharmaceutical composition of the invention for disclosing compound With once daily, or according to dosage regimen, at the appointed time in section, it is administered several times in different time intervals.For example, It is 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.It 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 for disclosing compound comprising the present invention depends on the compound Pharmacokinetic property, such as dilution, distribution and half-life period, these can be by determination of technical staff.In addition, the present invention discloses Compound or include the present invention disclose compound pharmaceutical composition appropriate dosage regimen, including implementation the program it is lasting when Between, depending on treated disease, the order of severity of disease being treated, the age of patient under consideration and health, it is treated The factor in the range of technical staff's knowledge and experience such as the medical history of patient while 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 and can be administered simultaneously, or before it or afterwards with one or more other therapeutic agents. The compounds of this invention can be administered respectively with other therapeutic agents by identical or different method of administration, or therewith with medicine group Solvate form is administered.

For about 50-70kg individual, 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 depending 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, can also such as enteral of suspension or aqueous solution form in vivo, it is parenteral, it is especially intravenous to use.

In some embodiments, the treatment effective dose that the present invention discloses compound is daily about 0.1mg to about 2, 000mg.Its pharmaceutical composition should provide about 0.1mg to the compound of about 2,000mg dosage.In a particular In, the pharmaceutical dosage unit forms of preparation can provide about 1mg to about 2,000mg, and about 10mg to about 1,000mg, about 20mg is to about The combination of each main component in 500mg, or about 25mg to about 250mg main active or every dosage unit form.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.

In addition, compound disclosed by the invention can be administered with prodrug forms.In the present invention, the present invention discloses compound " prodrug " be that can finally discharge the functional derivatives that the present invention discloses compound in vivo when patient is administered.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 onset time inside compound；(b) acting duration inside compound is changed；(c) change inside compound Conveying or distribution；(d) solubility inside compound is changed；And (e) overcomes the side effect or other difficult points that compound faced. For preparing the typical functional derivatives of prodrug, comprising in vivo chemically or the compound that cracks of mode of enzyme 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

For the description present invention, embodiment is listed below.But it is to be understood that the invention is not restricted to these embodiments, it is The method that the practice present invention is provided.

Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I).Following reaction scheme and embodiment are used to this is further illustrated The content of invention.

The professional of art will be recognized that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent 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 temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified during use, unless other aspects show.In 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 It can buy.

Anhydrous tetrahydro furan, dioxane, toluene, ether are 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 to dry to use in advance through anhydrous sodium sulfate.

Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.

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-d₆For solvent (in units of ppm), marked by the use of TMS (0ppm) or chloroform (7.26ppm) as reference 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, 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 0.6mL/min.Mobile phase：5%-95% (contains 0.1% The CH of formic acid₃CN) (H of 0.1% formic acid is being contained₂O the ratio in)), using electron spray ionisation (ESI), under 210nm/254nm, Detected with UV.

Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar types Number：NOVASEP50/80mm DAC), detected in 210nm/254nm with UV.

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 triethylamines

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- tetramethylurea hexafluorophosphoric acid esters

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 sodium hydroxides

Na₂SO₄Sodium sulphate

Na₂S₂O₃Sodium thiosulfate

NaHCO₃Sodium acid carbonate

NaOAc ammonium acetates

Ti(Oi-Pr)₄The isopropyl ester of metatitanic acid four

NBS NBSs

MeOH methanol

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

Prepare the present invention and disclose the typical synthesis step of compound as shown in following 1~synthetic schemes of synthetic schemes 2.Remove Non- explanation in addition, each Z, Z¹、R¹、R³And R⁵With definition as described in the present invention, p 0,1,2,3 or 4, q 0,1,2 or 3.PG For blocking group, W is oxazolyl compound.

Synthetic schemes 1：

With such as formula (6) or (7) shown in structure the present invention disclose compound can be described by synthetic schemes 1 it is general Synthetic method is prepared, and specific steps refer to embodiment.In synthetic schemes 1, substituted dichloro pyrimidine (1) with carrying protection Base optional substituted heterocyclic compound (2) in alkali, in the presence of triethylamine, generate the heteroaryl compound optionally substituted (3).Compound (3) with optionally substitute Aminoindazole compound (4) or its hydrochloride, in alkali, such as diisopropyl ethyl amine, three Ethamine, or under the catalytic action of suitable Pd catalyst, reaction generation compound (5).Compound (5) in blocking group can In acid condition, as removed in the ethyl acetate solution of trifluoroacetic acid or hydrogen chloride, obtain kinases inhibitor (6).Closing Under conditions of suitable to compound (6) in introduce different substituent, can obtain with formula (7) shown in structure protein kinase suppression Preparation.

Synthetic schemes 2：

With such as formula (10) or (11) shown in structure the present invention disclose compound can be described by synthetic schemes 2 one As synthetic method be prepared, specific steps refer to embodiment.In synthetic schemes 2, compound (3) with the amino that optionally substitutes Azole compounds (8) or its hydrochloride, in alkali, such as diisopropyl ethyl amine, triethylamine or in acid, such as trifluoroacetic acid, chlorination The ethyl acetate solution of hydrogen, or under the catalytic action of suitable Pd catalyst, reaction generation compound (9).Compound (9) in Blocking group can in acid condition, such as trifluoroacetic acid, the ethyl acetate solution of hydrogen chloride, or the effect in hydrazine hydrate Under, or remove under otherwise suitable conditions, obtain kinases inhibitor (10).Under suitable conditions to compound (10) in Introduce different substituents, can obtain with formula (11) shown in structure kinases inhibitor.

Embodiment

Embodiment 1N²- (2,3- dimethyl -2H- indazole -6- bases)-N⁴- methyl-N⁴- (2- azaspiros [4.5] decane -8- Base) pyrimidine -2,4- diamines

Step 1) 2- (1,4- dioxo spiros [4.5] decane -8- subunits) ethyl acetate

NaH (60% mineral oil suspends, 33.3g, 832.38mmol) is suspended in anhydrous THF (1L), at 0 DEG C, to Wherein anhydrous THF (500mL) solution of addition Isosorbide-5-Nitrae-dioxo spiro [4.5] decane -8- ketone (100g, 640.29mmol), 1 hour Inside drip off.Then, at -20 DEG C, phosphonoacetate (203.23g, 832.38mmol) is added drop-wise to above-mentioned suspension body In system, dripped off in 1 hour.Gained system is moved into room temperature, continues stirring 2 hours, then plus reaction is quenched in water (1L), and uses second Acetoacetic ester (1L x 3) extracts.The organic phase of merging, washed with saturated aqueous common salt (1L), anhydrous Na₂SO₄Dry, filter and depressurize Concentration, gained residue purify through silica gel column chromatography (PE/EtOAc (v/v)=10/1), and it is faint yellow oil to obtain title compound Shape thing (157g, 100%).

¹H NMR(600MHz,CDCl₃):δ (ppm) 5.64 (s, 1H), 4.12 (q, J=7.1Hz, 2H), 3.95 (s, 4H), 2.97 (m, 2H), 2.36 (m, 2H), 1.74 (m, 4H), 1.25 (t, J=7.2Hz, 4H).

Step 2) 2- (8- (nitre methyl) -1,4- dioxo spiros [4.5] decane -8- bases) ethyl acetate

2- (1,4- dioxo spiros [4.5] decane -8- subunits) ethyl acetate (157g, 693.86mmol) is dissolved into THF In (800mL), under normal temperature, nitromethane (55.8mL, 1.04mmol) is added dropwise thereto, then, is added dropwise TBAF's into system Tetrahydrofuran solution (1M, 763.25mL, 763.25mmol).Gained reaction solution is heated to flowing back, and stirs 20 hours.Will reaction Mixture is concentrated under reduced pressure, and gained residue is diluted with water (800mL), and is extracted with ethyl acetate (800mL x 3), and merging has Machine layer is washed, anhydrous sodium sulfate drying with saturated aqueous common salt (1L x 3), is filtered and is concentrated under reduced pressure.Gained residue is through silicagel column Chromatograph (petrol ether/ethyl acetate (v/v)=10/1) purifying, obtain title compound for pale yellow oil (165g, 82.9%).

¹H NMR(600MHz,CDCl₃):δ (ppm) 4.66 (s, 2H), 4.09 (q, J=7.1Hz, 2H), 3.88 (s, 4H), 2.49 (s, 2H), 1.64 (m, 8H), 1.21 (t, J=7.2Hz, 4H).

Spiral shell [4.2.4.2] myristyl -9- ketone of step 3) 1,4- dioxy -10- azepines-two

By 2- (8- (nitre methyl) -1,4- dioxo spiros [4.5] decane -8- bases) ethyl acetate (109g, 379.38mmol) It is dissolved in ethanol (600mL), adds Raney's nickel (10g) thereto.Under normal temperature, gained reaction solution stirs 72 in atmosphere of hydrogen Hour, filtering, filter cake is washed with DCM/MeOH (1/1 (v/v), 500mL) mixed solution.Merging filtrate, it is concentrated under reduced pressure, gained The mixed solvent of residue petroleum ether and ethyl acetate (10/1 (v/v), 800mL) washs, and being filtrated to get title compound is White solid (67g, 83.8%).

MS(ESI,pos.ion)m/z:212.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃):δ(ppm)6.60(s,1H),3.95(s,4H),3.20(s,2H),2.23(s, 2H),1.72(m,4H),1.65(m,4H)。

Spiral shell [4.2.4.2] myristyl of step 4) 1,4- dioxy -10- azepines-two

By LiAlH₄(21g, 558.56mmol) is suspended in anhydrous tetrahydro furan (500mL), at 0 DEG C, is added thereto Enter the anhydrous tetrahydro furan of spiral shell [4.2.4.2] myristyl -9- ketone (59g, 279.28mmol) of 1,4- dioxy -10- azepines-two (400mL) solution.Gained reaction solution is warming up to backflow, reacts 2 hours, then, drips to add water into system at 0 DEG C and no longer produce Anger bubble, is quenched reaction.Filtering, filter cake are washed with MeOH/DCM (1/1 (v/v), 500mL) mixed solvent.Merging filtrate, decompression Concentration, gained residue purify through silica gel column chromatography (DCM/MeOH (v/v)=10/1), and it is yellow solid to obtain title compound (52g, 94%).

MS(ESI,pos.ion)m/z:198.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃):δ (ppm) 3.88 (s, 4H), 2.90 (t, J=7.1Hz, 2H), 2.65 (s, 3H), 1.56 (ddd, J=29.3,13.4,6.9Hz, 10H).

Step 5) 2- azaspiros [4.5] decane -8- ketone

Spiral shell [4.2.4.2] myristyl (10g, 50.69mmol) of dioxy -10- azepines-two is dissolved in methanol (100mL) In, under normal temperature, 2M hydrochloric acid (30mL, 60mmol) is added thereto.Gained reaction solution at normal temperatures, is stirred overnight, and is concentrated under reduced pressure, Gained residue is dissolved in water (100mL), is added saturated aqueous sodium carbonate and is adjusted to pH=10, then, with dichloromethane (200mL x 3) is extracted, and the organic layer of merging is washed with saturated aqueous common salt (200mL), anhydrous sodium sulfate drying, filters and depressurize Concentration, gained residue purify through silica gel column chromatography (DCM/MeOH (v/v)=7/1), and it is yellow solid to obtain title compound (10g, 100%).

MS(ESI,pos.ion)m/z:154.2[M+H]⁺。

Step 6) 8- oxo -2- azaspiros [4.5] decane -2- t-butyl formates

2- azaspiros [4.5] decane -8- ketone (10g, 65.26mmol) is dissolved in water and tetrahydrofuran (1/3 (v/v)) In mixed solution (200mL), (Boc) is added thereto under normal temperature₂O (28.48g, 130.53mmol) and sodium carbonate (13.83g, 130.53mmol).Gained reaction solution stirs 2 hours at normal temperatures, then, adds water (200mL) that reaction is quenched.With ethyl acetate (300mL x 3) is extracted, and the organic layer of merging is washed with saturated aqueous common salt (500mL), anhydrous sodium sulfate drying, filters and depressurize Concentration, gained residue purify through silica gel column chromatography (PE/EtOAc (v/v)=10/1), and it is colorless oil to obtain title compound Thing (9g, 54.5%).

MS(ESI,pos.ion)m/z:198.1[(M-C₄H₈)+H]⁺。

Step 7) 8- (methylamino) -2- azaspiros [4.5] decane -2- t-butyl formates

8- oxo -2- azaspiros [4.5] decane -2- t-butyl formates (4g, 15.80mmol) are added into methylamine (33% [w/ W] ethanol solution, 7.42g, 79.0mmol) in, after gained reaction solution is stirred at room temperature overnight, then NaBH is added thereto₃CN (2.98g, 47.4mmol), add rear reaction solution and continue to stir 2 hours at normal temperatures.Reactant mixture is concentrated under reduced pressure, gained Residue is diluted with water (50mL), and is extracted with dichloromethane (80mL x 3), the organic layer saturated aqueous common salt of merging (100mL) is washed, and anhydrous sodium sulfate drying, is filtered and is concentrated under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/ V)=10/1) purify, it is yellow oil (3.2g, 75.7%) to obtain title compound.

MS(ESI,pos.ion)m/z:269.2[M+H]⁺。

Step 8) 8- ((2- chlorine pyrimidine-4-yl) (methyl) amino) -2- azaspiros [4.5] decane -2- t-butyl formates

By 2,4- dichloro pyrimidines (596mg, 4.0mmol) and 8- (methylamino) -2- azaspiros [4.5] decane -2- formic acid The tert-butyl ester (1.29g, 4.8mmol) is dissolved in EtOH (10mL), adds Et thereto₃N (0.92g, 9.1mmol) is anti-after adding Answer and be stirred overnight under mixture normal temperature, is concentrated under reduced pressure.Gained residue is pure through silica gel column chromatography (PE/EtOAc (v/v)=2/1) Change, it is faint yellow solid (580mg, 38.1%) to obtain title compound.

MS(ESI,pos.ion)m/z:381.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ (ppm) 8.01 (d, J=6.2Hz, 1H), 6.31 (d, J=5.3Hz, 1H), 3.41 (ddd, J=20.4,14.0,7.1Hz, 2H), 3.13 (d, J=25.2Hz, 2H), 2.93 (s, 2H), 1.81 (m, 2H), 1.65(m,8H),1.48(m,11H)。

Step 9) 8- ((2- ((2,3- dimethyl -2H- indazole -6- bases) amino) pyrimidine-4-yl) (methyl) amino) -2- nitrogen Miscellaneous spiral shell [4.5] decane -2- t-butyl formates

By 8- ((2- chlorine pyrimidine-4-yl) (methyl) amino) -2- azaspiros [4.5] decane -2- t-butyl formates (500.0mg, 1.3mmol) and 2,3- dimethyl -2H- indazole -6- amine hydrochlorates (778.6mg, 3.9mmol) are suspended in n-BuOH In (10mL), DIPEA (1.04g, 8.0mmol) is added thereto, and gained reaction system is warming up to 150 DEG C, and tube sealing reaction is overnight. It is concentrated under reduced pressure after reactant mixture is cooled into room temperature, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=10/1) Purifying, it is yellow solid (657mg, 100%) to obtain title compound.

MS(ESI,pos.ion)m/z:506.3[M+H]⁺。

Step 10) N²- (2,3- dimethyl -2H- indazole -6- bases)-N⁴- methyl-N⁴- (2- azaspiros [4.5] decane -8- Base) pyrimidine -2,4- diamines

By 8- ((2- ((2,3- dimethyl -2H- indazole -6- bases) amino) pyrimidine-4-yl) (methyl) amino) -2- azaspiros [4.5] decane -2- t-butyl formates (657mg, 1.3mmol) are dissolved in DCM (10mL), add the acetic acid second of hydrogen chloride thereto Ester solution (10mL, 40mmol).Gained reactant mixture is concentrated under reduced pressure, residue is dissolved in water (30mL), adds saturated carbon Acid sodium aqueous solution is adjusted to pH=10, is extracted with DCM (250mL x 3).The organic phase of merging is washed with saturated aqueous common salt (250mL) Wash, anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (DCM/MeOH (v/v)=5/1), obtains Title compound is brown solid (0.30g, 56.9%).

MS(ESI,pos.ion)m/z:406.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ (ppm) 9.05 (s, 1H), 8.02 (s, 1H), 7.74 (d, J=6.7Hz, 1H), 7.37 (d, J=8.9Hz, 1H), 6.91 (d, J=8.8Hz, 1H), 5.97 (d, J=6.6Hz, 1H), 3.96 (s, 3H), 3.32 (m, 2H), 3.00 (s, 2H), 2.91 (s, 4H), 2.49 (s, 3H), 1.93 (s, 1H), 1.87 (t, J=7.4Hz, 3H), 1.71 (m,6H)。

The 3- of embodiment 2 (8- ((2- ((2,3- dimethyl -2H- indazole -6- bases) amino) pyrimidine-4-yl) (methyl) ammonia Base) -2- azaspiros [4.5] decane -2- bases) -3- oxo propionitriles

By N²- (2,3- dimethyl -2H- indazole -6- bases)-N⁴- methyl-N⁴- (2- azaspiros [4.5] decane -8- bases) is phonetic Pyridine -2,4- diamines (300mg, 0.74mmol) and itrile group acetic acid (156mg, 1.83mmol) are dissolved in DCM and DMF mixed solvent In (4/1 (v/v), 35mL), HATU (925.8mg, 2.44mmol) and Et is added thereto₃N(0.49g,4.84mmol).Add Afterwards, stirring at normal temperature 0.5 hour, add water (30mL), extracted with DCM (100mL x 3), the organic phase of merging is with saturated aqueous common salt (100mL) is washed, and anhydrous sodium sulfate drying, is concentrated under reduced pressure, gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=20/ 1) purify, it is brown solid (210mg, 60.0%) to obtain title compound.MS(ESI,pos.ion)m/z:473.4[M+H]⁺；

¹H NMR(600MHz,CDCl₃):δ (ppm) 8.16 (d, J=9.2Hz, 1H), 7.99 (dd, J=5.9,3.3Hz, 1H), 7.45 (dd, J=8.8,4.4Hz, 1H), 6.98 (m, 2H), 5.96 (t, J=5.5Hz, 1H), 4.08 (d, J=9.3Hz, 3H), 3.64 (dd, J=13.4,6.7Hz, 2H), 3.44 (s, 3H), 3.36 (s, 1H), 2.96 (d, J=7.2Hz, 3H), 2.59 (s, 3H), 2.02 (t, J=7.1Hz, 1H), 1.93 (t, J=7.3Hz, 1H), 1.75 (m, 6H), 1.31 (s, 2H).

The chloro- N of the 5- of embodiment 3²- (2,3- dimethyl -2H- indazole -6- bases)-N⁴- (octahydro pentamethylene simultaneously [c] pyrroles -5- Base) pyrimidine -2,4- diamines

(the 3H)-t-butyl formate of step 1) 3a, 4,7,7a- tetrahydrochysene -1H- iso-indoles -2

LAH (22.80g, 600mmol) is suspended in THF (600mL), it is sub- to add tetrahydrochysene phthaloyl at 0 DEG C by several times thereto Amine (39.45g, 260.9mmol), add rear reaction system and stirred 18 hours at 60 DEG C, be subsequently cooled to 0 DEG C, successively slowly Water (25mL), the 15%KOH aqueous solution (25mL) and water (75mL) are added, continues stirring 1 hour, diatom under gained mixture normal temperature Soil filtering, DCM (500mL) washing filter cakes, filtrate decompression concentration, it is yellow oil to obtain product iso-indoles, and this crude product is straight Connect for reacting in next step.

This crude product is dissolved in DCM (300mL), Et is added thereto at 0 DEG C₃N (39.61g, 391.4mmol) and (Boc)₂O (68.32g, 313.1mmol), is added in 0.5 hour, and normal temperature is moved to after adding, and continues stirring 21 hours.Will reaction Mixture is concentrated under reduced pressure, and gained residue is dissolved in EtOAc (600mL), successively with aqueous citric acid solution (1M, 2x 130mL), saturation NaHCO₃The aqueous solution (2x 130mL), saturated aqueous common salt (250mL) washing, the anhydrous sulphur of the organic layer of merging Sour sodium is dried, and is filtered and is concentrated under reduced pressure, and gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=5/1), obtains title Compound is Chinese red grease (45.00g, 77.3%)

MS(ESI,pos.ion)m/z:168.2[(M-C₄H₈)+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)5.64(s,2H),3.40(m,2H),3.16(m,1H),3.07(m, 1H),2.25(m,4H),1.90(m,2H),1.46(s,9H)。

Step 2) 2,2'- (1- (tertbutyloxycarbonyl) nafoxidine -3,4- diyls) diacetic acid

By 3a, (the 3H)-t-butyl formate (4.91g, 22mmol) of 4,7,7a- tetrahydrochysene -1H- iso-indoles -2 and (NH₄)₂SO₄ (1.55g, 12mmol) is dissolved in H₂In O (40mL), at 5 DEG C, KMnO is added portionwise thereto₄(8.20g, 52mmol), add Time is 0.5 hour, and after adding, reaction solution continues stirring 6 hours at 5 DEG C, then filters, and filter cake is rushed with water (40mL x 3) Wash, filtrate uses CH₂Cl₂(40mL x 3) is extracted, and water layer is adjusted to pH=2~3 with 3M HCl/water solution, then with EtOAc (50mL X 3) extract, the organic phase of merging is washed, anhydrous Na with saline solution (50mL x 3)₂SO₄Dry, be filtered, and concentrated under reduced pressure to give Light yellow solid (4.52g, 71.5%).

MS(ESI,pos.ion)m/z:232.2[(M-C₄H₈)+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)3.53(m,2H),3.04(m,2H),2.80(m,2H),2.44(m, 4H),1.43(s,9H)。

Step 3) 5- oxo hexahydros pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate

2,2'- (1- (tertbutyloxycarbonyl) tetrahydro pyrrolidine -3,4- diyls) acetoacetate (3.40g, 11.8mmol) is molten Solution is in Ac₂In O (21mL), and NaOAc (0.78g, 9.5mmol) is added thereto.Reaction solution reacts 3 hours at 120 DEG C, so After be down to room temperature and filter, filter cake is rinsed with EtOAc (20mL x 2), filtrate decompression is concentrated, gained residue is through silicagel column (PE/EtOAc (v/v)=1/4) purifying is chromatographed, it is crocus grease (1.38g, 55.0%) to obtain title compound.

MS(ESI,pos.ion)m/z:170.2[(M-C₄H₈)+H]⁺；

¹H NMR(400MHz,CDCl₃):δ (ppm) 3.69 (m, 2H), 3.00 (m, 4H), 2.61 (dd, J=8.2, 18.4Hz, 2H), 2.29 (dd, J=5.8,18.4Hz, 2H), 1.43 (s, 9H).

Step 4) 5- (benzyl amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate

By 5- oxo hexahydros pentamethylene, simultaneously [c] pyrroles -2 (1H)-t-butyl formate (9.57g, 42.5mmol) is dissolved in DCM In (170mL), at 0 DEG C, BnNH is added thereto₂(4.56g, 42.5mmol) and AcOH (2.55g, 42.5mmol), after adding, Reaction solution stirs 0.5 hour at 0 DEG C.Then, NaBH (OAc) is added thereto in batches₃(18.00g, 85.0mmol), gained Mixture continues stirring 20 hours at room temperature.Add NaHCO₃The aqueous solution (142mL), extracted, closed with DCM (250mL x 3) And organic phase washed, anhydrous Na with saturated aqueous common salt (250mL x 3)₂SO₄Dry, filter and be concentrated under reduced pressure, gained residue Purified through silica gel column chromatography (EtOAc), it is yellow solid (7.44g, 55.3%) to obtain title compound.

MS(ESI,pos.ion)m/z:317.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)7.31(m,4H),7.26(m,1H),3.79(s,2H),3.46(m, 2H), 3.28 (d, J=8.8Hz, 1H), 3.16 (tt, J=9.6,6.9Hz, 1H), 2.55 (m, 2H), 2.28 (s, 2H), 2.22 (m,2H),1.45(s,9H),1.31(m,2H)。

Step 5) 5- amino hexahydros pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate

By 5- (benzyl amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate (6.50g, 20.5mmol) and AcOH (1.23g, 20.5mmol) is dissolved in MeOH (150mL), adds Pd (OH) thereto₂/ C (10%wt, 1.00g), gained Reaction system is warming up to 40 DEG C, is stirred overnight in atmosphere of hydrogen, and gained reactant mixture filters through diatomite, and filtrate decompression is dense Contracting, gained residue are dissolved in saturation NaHCO₃In the aqueous solution (70mL), DCM (100mL x 3) extractions, the organic phase of merging is used Saline solution (100mL x 3) washs, anhydrous Na₂SO₄Dry, filter and be concentrated under reduced pressure, gained residue is through silica gel column chromatography (EtOAc, 100%) is purified, and it is yellow solid (4.00g, 86.2%) to obtain title compound.

MS(ESI,pos.ion)m/z:227.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)3.44(m,2H),3.31(m,3H),2.98(br.s,2H),2.57(m, 2H), 2.22 (dt, J=14.0,7.2Hz, 2H), 1.44 (s, 9H).

Step 6) 5- ((2,5- dichloro pyrimidine -4- bases) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate

By 5- amino hexahydros pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate (3.11g, 13.74mmol) and 2,4,5- Trichloropyrimidine (1.46g, 7.96mmol) is dissolved in EtOH (60mL), adds Et thereto₃N(2.21g,21.84mmol).Add After complete, reactant mixture is stirred overnight at normal temperatures, is concentrated under reduced pressure, and gained residue is dissolved in EtOAc (50mL) and water The in the mixed solvent of (50mL), extracted with EtOAc (150mL x 3), the organic layer of merging is washed with saline solution (150mL), nothing Water Na₂SO₄Dry, filter and be concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=5/1), obtains It is faint yellow solid (2.97g, 100%) to title compound.

MS(ESI,pos.ion)m/z:373.0[M+H]⁺。

Step 7) 5- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- bases) amino) pyrimidine-4-yl) amino) hexahydro ring Pentane simultaneously [c] pyrroles -2 (1H)-t-butyl formate

To 5- ((2,5- dichloro pyrimidine -4- bases) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate (621.8mg, 1.666mmol) and 2,3- dimethyl indazole -6- amine hydrochlorates (999.6mg, 5.057mmol) n-butanol DIPEA (1.10g, 8.43mmol) is added in (6mL) solution.Reaction system is warming up to 150 DEG C, microwave reaction 2 hours, depressurizes dense Contracting.Gained residue purifies through silica gel column chromatography (EtOAc/PE (v/v)=2/1), and it is light tan solid to obtain title compound (452.1mg, 54.5%).

MS(ESI,pos.ion)m/z:498.3[M+H]⁺。

The chloro- N of step 8) 5-²- (2,3- dimethyl -2H- indazole -6- bases)-N⁴- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) Pyrimidine -2,4- diamines

To 5- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- bases) amino) pyrimidine-4-yl) amino) hexahydro pentamethylene And the second of hydrogen chloride is added in DCM (10mL) solution of [c] pyrroles -2 (1H)-t-butyl formate (452.1mg, 0.908mmol) Acetate solution (10mL, 40mmol), gained reaction system are stirred overnight at normal temperatures.Reaction finishes, and is concentrated under reduced pressure, and gained is residual Thing is stayed to add water (30mL) to dissolve, with saturation Na₂CO₃The aqueous solution is adjusted to pH=10, is then diluted with water, and is extracted with DCM (250mLx3) Take.The organic phase of merging is washed through saturated aqueous common salt (250mL), anhydrous sodium sulfate drying, is filtered and is concentrated under reduced pressure, gained residual Thing through silica gel column chromatography (DCM/MeOH (v/v)=5/1) purify, obtain title compound for brown solid (179.6mg, 49.7%).

MS(ESI,pos.ion)m/z:398.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)9.14(s,1H),8.10(s,1H),7.96(s,1H),7.47(d,J =8.9Hz, 1H), 7.39 (d, J=6.4Hz, 1H), 7.11 (d, J=8.9Hz, 1H), 4.45 (m, 1H), 3.96 (s, 3H), 3.17 (s, 1H), 3.05 (m, 2H), 2.92 (d, J=9.8Hz, 2H), 2.73 (br.s, 2H), 2.53 (s, 3H), 2.30 (m, 2H),1.492(m,2H)。

The 3- of embodiment 4 (5- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- bases) amino) pyrimidine-4-yl) amino) Hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) -3- oxo propionitriles

To the chloro- N of 5-²- (2,3- dimethyl -2H- indazole -6- bases)-N⁴- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) pyrimidine - 2,4- diamines (484.7mg, 1.22mmol) and itrile group acetic acid (155.0mg, 1.82mmol) are dissolved in DCM and DMF mixed solvent In (40mL/10mL), HATU (673.2mg, 1.77mmol) and triethylamine (0.60g, 5.90mmol) are added thereto.Add Afterwards, stirring at normal temperature 5.5 hours, add water (30mL) that reaction is quenched, extracted with DCM (100mL x 3).The organic phase of merging is through saturation Saline solution (100mL) washs, and anhydrous sodium sulfate drying, filters and is concentrated under reduced pressure, gained residue is through silica gel column chromatography (DCM/ MeOH (v/v)=40/1) purifying, it is brown solid (0.49g, 87%) to obtain title compound.

MS(ESI,pos.ion)m/z:465.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ (ppm) 8.09 (s, 1H), 7.94 (s, 1H), 7.47 (d, J=8.9Hz, 1H), 6.98 (m, 2H), 5.27 (d, J=6.8Hz, 1H), 4.53 (m, 1H), 4.07 (s, 3H), 3.73 (m, 2H), 3.61 (dd, J= 12.8,4.3Hz, 1H), 3.48 (dd, J=22.5,4.3Hz, 1H), 3.42 (s, 2H), 2.90 (m, 2H), 2.64 (m, 2H), 2.60(s,3H),1.46(m,2H)。

The chloro- N of the 5- of embodiment 5²- (2,3- dimethyl -2H- indazole -6- bases)-N⁴- (3- azaspiros [5.5] hendecane -9- Base) pyrimidine -2,4- diamines

Step 1) 9- oxo -3- azaspiros [5.5] hendecane -7- alkene -3- t-butyl formates

To 4- formyl piperidine -1- t-butyl formates (10.0g, 46.9mmol) and KOH (1.3g, 23.5mmol) EtOH In (200mL) solution, butyl- 3- alkene -2- ketone (3.9g, 56.3mmol) is added, gained reactant mixture is warming up to 70 DEG C of stirrings 16 Hour.After reaction terminates, it is concentrated under reduced pressure.Gained residue purifies through silica gel column chromatography (EtOAc/PE (v/v)=1/4), must mark Topic compound is light brown oily substance (5.2g, 41.8%).

MS(ESI,pos.ion)m/z:210.2[M-55]⁺.

Step 2) 9- oxo -3- azaspiros [5.5] hendecane -3- t-butyl formates

To the DCM of 9- oxo -3- azaspiros [5.5] hendecane -7- alkene -3- t-butyl formates (5.2g, 19.6mmol) 10%Pd/C (0.5g) is added in (80mL) solution, at normal temperatures, in atmosphere of hydrogen, stirring reaction is overnight for gained suspension.Will Reactant mixture is filtered, and filtrate decompression concentration, gained residue is purified through silica gel column chromatography (EtOAc/PE (v/v)=1/4), obtained Title compound is light brown oily substance (3.1g, 59.0%).

MS(ESI,pos.ion)m/z:212.1[M-55]⁺。

Step 3) 9- amino -3- azaspiros [5.5] hendecane -3- t-butyl formates

To the EtOH (40mL) of 9- oxo -3- azaspiros [5.5] hendecane -3- t-butyl formates (5.35g, 20.0mmol) The methanol solution (7M, 40mL, 280.0mmol) and Ti (Oi-Pr) of ammonia are added in solution₄(11.30g, 40.0mmol), reactant System is stirred at room temperature overnight.By NaBH₄(1.51g, 40.0mmol) is added portionwise in reaction system, after adding, gained reaction Mixture is stirred at room temperature 5 hours, add water quenching go out (40mL) reaction, stirring 1 hour after filter.Filtrate decompression concentrates, gained Residue through silica gel column chromatography (MeOH/DCM (v/v)=1/25) purify, obtain title compound for faint yellow solid (1.20g, 22.4%).

MS(ESI,pos.ion)m/z:269.3[M+H]⁺。

Step 4) 9- ((2,5- dichloro pyrimidine -4- bases) amino) -3- azaspiros [5.5] hendecane -3- t-butyl formates

9- amino -3- azepines are added into 2,4,5- trichloropyrimidines (495.9mg, 2.7mmol) ethanol (30mL) solution Spiral shell [5.5] hendecane -3- t-butyl formates (1.08g, 4.0mmol) and Et₃N(413.6mg,4.1mmol).Gained reaction system After being stirred at room temperature 12 hours, it is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/ 7) purify, it is faint yellow solid (387.1mg, 34.5%) to obtain title compound.

MS(ESI,pos.ion)m/z:415.0[M+H]⁺。

Step 5) 9- ((5- chlorine 2- ((2,3- dimethyl -2H- indazole -6- bases) amino) pyrimidine-4-yl) amino) -3- azepines Spiral shell [5.5] hendecane -3- t-butyl formates

To 9- ((2,5- dichloro pyrimidine -4- bases) amino) -3- azaspiros [5.5] hendecane -3- t-butyl formates (659.8mg, 1.59mmol) and 2,3- dimethyl indazole -6- amine hydrochlorates (580.6mg, 2.94mmol) butanol solution DIPEA (755.5mg, 5.79mmol) is added in (6mL).Gained reaction system is warming up to 150 DEG C, tube sealing reaction 2 hours, reacts After end, room temperature is cooled to, is concentrated under reduced pressure.Gained residue purifies through silica gel column chromatography (EtOAc/PE (v/v)=2/1), obtains Title compound is yellow solid (169.7mg, 19.8%).

MS(ESI,pos.ion)m/z:540.4[M+H]⁺；

¹H NMR(600MHz,CDCl₃):δ (ppm) 8.02 (d, J=1.2Hz, 1H), 7.92 (s, 1H), 7.45 (d, J= 8.9Hz, 1H), 7.07 (dd, J=8.9,1.7Hz, 1H), 7.00 (s, 1H), 5.17 (d, J=7.4Hz, 1H), 4.06 (s, 4H), 3.42 (m, 4H), 2.59 (s, 3H), 2.02 (d, J=9.5Hz, 2H), 1.74 (m, 2H), 1.55 (br.s, 2H), 1.49 (s, 9H),1.44(m,6H)。

The chloro- N of step 6) 5-²- (2,3- dimethyl -2H- indazole -6- bases)-N⁴- (3- azaspiros [5.5] hendecane -9- bases) Pyrimidine -2,4- diamines

To 9- ((5- chlorine 2- ((2,3- dimethyl -2H- indazole -6- bases) amino) pyrimidine-4-yl) amino) -3- azaspiros [5.5] the acetic acid second of hydrogen chloride is added in DCM (10mL) solution of hendecane -3- t-butyl formates (161.5mg, 0.30mmol) Ester solution (10mL, 40mmol), gained reaction system stir 2 hours at normal temperatures.Reaction finishes, and is concentrated under reduced pressure, gained residual Thing adds water (30mL) to dissolve, with saturation Na₂CO₃The aqueous solution is adjusted to pH=10, is then diluted with water, and is extracted with DCM (100mLx3). The organic phase of merging is washed through saturated aqueous common salt (100mL), anhydrous sodium sulfate drying, is filtered and is concentrated under reduced pressure, gained residue Through silica gel column chromatography (DCM/MeOH (v/v)=10/1) purify, obtain title compound for brown solid (131.6mg, 100%).

MS(ESI,pos.ion)m/z:440.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ (ppm) 7.99 (s, 1H), 7.91 (s, 1H), 7.46 (d, J=8.9Hz, 1H), 7.11 (dd, J=8.9,1.5Hz, 1H), 6.94 (s, 1H), 5.16 (d, J=7.4Hz, 1H), 4.11 (t, J=6.7Hz, 1H), 4.07 (s, 4H), 2.85 (m, 4H), 2.59 (s, 3H), 2.00 (m, 2H), 1.78 (d, J=13.3Hz, 2H), 1.56 (d, J= 5.5Hz,2H),1.39(m,6H)。

The 3- of embodiment 6 (9- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- bases) amino) pyrimidine-4-yl) amino) - 3- azaspiros [5.5] hendecane -3- bases) -3- oxo propionitriles

By the chloro- N of 5-²- (2,3- dimethyl -2H- indazole -6- bases)-N⁴- (3- azaspiros [5.5] hendecane -9- bases) pyrimidine - 2,4- diamines (485.3mg, 1.10mmol) and 2- itrile groups acetic acid (137.0mg, 1.61mmol) are dissolved in DCM (40mL) and DMF The in the mixed solvent of (10mL), HATU (520.8mg, 1.37mmol) and Et is added thereto₃N(0.36g,3.55mmol).Add After complete, reaction system stirs 6 hours at normal temperatures, and then plus reaction is quenched in water (30mL), and is extracted with DCM (100mL x 3). The organic phase of merging is washed through saturated aqueous common salt (100mL), anhydrous sodium sulfate drying, is filtered and is concentrated under reduced pressure, gained residue Through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purify, obtain title compound for brown solid (171.0mg, 30.6%).

MS(ESI,pos.ion)m/z:507.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ (ppm) 8.06 (d, J=3.5Hz, 1H), 7.93 (s, 1H), 7.46 (d, J= 8.9Hz, 1H), 7.03 (m, 1H), 6.96 (s, 1H), 5.16 (d, J=6.8Hz, 1H), 4.10 (m, 1H), 4.06 (s, 3H), 3.63(m,2H),3.49(2,2H),3.45(m,3H),2.59(s,3H),2.05(m,2H),1.78(m,2H),1.69(m,2H), 1.50(m,6H)。

The 1- of embodiment 7 (9- ((the chloro- 2- of 5- ((2,3- dimethyl -2H- indazole -6- bases) amino) pyrimidine-4-yl) amino) - 3- azaspiros [5.5] hendecane -3- bases) ethyl ketone

By the chloro- N of 5-²- (2,3- dimethyl -2H- indazole -6- bases)-N⁴- (3- azaspiros [5.5] hendecane -9- bases) pyrimidine - In anhydrous DCM (10.0mL) solution of 2,4- diamines (0.10g, 0.23mmol), add triethylamine (0.036g, 0.35mmol) and Acetic anhydride (0.029g, 0.29mmol).After gained reaction system is stirred at room temperature 30 minutes plus DCM (40mL) dilutes, then Successively with water (20mL x 2), saturation NaHCO₃(20mL) and saturated aqueous common salt (20mL) are washed, and are concentrated under reduced pressure.Gained residue passes through Silica gel column chromatography (DCM/MeOH (v/v)=30/1 to 15/1) purify, obtain title compound for light green solid (75mg, 68%).

MS(ESI,pos.ion)m/z:482.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ (ppm) 8.03 (d, J=2.8Hz, 1H), 7.90 (s, 1H), 7.43 (d, J= 8.9Hz,1H),7.05-7.02(m,1H),7.01(s,1H),5.19-5.12(m,1H),4.08-4.00(m,4H),3.62- 3.54(m,2H),3.45-3.38(m,2H),2.57(s,3H),2.09(s,3H),2.05-1.99(m,2H),1.78-1.71(m, 2H),1.58-1.53(m,2H),1.51-1.43(m,6H)。

Embodiment 8N²- (2,3- methyl -2H- indazole -6- bases) -5- methyl-N⁴- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) Pyrimidine -2,4- diamines

Step 1) 5- ((the chloro- 5- methylpyrimidines -4- bases of 2-) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-formic acid uncle Butyl ester

By the chloro- 5- methylpyrimidines (2.00g, 12.3mmol) of 2,4- bis- and 5- amino hexahydros pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate (4.64g, 20.5mmol) is dissolved in EtOH (25mL), and adds Et thereto₃N(2.62g, 25.9mmol), reactant mixture is stirred overnight at 50 DEG C, is then concentrated under reduced pressure, residue obtained through silica gel column chromatography (EtOAc/ PE (v/v)=1/2) purifying, it is yellow oil (2.42g, 55.9%) to obtain title compound.

MS(ESI,pos.ion)m/z:353.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃):δ (ppm) 7.68 (s, 1H), 5.25 (d, J=7.5Hz, 1H), 4.48 (m, 1H), 3.42 (m, 2H), 3.26 (d, J=11.1Hz, 2H), 2.63 (m, 2H), 2.38 (m, 2H), 1.92 (s, 3H), 1.41 (s, 9H), 1.33(m,2H)。

Step 2) 5- ((2- ((2,3- dimethyl -2H- indazole -6- bases) amino) -5- methylpyrimidine -4- bases) amino) hexahydro Pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate

By 5- ((the chloro- 5- methylpyrimidines -4- bases of 2-) amino) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-t-butyl formate (421.5mg, 1.19mmol) and 2,3- dimethyl indazole -6- amine hydrochlorates (734.5mg, 3.72mmol) are suspended in n-BuOH In (10mL), and DIPEA (795.2mg, 6.09mmol) is added thereto.Reactant mixture stirs 2 hours at 150 DEG C, so After be concentrated under reduced pressure, it is residue obtained through silica gel column chromatography (MeOH/DCM (v/v)=1/10) purify, it is brown to obtain title compound Grease (570.5mg, 100%).

MS(ESI,pos.ion)m/z:478.2[M+H]⁺。

Step 3) N²- (2,3- methyl -2H- indazole -6- bases) -5- methyl-N⁴- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) Pyrimidine -2,4- diamines

By 5- ((2- ((2,3- dimethyl -2H- indazole -6- bases) amino) -5- methylpyrimidine -4- bases) amino) hexahydro ring penta Simultaneously [c] pyrroles -2 (1H)-t-butyl formate (597.9mg, 1.25mmol) is dissolved in DCM (15mL), and added thereto alkane The ethyl acetate solution (15mL, 60mmol) of hydrogen chloride.Reactant mixture is stirred at room temperature 1 hour, is then concentrated under reduced pressure, will Residue is dissolved in water (30mL), gained mixture saturation Na₂CO₃The aqueous solution is adjusted to pH=10, then with DCM (250mL x 3) extract, the organic phase of merging is washed with saline solution (250mL), then uses anhydrous Na₂SO₄Dry, filter and then be concentrated under reduced pressure, institute Obtain residue to purify through silica gel column chromatography (MeOH/DCM (v/v)=1/5), it is buff white solid to obtain title compound (202.4mg, 42.8%).

MS(ESI,pos.ion)m/z:378.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)9.20(s,1H),9.13(s,1H),7.96(s,1H),7.72(s, 1H), 7.58 (d, J=8.8Hz, 1H), 7.04 (d, J=8.8Hz, 1H), 4.39 (m, 1H), 4.00 (s, 3H), 3.06 (m, 2H), 2.81(m,2H),2.57(s,3H),2.37(m,2H),2.00(s,3H),1.61(m,2H)。

The 3- of embodiment 9 (5- ((2- ((2,3- methyl -2H- indazole -6- bases) amino) -5- methylpyrimidine -4- bases) amino) Hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) -3- oxo propionitriles

By N²- (2,3- methyl -2H- indazole -6- bases) -5- methyl-N⁴- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) pyrimidine - 2,4- diamines (86.9mg, 0.23mmol) and 2- cyanoacetic acids (31.3mg, 0.37mmol) are dissolved in DCM (8mL) and DMF The in the mixed solvent of (2mL), and HOAT (65.5mg, 0.48mmol) and EDCI (77.6mg, 0.40mmol) is added thereto.Instead Answer mixture to be stirred 1 hour at 45 DEG C, then use H₂Reaction is quenched in O (30mL), then is extracted with DCM (100mL x 3).Merge Organic phase washed with saline solution (100mL), then use anhydrous Na₂SO₄Dry, filter and then be concentrated under reduced pressure, residue is through silica gel column layer (MeOH/DCM (v/v)=1/10) purifying is analysed, it is buff white solid (69.8mg, 68.2%) to obtain title compound.

MS(ESI,pos.ion)m/z:445.0[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)8.90(s,1H),8.14(s,1H),7.69(s,1H),7.45(d,J =8.9Hz, 1H), 7.11 (d, J=8.9Hz, 1H), 6.62 (s, 1H), 4.55 (m, 1H), 3.96 (s, 3H), 3.58 (dd, J= 10.4,8.1Hz, 2H), 3.51 (dd, J=12.1,8.5Hz, 2H), 2.73 (m, 1H), 2.65 (m, 1H), 2.53 (s, 3H), 2.34(m,2H),1.93(s,3H),1.49(m,2H)。

Embodiment 10N²- (2,3- dimethyl -2H- indazole -6- bases) -5- methyl-N⁴- (2- (mesyl) octahydro pentamethylene And [c] pyrroles -5- bases) pyrimidine -2,4- diamines

The 1- of embodiment 11 (5- ((2- ((2,3- dimethyl -2H- indazole -6- bases) amino) -5- methylpyrimidine -4- bases) ammonia Base) hexahydro pentamethylene simultaneously [c] pyrroles -2 (1H)-yl) ethyl ketone

By N²- (2,3- methyl -2H- indazole -6- bases) -5- methyl-N⁴- (octahydro pentamethylene simultaneously [c] pyrroles -5- bases) pyrimidine - 2,4- diamines (127.3mg, 0.34mmol) and triethylamine (68.3mg, 0.68mmol) are suspended in DCM (10mL), and thereto Add methylsufonyl chloride (64.2mg, 0.56mmol).Reactant mixture is stirred at room temperature 2 hours, then uses H₂O (30mL) quenches Go out reaction, then extracted with DCM (100mL x 3).The organic phase of merging is washed with saline solution (100mL), then uses anhydrous Na₂SO₄It is dry It is dry, filter and then be concentrated under reduced pressure, it is residue obtained to be purified with silica gel column chromatography, first with eluant, eluent (MeOH/DCM (v/v)=1/20) Elution, it is buff white solid (90.5mg, 58.9%) to obtain the compound of embodiment 10, then uses eluant, eluent (MeOH/DCM (v/v) instead =1/10) elute, it is buff white solid (50.2mg, 35.5%) to obtain the compound of embodiment 11.

Embodiment 10:

MS(ESI,pos.ion)m/z:456.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ (ppm) 8.15 (s, 1H), 7.75 (s, 1H), 7.44 (d, J=8.9Hz, 1H), 7.01 (dd, J=8.9,1.5Hz, 1H), 6.87 (br.s, 1H), 4.77 (d, J=7.5Hz, 1H), 4.58 (m, 1H), 4.06 (s, 3H), 3.37 (s, 2H), 3.21 (dd, J=9.6,7.0Hz, 2H), 2.90 (m, 2H), 2.87 (s, 3H), 2.61 (m, 2H), 2.58 (s,3H),1.99(s,3H),1.51(m,2H)。

Embodiment 11:

MS(ESI,pos.ion)m/z:420.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃):δ (ppm) 8.13 (s, 1H), 7.76 (s, 1H), 7.44 (d, J=8.9Hz, 1H), 7.02 (m, 1H), 6.86 (s, 1H), 4.59 (m, 1H), 4.50 (d, J=6.7Hz, 1H), 4.06 (s, 3H), 3.62 (m, 3H), 3.41 (dd, J=10.9,3.4Hz, 1H), 2.85 (m, 2H), 2.66 (m, 2H), 2.59 (s, 3H), 2.08 (s, 3H), 1.96 (s, 3H),1.41(m,2H)。

The 3- of embodiment 12 (9- ((2- ((2,3- dimethyl -2H- indazole -6- bases) amino) -5- methylpyrimidine -4- bases) ammonia Base) -3- azaspiros [5.5] hendecane -3- bases) -3- oxo propionitriles

Step 1) 9- ((the chloro- 5- methylpyrimidines -4- bases of 2-) amino) -3- azaspiros [5.5] hendecane -3- t-butyl formates

To the chloro- 5- methylpyrimidines (0.58g, 3.60mmol) of 2,4- bis- and 9- amino -3- azaspiros [5.5] hendecane -3- Triethylamine (0.86g, 8.50mmol) is added in ethanol (25mL) solution of t-butyl formate (1.44g, 5.37mmol).Gained is anti- Answer system to be warming up to 100 DEG C, stir 25.5 hours, be then concentrated under reduced pressure.Gained residue is through silica gel column chromatography (EtOAc/PE (v/v)=1/2) purify, it is yellow solid (332.2mg, 24%) to obtain title compound.

MS(ESI,pos.ion)m/z:395.4[M+H]⁺。

Step 2) 9- ((2- ((2,3- dimethyl -2H- indazole -6- bases) amino) -5- methylpyrimidine -4- bases) amino) -3- Azaspiro [5.5] hendecane -3- t-butyl formates

By mixture 9- ((the chloro- 5- methylpyrimidines -4- bases of 2-) amino) the tertiary fourth of -3- azaspiros [5.5] hendecane -3- formic acid Ester (1.2g, 3.0mmol), 2,3- dimethyl indazole -6- amine hydrochlorates (896.5mg, 4.536mmol), palladium (132.4mg, 0.5898mmol), the double diphenyl phosphines (370.3mg, 0.5947mmol) of 1,1'- dinaphthalenes -2,2'- and cesium carbonate (2.98g, 9.15mmol) it is dissolved in dioxane (10mL), reactant mixture is warming up to 150 DEG C and reacted 2 hours under microwave, then subtracts Pressure concentration, residue is through silica gel column chromatography (DCM/MeOH (v/v)=30/1)) purifying, it is yellow solid to obtain title compound (1.04g, 66%).

MS(ESI,pos.ion)m/z:520.1[M+H]⁺。

Step 3) N²- (2,3- dimethyl -2H- indazole -6- bases) -5- methyl-N⁴- (3- azaspiros [5.5] hendecane -9- Base) pyrimidine -2,4- diamines

By 9- ((2- ((2,3- dimethyl -2H- indazole -6- bases) amino) -5- methylpyrimidine -4- bases) amino) -3- azepines Spiral shell [5.5] hendecane -3- t-butyl formates (1.04g, 2.00mmol) be added to hydrogen chloride ethyl acetate solution (8mL, In 3mol/L), reactant mixture is stirred at room temperature overnight, and is then concentrated under reduced pressure.Gained residue saturation Na₂CO₃The aqueous solution (100mL) dilutes, then with DCM and MeOH (10/1,150mL x3) mixed extractant solvent, and the organic phase of merging is with anhydrous Na₂SO₄Dry, filter and then be concentrated under reduced pressure, it is yellow solid (804mg, 95.8%) to obtain title compound.

MS(ESI,pos.ion)m/z:420.0[M+H]⁺。

Step 4) 3- (9- ((2- ((2,3- dimethyl -2H- indazole -6- bases) amino) -5- methylpyrimidine -4- bases) amino) - 3- azaspiros [5.5] hendecane -3- bases) -3- oxo propionitriles

By N²- (2,3- dimethyl -2H- indazole -6- bases) -5- methyl-N⁴- (3- azaspiros [5.5] hendecane -9- bases) is phonetic Pyridine -2,4- diamines (203.2mg, 0.4843mmol), HOAT (105.8mg, 0.7773mmol) and EDCI (144.5mg, 0.7538mmol) be dissolved in DCM and DMF (4mL/1mL) in the mixed solvent, and add thereto triethylamine (209.1mg, 2.066mmol) and 2- cyanoacetic acids (48.1mg, 0.565mmol).Reactant mixture is stirred at room temperature 2.5 hours, then subtracts Pressure concentration.It is residue obtained to be purified through silica gel column chromatography (DCM/MeOH (v/v)=30/1), obtain title compound pale pink solid (48.4mg, 20.4%).

MS(ESI,pos.ion)m/z:487.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.52 (s, 1H), 8.11 (s, 1H), 7.60 (s, 1H), 7.43 (d, J= 8.9Hz, 1H), 7.05 (d, J=7.3Hz, 1H), 4.84 (dd, J=16.7,7.0Hz, 1H), 4.11 (s, 1H), 4.03 (d, J= 2.2Hz, 3H), 3.66-3.53 (m, 2H), 3.51-3.34 (m, 4H), 2.57 (s, 3H), 2.05 (d, J=10.9Hz, 2H), 1.97 (s, 3H), 1.75 (d, J=10.4Hz, 2H), 1.68-1.41 (m, 8H).

The 1- of embodiment 13 (9- ((2- ((2,3- dimethyl -2H- indazole -6- bases) amino) -5- methylpyrimidine -4- bases) ammonia Base) -3- azaspiros [5.5] hendecane -3- bases) ethyl ketone

By N²- (2,3- dimethyl -2H- indazole -6- bases) -5- methyl-N⁴- (3- azaspiros [5.5] hendecane -9- bases) is phonetic Pyridine -2,4- diamines (201.5mg, 0.4802mmol), HOAT (106.4mg, 0.7817mmol) and EDCI (145.7mg, 0.7600mmol) be dissolved in DCM and DMF (4mL/1mL) in the mixed solvent, and add thereto triethylamine (207.6mg, 2.052mmol) and acetic acid (36.7mg, 0.611mmol).Reaction solution is stirred at room temperature 2 hours, is then concentrated under reduced pressure.Gained Residue purifies through silica gel column chromatography (DCM/MeOH (v/v)=30/1), and it is faint yellow solid (92mg) to obtain crude product.Crude product Through the mixed solvent of acetone and methanol (6mL/0.5mL) recrystallize, purifying obtain title compound for white solid (50.4mg, 21.6%).

MS(ESI,pos.ion)m/z:462.4[M+H]⁺。

Biologic test

The LC/MS/MS systems of analysis include 1200 serial vacuum degassing furnaces of Agilent, and binary syringe pump, orifice plate is certainly Dynamic sampler, post insulating box, charged spray ionize 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

More 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, injects 5 μ L samples.Analysis condition：Mobile phase Aqueous formic acid (A) and 0.1% formic acid methanol solution (B) for 0.1%.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

In addition, also having the serial LC/MS/MS spectrometers of Agilent 6330 for analysis, noted equipped with G1312A binary Penetrate pump, G1367A automatic samplers and G1314C UV detectors；LC/MS/MS spectrometers use ESI radioactive sources.Use titer Suitable cation model treatment and MRM conversion is carried out to each analyte and carries out optimal analysis.Used during analysis Capcell MP-C18 posts, specification are：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 cumulative volume are 200 μ L NADPH (1.0mM) potassium phosphate Buffer solution (PBS, 100mM, pH value 7.4), compound is dissolved in DMSO, and is diluted using PBS, makes it final The concentration of DMSO solution is 0.05%.And be incubated in the water-bath communicated at 37 DEG C with air, preincubate mixes for 3 minutes backward Close and albumen is added in liquid and starts to react.At different time points (0,5,10,15,30 and 60min), the ice-cold second of same volume is added Nitrile terminating reaction.Sample is preserved at -80 DEG C until carrying out LC/MS/MS analyses.

Concentration of the compound in people or rat liver microsomes mixtures incubated is determined by LC/MS/MS method '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 being denatured to be incubated at 37 DEG C as negative control, react when different Between point (0,15 and 60 minute) terminate.

Dextromethorphan (70 μ Μ) is used as positive control, is incubated at 37 DEG C, react 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.

In addition, 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 cumulative volume be 30 μ L K- buffer Solution (EDTA containing 1.0mM, 100mM, pH 7.4).Compound is dissolved in DMSO, and diluted with K- cushioning liquid, is made DMSO ultimate density is 0.2%.After preincubate 10 minutes, 15 μ L NADPH (ultimate densities are added：It is anti-2mM) to carry out enzymatic 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.Centrifuged 10 minutes with 4000rpm, except deproteinized, collect supernatant, analyzed with LC-MS/MS.

In above-mentioned experiment, ketanserin (1 μM) is selected as positive control, is incubated, is reacted in the different time at 37 DEG C 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 of the compound in people or rat liver microsomes are incubated is pressed (as a percentage) With respect to the plotted as percentage of zero time point, internal liver clearance rate CL is inferred with this_int(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.).As a result referring to table 1, table 1 is compound provided in an embodiment of the present invention in people 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

As shown in Table 1, when the compounds of this invention is incubated in 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 evaluation

The present invention is commented pharmacokinetic of the compounds of this invention in mouse, rat, dog or monkey body Estimate.The compounds of this invention is with the aqueous solution or the aqueous solution of 2%HPMC+1% Tween-80s, 5%DMSO+5% saline solution, and 4% MC or capsule form are administered.It is administered for intravenous injection, animal gives 1 or 2mg/kg dosage.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 Solution is starched, and is preserved at -20 DEG C or -70 DEG C until carrying out above-mentioned LC/MS/MS analyses.As a result referring to table 2, table 2 is this hair Experimental result of medicine of the compound that bright embodiment provides in rat body for feature.

Experimental result of medicine of 2 compound provided in an embodiment of the present invention of table in rat body for feature

As shown in Table 2, when compound intravenous injection provided by the invention being administered or is administered orally, chemical combination of the present invention Thing shows good pharmacokinetic property, including preferably absorbs, preferable half-life period (T_1/2) become reconciled oral bio profit Expenditure (F).

Embodiment C Kinase activity assays

The present invention discloses compound and can evaluated as the effectiveness of kinases inhibitor by following experiment.

The general description of kinase assay

Kinase assay by detect incorporation γ-³³P-ATP myelin basic protein (MBP) is come what is completed.Prepare 20 μ g/ Ml MBP (Sigma#M-1891) trishydroxymethylaminomethane buffer salt solution (TBS；50mM Tris pH 8.0,138mM NaCl, 2.7mM KCl), white 384 orifice plate (Greiner) of high associativity 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, added in each hole, DMSO ultimate density is 1%.Each twice of data determination, often The measure of individual compound is at least tested twice.For example 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 to react.Reaction is shaken at room temperature Carry out 1 hour.384 orifice plate 7x PBS, then add the scintillation solution per the μ L of hole 50.Counted with Wallac Trilux Device testing result.To those of ordinary skill in the art, this is only 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 K_i。IC₅₀It is defined as under test conditions, suppression Make compound concentration during 50% enzymatic activity.The curve for including 10 concentration points is made using 1/2log extension rate, is estimated IC₅₀Value by following compound concentration (for example, make a typical curve：3μM、1μM、0.3μM、0.1μM、0.03μM、 0.01μM、0.003μM、0.001μM、0.0003μM、0μM)。

JAK1(h)

JAK1 (h) is in 20mM Tris/HCl pH 7.5,0.2mM EDTA, 500 μM of GEEPLYWSFPAKKK, 10mM vinegar Sour magnesium and [γ-³³P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing. Start to react after adding MgATP mixtures.After being incubated 40 minutes at room temperature, it is anti-to terminate to add 3% phosphoric acid solution thereto Should.10 μ L reaction solution is distributed on P30 filters in mottled, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and Dry and scinticounting is put into methanol solution preserves before at once.

JAK2(h)

JAK2 (h) is 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 determine according to demand) it is existing under the conditions of be incubated.Start to react after adding MgATP mixtures. After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto and carrys out terminating reaction.It it is in mottled point by 10 μ L reaction solution 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] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing.Add Start to react after MgATP mixtures.After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto and carrys out terminating reaction.Will 10 μ L reaction solution is distributed on P30 filters in mottled, and clean 3 times in 5 minutes with 75mM phosphoric acid, and drying with It is put into methanol solution and preserves at once before scinticounting.

TYK2(h)

TYK2 (h) is in 8mM MOPS pH 7.0,0.2mM EDTA, 250 μM of GGMEDIYFEFMGGKKK, 10mM magnesium acetates [γ-³³P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing.Add Start to react after MgATP mixtures.After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto and carrys out terminating reaction.Will 10 μ L reaction solution is distributed on P30 filters in mottled, and clean 3 times in 5 minutes with 75mM phosphoric acid, and drying with It is put into methanol solution and preserves at once before scinticounting.

FLT3(h)

FLT3 (h) is in 8mM MOPS pH 7.0,0.2mM EDTA, 50 μM of EAIYAAPFAKKK, 10mM magnesium acetates and [γ-³³P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing.Add Start to react after MgATP mixtures.After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto and carrys out terminating reaction.Will 10 μ L reaction solution is distributed on P30 filters in mottled, and clean 3 times in 5 minutes with 75mM phosphoric acid, and drying with It is put into methanol solution and preserves at once before scinticounting.

Aurora-A(h)

Aurora-A (h) is in 8mM MOPS pH 7.0,0.2mM EDTA, 200 μM of LRRASLG (Kemptide), 10mM Magnesium acetate and [γ-³³P-ATP] incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing Educate.Start to react after adding MgATP mixtures.After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto to terminate Reaction.10 μ L reaction solution is distributed on P30 filters in mottled, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and Preserved drying and being put at once in methanol solution before scinticounting.

Aurora-B(h)

Aurora-B (h) is in 8mM MOPS pH 7.0,0.2mM EDTA, 30 μM of AKRRRLSSLRA, 10mM magnesium acetates and [γ-³³P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing.Add Start to react after MgATP mixtures.After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto and carrys out terminating reaction.Will 10 μ L reaction solution is distributed on P30 filters in mottled, and clean 3 times in 5 minutes with 75mM phosphoric acid, and drying with It is put into methanol solution and preserves at once before scinticounting.

Kinase assay in the present invention be by Millipore companies of Britain come complete (Millipore UK Ltd, Dundee Technology Park,Dundee DD21SW,UK)。

In addition, the kinase activity of compound can pass through KINOMEscan^TMDetection, this detection are to be based on using active sites The quantitative detection compound of point guidance type Competition binding assay method.The experiment is by being combined progress, i.e. DNA marks with three kinds of compounds Remember enzyme, fixed ligand and detection compound, the competition energy of qPCR detection compounds and fixed ligands is carried out by DNA marker Power.

Most of experiment is all that the T7 bacteriophage bacterium of kinases mark are cultivated from escherichia coli host derived from BL21 bacterial strains Strain, after being in the Escherichia coli of exponential phase with T7 phage-infects, 32 DEG C of oscillation incubations centrifuge lysate to bacteriolyze Filter off and remove cell fragment, remaining kinases goes in HEK-293 cells and carries out qPCR detections with DNA marker.Streptavidin Coated particle can be produced affine resin and be used for kinase assay with after biotinylated smaller ligand room temperature treatment 30min.Match somebody with somebody Body particle is after unnecessary biotin closing, through confining liquid (SEABLOCK^TM(Pierce), 1% bovine serum albumin(BSA), 0.05% Tween-20,1mM DTT) the uncombined part of cleaning, reduces non-specific binding.Pass through the combination buffer (20% in 1x SEABLOCK^TM, 0.17x phosphate buffer solutions, 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 Swing and be incubated 1h, add lavation buffer solution (1x phosphate buffer solutions, 0.05% polysorbas20) and clean affine particle, it is slow to add elution After (1x phosphate buffer solutions, 0.05% polysorbas20,0.5 μM of non-biotinylated affinity ligand) is resuspended in fliud flushing, shaken at room temperature 30min is incubated, the concentration of kinases in eluent is detected by qPCR.Kinase activity measure described in text is in the U.S. The KINOMEscan of DiscoveRx companies (Albrae St.Fremont, CA 94538, USA)^TMDepartment, it is measured.

For Kinase activity assays result referring to table 3 and table 4, table 3 is the kinase assay of compound provided in an embodiment of the present invention As a result, table 4 is JAK3, TYK2, Aurora-A and FLT3 kinase assay result of compound provided in an embodiment of the present invention

JAK1 the and JAK2 kinase assay results of 3 compound provided in an embodiment of the present invention of table

NT：Do not test

JAK3, TYK2, Aurora-A and FLT3 kinase assay result of 4 compound provided in an embodiment of the present invention of table

NT：Do not test

From table 3 and table 4, compound of the present invention in kinase assay to JAK1, JAK2, JAK3, TYK2, Aurora-A and FLT3 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 It will 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 will all be used as this hair Bright bibliography.

Claims

1. a kind of compound, it is the stereoisomer of compound shown in the compound or formula (I) shown in formula (I) or pharmaceutically may be used The salt of receiving,

Wherein,

Z is C₇-C₁₂Spiral shell bicyclic alkyl, C₇-C₁₂Condensed-bicyclic alkyl, the 7-12 former molecular miscellaneous bicyclic group of spiral shell or 7-12 original The molecular miscellaneous bicyclic alkyl of fusion, wherein, Z is optionally by 1,2,3,4 or 5 R³Group is substituted；

Z¹For H, C₁-C₆Alkyl or C₃-C₆Cycloalkyl；

A is indazolyl or Pyrazolopyridine base, and it is optionally by 1,2,3,4 or 5 R⁵Group is substituted；

W is N；

R¹For H, F, Cl, Br, C₁-C₆Alkyl or C₁-C₆Haloalkyl；

Each R³It independently is H, F, Cl, OH, NH₂,-C (=O) CH₂CN、C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy ,- C (=O) R⁶Or-S (=O)₂R⁶；

Each R⁵It is separately H, F, Cl, Br or C₁-C₆Alkyl；

Each R⁶It independently is H, C₁-C₆Alkyl or C₁-C₆Haloalkyl.

2. compound according to claim 1, wherein, Z C₈-C₁₁Spiral shell bicyclic alkyl, C₈-C₁₀Condensed-bicyclic alkyl, 8- The miscellaneous bicyclic group of 11 molecular spiral shells of original or the 8-10 former molecular miscellaneous bicyclic alkyl of fusion, wherein, Z is optionally by 1,2,3 Or 4 R³Group is substituted.

3. compound according to claim 1, wherein, Z is following subformula：

Or their stereoisomer, wherein, each X, X ', X²And X³It is separately CH₂, NH or O, condition be to work as X²When being O, X³It is not O；Each minor structure or its stereoisomer shown in formula (Z-1)~(Z-54) are individually optionally by 1,2 or 3 R³Group Substituted.

4. compound according to claim 1, wherein, A is following subformula：

5. compound according to claim 1, wherein, Z¹For H, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

6. compound according to claim 1, wherein, R¹For H, F, Cl, C₁-C₄Alkyl or C₁-C₄Haloalkyl.

7. compound according to claim 1, wherein, each R³It independently is H, F, OH, NH₂,-C (=O) CH₂CN、C₁-C₄ Alkyl, C₁-C₄Haloalkyl ,-C (=O) R⁶Or-S (=O)₂R⁶、。

8. compound according to claim 1, wherein, each R⁶It independently is H, C₁-C₄Alkyl or C₁-C₄Haloalkyl.

9. compound according to claim 1, there is the structure of one of：

Or its stereoisomer or pharmaceutically acceptable salt.

10. a kind of pharmaceutical composition, it includes the compound described in claim 1-9 any one.

11. pharmaceutical composition according to claim 10, wherein further comprising pharmaceutically acceptable excipient, load Body, adjuvant, solvent or combinations thereof.

12. the pharmaceutical composition according to claim 10 or 11, 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.

13. compound described in claim 1-9 any one or claim 10-12 any one described pharmaceutical composition are being made Purposes in standby medicine, the medicine are used to preventing, handle, treat or mitigating protein kinase mediated disease.

14. purposes according to claim 13, wherein the disease that the protein kinase mediated disease, which is JAK-, to be mediated, The disease of FLT3- mediations or the disease of Aurora- mediations.

15. purposes according to claim 14, it is characterised in that the protein kinase mediated disease is proliferative disease Disease, autoimmune disease, anaphylactia, inflammatory disease, graft rejection, myelofibrosis, COPD, heavy breathing Asthma, psoriasis, type i diabetes, eczema, measles.

16. purposes according to claim 15, it is characterised in that the proliferative diseases are cancer, genuine erythrocyte increasing More diseases, primary thrombocytosis, acute myelocytic leukemia, chronic granulocytic leukemia or acute lymphoblastic are white Blood disease；

The autoimmune disease is systemic loupus erythematosus, skin lupus erythematosus, lupus nephritis, Sjogren syndrome or class Rheumatic arthritis；

The anaphylactia is respiratory anaphylactic disease, food hypersenstivity or insect venom allergies；

The inflammatory disease is lupus nephritis, dermatomyositis, nasosinusitis, inflammatory bowel disease, rheumatoid arthritis, juvenile form joint Scorching or psoriasis arthropathica；

The graft rejection is organ-graft refection, tissue transplantation rejection or cell transplant rejection.

17. purposes according to claim 16, it is characterised in that the inflammatory enteritis is Crohn disease.

18. compound described in claim 1-9 any one or claim 10-12 any one described pharmaceutical composition are being made Purposes in standby medicine, the medicine are used for the activity of regulatory protein kinases.

19. purposes according to claim 18, wherein the protein kinase is jak kinase, FLT3 kinases, Aurora A Or combinations thereof.